Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CC(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and isovaleryl chloride. m.p.: 182-185° C. 1H-NMR (CDCl3) δ: 10.05 (1H, br s), 8.42-8.17 (2H, m), 7.62-7.53 (2H, m), 7.48-7.40 (2H, m), 7.30-7.25 (1H, m), 7.12-7.03 (1H, m), 2.45 (3H, s), 2.39-2.17 (3H, m), 1.04 (6H, dd, J=6.6 Hz)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=3)[CH:19]=[CH:20][C:21]=1[CH3:22])[N:9]=2)=[O:4].[CH2:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH3:38].C(=O)([O-])O.[Na+]>O1CCCC1>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH2:37][CH3:38])[CH2:40][CH2:41]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:36])([CH3:32])[CH3:33])#[N:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Reactant: CCN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C)nc3s2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (284 mg, 0.547 mmol) produced in Example C15(i), 1-ethylpiperazine (114 μL, 0.901 mmol) triethylamine (125 μL, 0.901 mmol) and tetrahydrofuran (5 mL) was stirred at 60° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and filtered through a pad filled with basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to give the title compound (138 mg, 51%) as white crystals.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:41]1([SH:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.C(OCC)(=O)C>[C:41]1([S:47][CH2:32][CH2:31][C:30]([NH:29][C:25]2[CH:24]=[C:23]([C:9]3[S:10][C:11]([C:12]4[NH:16][CH:15]=[N:14][N:13]=4)=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH:28]=[CH:27][N:26]=2)=[O:33])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Sc1ccccc1
Reactant: C=CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCSc1ccccc1)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a solution of N-(4-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) were added triethylamine (30 mg, 0.3 mmol) and thiophenol (29 mg, 0.26 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate (25 mL), and washed with saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was extracted with ethyl acetate (25 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (8.0 mL), and the mixture was stirred at room temperature for 6 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (69 mg, 71%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]1[C@@H:10]([C@@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)[O:9][C:8](=[O:28])[NH:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]1[C@@H:10]([C@@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:28])[NH:7]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@@H]2Cc3ccccc3CN2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of (S)-tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (step E (1), 550 mg) in CH2Cl2 (20 mL) was treated with TFA (10 mL). This reaction mixture was stirred at rt for 2 h. The mixture was then concentrated in vacuo with addition of toluene. The residue was added 1N aqueous HCl solution (50 mL) and washed with diethyl ether (80 mL). The diethyl ether layer was washed with 1N aqueous HCl solution again. The combined aqueous layers were neutralized with 50% aqueous NaOH solution, extracted with ethyl acetate. The organic phase was washed with H2O, and dried (Na2SO4), and concentrated in vacuo to give 350 mg (81% yield) of the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.23 (1H, brd s), 2.72 (1H, dd, J=5, 15 Hz), 2.88 (1H, dd, J=10, 15 Hz), 3.02 (1H, m), 3.10 (1H, dd, J=10, 15 Hz), 3.22 (1H, m), 4.06 (2H, s), 4.12 (1H, m), 4.63 (1H, m), 5.64 (1H, s), 6.69-6.77 (3H, m), 7.04 (1H, t, J=5 Hz), 7.08 (1H, t, J=5 Hz), 7.12-7.15 (2H, m).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[CH2:19]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20]>>[CH2:19]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: CCNC(=O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCNC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.37 g (5.1 mmol) of N-ethyl-4-iodobenzamide, 596 mg (31%) of the expected amide, with a melting point of 153°-154° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]1[CH2:16][S:15][CH2:14][CH:13]1[C:17](OC)=[O:18]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:17](=[O:18])[C:13]3[CH2:14][S:15][CH2:16][C:12]=3[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: COC(=O)C1CSCC1=O
Solvent: c1ccccc1
Product: O=C1Nc2cc(Cl)c(Cl)cc2NC2=C1CSC2
Temperature: 25 °C

Procedure:
A reaction mixture comprising 106 g. of 4,5-dichloro-o-phenylenediamine and 96 g. of tetrahydro-4-oxo-3-thiophene carboxylic acid, methyl ester in 4 liters of benzene is refluxed for 5 hours and then cooled overnight. The benzene is removed by distillation and replaced by toluene. The mixture is refluxed 2 hours, 10 ml. of water and 0.5 ml. of acetic acid are added and the mixture is refluxed overnight, cooled to room temperature and filtered. The solid is washed with three 100 ml. portions of toluene and air dried giving 6,7-dichloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:35])[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C@H:16]([CH2:36][C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)[CH2:15]1)=[O:10])C1C=CC=CC=1>CO>[C:9]([CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:35])[C:21]2[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=2)[C@H:16]([CH2:36][C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)[CH2:15]1)([OH:10])=[O:8]
Reactant: O=C(CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)OCc1ccccc1
Solvent: CO
Product: O=C(O)CCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A mixture of (2R)-4-[3-(benzyloxycarbonyl)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.15 g), 10% Pd charcoal (15 mg) and methanol (4.5 ml) was stirred for 3 hours under hydrogen atmosphere (1 atm). The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography on a silica gel using chloroform-methanol (5:1) as eluent to give (2R)-4-(3-carboxypropyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.067 g) as a powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21].[Li]CCCC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33].O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=2[O:20][CH3:21])[OH:33])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)c2ccccc2SCc2c(OC)cc(OC)cc2OC)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 0.35 g (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (0.96 mmol) in dry THF was added slowly 1.2 eq n-BuLi. The reaction was stirred 25 minutes at −78° C. before 1.2 eq 3-methoxybenzaldehyde was added slowly. The reaction was warmed to ambient temperature and stirred for one additional hour before the addition of water. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.288 g product (0.68 mmol, 70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])(O)[CH3:12])=[C:6]([SH:8])[CH:7]=1>S(=O)(=O)(O)O>[CH3:12][C:11]1([CH3:14])[CH2:10][C:9]([CH3:16])([CH3:15])[C:5]2[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[S:8]1
Reactant: CC(C)(O)CC(C)(C)c1ccc(Br)cc1S
Agent: O=S(=O)(O)O
Product: CC1(C)CC(C)(C)c2ccc(Br)cc2S1
Temperature: 25 °C

Procedure:
A mixture of 10 g (33 mmol) of 5-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 35) and 100 ml of 20 percent aqueous sulfuric acid was heated at reflux for 48 hours. The mixture was cooled to room temperature and extracted with 2×50 ml of ether. The ether extracts were combined and washed with 25 ml of saturated sodium bicarbonate solution and 25 ml of saturated NaCl solution and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash column chromatography (silica: 2% ethyl acetate in hexanes) followed by kugelrohr distillation to give the title compound as a clear oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([Cl:33])=[CH:26][N:25]=1.C(N(CC)CC)C>C1COCC1>[Cl:23][C:24]1[N:25]=[CH:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:31]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc(Cl)cnc4Cl)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), 2,5-dichloropyridine-3-carbonyl chloride (0.42 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in THF (30 mL) was stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.50 g of the product (54% yield): mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.53-2.58 (m, 2H), 2.83-2.97 (m, 1H), 4.93 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.3 Hz, 1H), 7.82-7.91 (m, 3H), 8.28 (d, J=2.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 9.35 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 130.3, 131.6, 133.4, 134.9, 137.8, 138.0, 145.0, 148.8, 164.1, 166.9, 167.5, 169.8, 172.8; Anal. calcd for C20H14Cl2N4O5.0.2H2O: C, 51.68; H, 3.12; N, 12.05. Found: C, 51.64; H, 3.05; N, 11.98.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([CH2:36][O:3]/[N:4]=[C:5](/[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)\[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:34][CH:35]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1)c1ccccc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Sodium hydride (60%, in oil, 143 mg) was added to a solution of methyl E-4-(hydroxyimino)-4-phenylbutyrate (676 mg) and 5-chloro-2-(4-chloromethylphenoxymethyl)imidazo[1,2-α]pyridine (1.00 g) in N,N-dimethyformamide (10 ml) at room temperature and stirred for 1 hour. 1N hydrochloric acid (7 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[4-(5-chloroimidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.04 g, yield 67%) as a colorless oil from an ethyl acetate-hexane (2:1, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([NH:6][C:7]([NH:28][C:25]1[CH:26]=[N:27][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:23][CH:24]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Reactant: Cc1cccc(C)c1C(=O)N=C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(=O)NC(=O)Nc1ccc(Sc2ccc(Cl)cc2)nc1

Procedure:
2,6-Dimethylbenzoyl isocyanate (1.61 grams; 0.01 mole) and 6-(4-chlorophenylthio)-3-aminopyridine (2.36 grams; 0.01 mole) were mixed in 50 ml. of ethyl acetate and stirred at room temperature for 12 hours. Solvent was removed in vacuo. TLC showed four spots. The mixture was passed over a column of silica gel with a 1:1 mixture of toluene-ethyl acetate and the product (Rf ≅0.7) separated and crystallized from ethyl acetate-hexanes, yield 1.1 grams, m.p. 159°-160° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:7]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Cc2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2ccc(Cc3ccccc3)cc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 4-aminodiphenylmethane (20.3 g) and diethyl ethoxymethylenemalonate (24.3 mL) was heated at 110° C. for 3.5 hr under nitrogen. The resulting mixture was diluted with phenyl ether (50 mL) and heated at 220° C. for 7.5 hr. After cooling, ethyl ether was added to the reaction mixture. The precipitate was collected by filtration, and washed with ethyl ether to afford the title compound (12.6 g) as a pale brown powder: mp 265-270° C.; 1H NMR (400 MHz, CDCl3—CD3OD (1:1, v/v)) δ 1.39 (t, J=6.8 Hz, 3H), 4.12 (s, 2H), 4.35 (q, J=6.8 Hz, 2H), 7.14-7.33 (m, 4H), 7.47 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.65-7.75 (m, 2H), 8.23 (s, 1H), and 8.59 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[C:3](=[O:7])[CH:4]=[CH:5][CH3:6].[C:10]([OH:13])(=[S:12])[CH3:11]>N1CCCCC1>[C:10](=[O:13])([S:12][CH:5]([CH2:4][C:3](=[O:7])[CH:2]([CH3:1])[CH2:8][CH3:9])[CH3:6])[CH3:11]
Reactant: CC=CC(=O)C(C)CC
Reactant: CC(O)=S
Solvent: C1CCNCC1
Product: CCC(C)C(=O)CC(C)SC(C)=O
Temperature: 15 °C
Yield: 89.5 %

Procedure:
A reaction flask was charged with 5-methyl-2-hepten-4-one (200 g, 1.59 mol) and piperidine (6.6 g), and cooled to 15° C. using a cooling bath. Thioacetic acid (241 g, 3.17 mol) was subsequently added to the reaction flask dropwise through an addition funnel The feeding was exothermic. The reaction temperature was kept below 25° C. After the addition was completed, the cooling bath was removed while the reaction was stirred for another hour at room temperature. The reaction mixture was then transferred into a separatory funnel. The organic layer was washed with sodium bicarbonate solution (10%, 250 mL) followed by brine (250 mL), and dried with magnesium sulfate. Further distillation of the obtained crude product under a vacuum (at 78° C. with a pressure of 11.0 mmHg) provided S-(5-methyl-4-oxoheptan-2-yl) ethanethioate (288.0 g) (about 90% yield with a purity over 97% monitored with gas chromatography).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[F:23][B-](F)(F)F.[H+]>Cl.O>[F:23][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CCCCCC1CCC(c2ccc(N)cc2)OC1
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: CCCCCC1CCC(c2ccc(F)cc2)OC1

Procedure:
24.7 g of 2-p-aminophenyl-5-pentyl-tetrahydropyran are dissolved in a mixture of 25 ml of concentrated hydrochloric acid and 75 ml of water, and diazotized at 3°-6° with a solution of 8 g of NaNO2 in 15 ml of water. Then 24 g of 40% tetrafluoroboric acid are added, and the precipitated diazonium tetrafluoroborate is filtered off, washed with water and dried. The diazonium salt is heated to about 150°, and the residue is worked up as usual. 2-p-Fluorophenyl-5-pentyl-tetrahydropyran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:19][CH3:20])[C:9]2([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:19][CH3:20])[C:9]2([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26]
Reactant: COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)O)CC1
Reaction time: 0.5 h

Procedure:
151 mg (0.269 mmol) of tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)(methoxy)methyl]cyclopropanecarboxylate (as diastereomer mixture) were dissolved in 2.9 ml of dichloromethane, and 1.0 ml of TFA was added at RT. After 30 min at RT, the reaction mixture was concentrated under reduced pressure and the residue was concentrated under reduced pressure. The crude product obtained in this manner was purified by RP-HPLC (mobile phase acetonitrile/water). This gave 87 mg (64% of theory) of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:11]1[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.N#N.C(OCC)(=O)C>[CH:18]([O:17][C:15]1[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]([CH3:24])=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:16]=1)([CH3:20])[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Cl
Reactant: OB(O)c1ccncc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1-c1ccncc1
Temperature: 150 °C

Procedure:
4-Pyridineboronic acid (147 mg, 1.20 mmol, 1.1 equiv.) is dissolved in a 2:1 v/v mixture of dioxane and H2O (15 mL) and N2 is bubbled through for 5 minutes. Tris(dibenzylidene acetone)dipalladium (0) (100 mg, 0.109 mmol, 0.1 equiv.), 2-dicyclohexylphosphine-2′-6′-dimethoxy biphenyl (112 mg, 0.272 mmol, 0.25 equiv.), 1-chloro-5-isopropoxy-2-methyl-4-nitro-benzene (Intermediate 4, 250 mg, 1.09 mmol, 1.0 equiv.) and K3PO4 (462 mg, 2.18 mmol, 2.0 equiv.) are added under a N2 blanket. The reaction vessel is sealed and heated with microwave irradiation to 150° C. for 20 min. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2×), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine as a brown solid: ESMS m/z 273.1 (M+Ft).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[OH:20].C(=O)(O)[O-].[Na+].O>CS(C)=O.Cl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[OH:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@H]2CCCC[C@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), (1R,2S)-2-aminocyclohexanol hydrochloride (671 mg, 4.42 mmol, Small Molecules, Inc.) and sodium bicarbonate (991 mg, 11.8 mmol) in DMSO (14.7 mL), and water (2.1 mL) is heated at 130° C. for 48 h. After cooling to room temperature, the mixture is diluted with 1 N HCl and extracted twice with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane to furnish the title compound as an off-white solid (527 mg, 68%). LC-ES/MS m/z 265.2 (M+1).