Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=[O:8])=[CH:2]1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CS(O)(=O)=O.C(Cl)Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]([O:9][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:8])[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11])=[CH:2]1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)C(C(=O)O)c1ccsc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCCCCC)c1ccsc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.1 %

Procedure:
In a one-necked flask, 3-thienylmalonic acid (10.0 g, 53.7 mmol) and 1-dodecanol (4 eq., 40.0 g, 215 mmol) were dissolved in THF (80 mL) at room temperature. To this solution was added methanesulphonic acid (1.99 g, 20.7 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was then evaporated at 40° C. The residue was re-dissolved in CH2Cl2 to form a solution, which was loaded onto a column (eluent: CH2Cl2) to give didodecyl 2-(thiophen-3-yl)malonate (yield: 18.0 g, 69%). 1H NMR (CDCl3): 0.9 (6H, t), 1.3 (36H, m), 1.7 (4H, m), 4.2 (4H, t), 4.8 (1H, s), 7.2 (1H, d), 7.3 (1H, d), 7.4 (1H, s).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([F:21])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25](I)[CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[C:27]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[F:21])[CH:28]=1
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Fc1ccc(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)c(F)c1
Temperature: 80 °C
Yield: 57 %

Procedure:
To a solution of 2-[4-(ethylsulfonyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 45, 102 mg, 0.33 mmol) and 4-bromo-1-fluoro-2-iodobenzene (108 mg, 0.36 mmol) in toluene (0.56 mL) and ethanol (0.14 mL) was added aqueous Na2CO3 solution (1M, 0.55 mL, 0.55 mmol). A stream of nitrogen gas was bubbled through the reaction mixture for 5 minutes. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (13 mg, 0.016 mmol) was then added, and the mixture was heated at 80° C. for 1 hour. The reaction mixture was cooled, diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:EtOAc 100:0 to 70:30 to afford the title compound as a light yellow solid in 57% yield, 67 mg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:10][CH3:11])[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:12](O)=O>O>[CH3:11][S:10][C:4]1[S:5][C:6]2[C:7](=[O:8])[N:9]=[CH:12][NH:1][C:2]=2[N:3]=1
Reactant: O=CO
Reactant: CSc1nc(N)c(C(N)=O)s1
Solvent: O
Product: CSc1nc2[nH]cnc(=O)c2s1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 4-amino-2-(methylthio)thiazole-5-carboxamide (3.37 g, 17.8 mmol) in formic acid (10 mL) was stirred at reflux for 12 hours. After cooled to ambient temperature, the reaction mixture was diluted with water (30 mL) and the precipitate was collected by filtration. The resulting solid was further washed with water and dried in vacuo. The product was obtained as a yellow solid (2.978 g, 84%). 1H NMR (300 MHz, d6-DMSO) δ 12.83 (br, 1H), 8.26 (s, 1H), 2.80 (s, 3H); LC-MS: 200 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[N:40]([C@@H:43]([C@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1)[C:44](O)=[O:45])=[N+:41]=[N-:42].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:40]([C@@H:43]([C@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1)[C:44]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28]([O:29][CH3:30])=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:45])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H]1CCOC1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N=[N+]=[N-])[C@H]1CCOC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.6 %

Procedure:
A solution of the product of Example 2C (0.050 g, 0.094 mmol) in tetrahydrofuran (1.0 mL) was treated with 2(S)-azido 2-(3(R)-tetrahydrofuranyl)acetic acid (J. Med. Chem. 1993, 36, 2300-2310) (0.020 g, 0.117 mmol), DEPBT (0.045 g, 0.151 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 12 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 5% methanol in ethyl acetate to give the title compound (0.041 g, 64% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Cc1cncc(N)c1
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cncc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (100 mg, 0.3 mmol) and 3-amino-5-methylpyridine (36 mg, 0.3 mmol) in dry DCM (5 mL) is added sodium triacetoxyborohydride (106 mg, 0.45 mmol) in one portion. The suspension is stirred at RT for 4 hours. The mixture is partitioned between DCM and saturated sodium bicarbonate, passed through a phase separator to recover the DCM layer and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 12 g pre-packed column and isohexane/EtOAc gradient elution (0% to 100% EtOAc). Product-containing fractions are combined and evaporated and the product is isolated as a colourless solid after trituration with 20% EtOAclisohexane, 55 mg, [MH+ 426.40].
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH2:14][NH:15][CH2:16][C:17]([O:19]CC)=O)C.[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[O:31])=[CH:26][CH:25]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:22])=[C:8]([CH2:14][N:15]2[CH2:16][C:17](=[O:19])[N:29]([CH2:28][C:27]3[CH:32]=[CH:33][C:24]([Cl:23])=[CH:25][CH:26]=3)[C:30]2=[O:31])[CH:9]=1
Reactant: CCOC(=O)CNCc1cc(Br)ccc1OCC(=O)OCC
Reactant: O=C=NCc1ccc(Cl)cc1
Product: O=C(O)COc1ccc(Br)cc1CN1CC(=O)N(Cc2ccc(Cl)cc2)C1=O

Procedure:
Prepared from 4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid ethyl ester (235 mg, 0.63 mmol) and 4-chlorobenzylisocyanate (166 μL, 1.26 mmol) according to GP12 (yield: 183.4 mg, 62%): LC/MS (an10p8): Rt 2.3 min, m/z 465 [M−H]−; 1H NMR (DMSO-d6): δ 4.05 (s, 2H), 4.48 (s, 2H), 4.55 (s, 2H), 4.73 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 7.25-7.45 (m, 6H), 13.11 (br. s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)[CH2:2][CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:32][C@@H:33]([CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)[C@H:34]([OH:46])[CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[CH:39]=1.C(N(CC)CC)C>C1COCC1.ClCCl>[F:54][C:52]1[CH:53]=[C:48]([CH:49]=[C:50]([F:55])[CH:51]=1)[CH2:47][C@H:33]([NH:32][C:11]([C:9]1[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:15][CH2:16][CH3:17])[N:10]=1)=[O:13])[C@H:34]([OH:46])[CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[CH:39]=1
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)O)n1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To 2-(dipropylamino)-6-methylpyrimidine-4-carboxylic acid (0.101 g, 0.426 mmol) in THF (0.5 mL) was added 1,1′-carbonyldiimidazole (CDI) (0.076 g, 0.468 mmol). After 50 min the CDI mixture was added to a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (0.173 g, 0.425 mmol) and triethylamine (0.18 mL, 1.28 mmol) in THF (6 mL) and dichloromethane (2 mL). After stirring overnight, the solvents were removed under reduced pressure and the residue was partitioned between dichloromethane, aq. sodium bicarbonate, and aq. sodium bicarbonate-brine mixture. The organic layer was dried over sodium sulfate, concentrated, and the residue was chromatographed on silica gel using MeOH-dichloromethane (5/95) to give 0.199 g of the title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-:19].[Na+].[OH-].[Na+].Cl>O1CCOCC1>[CH:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:14][C:15]=2[CH:16]=[CH:17][C:4]=1[C:1]([OH:3])=[O:19]
Reactant: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1O2
Reaction time: 5 h

Procedure:
A mixture of 2-acetylphenoxathiin (4.80 g), sodium hypochlorite solution (95 ml; 5.7% available chlorine), 4% sodium hydroxide solution (100 ml) and dioxan (100 ml) was mechanically stirred on the steam bath for 5 hrs. The solution was poured on to ice and excess hydrochloric acid with stirring. The white precipitate was filtered off and dissolved in hot 4% sodium hydroxide solution (40 ml) and filtered. The sodium salt of the required acid crystallised from the filtrate on cooling and was filtered off, dissolved in boiling water, and the acid precipitated by addition of excess hydrochloric acid. It was filtered off and recrystallised from acetic acid, m.p. 253° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-nitro-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example A27) (1.01 g, 3.0 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange solid (669 mg, 74%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[Br-].[CH2:14]([Zn+])[CH:15]([CH3:17])[CH3:16]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(C)C[Zn+]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of methyl 4-bromo-3-fluorobenzoate (322 mg, 1.38 mmol) and isobutylzinc bromide (4.1 mL, 0.5 M in THF) in 10 mL of THF was added bis(tri-tert-butylphosphine)palladium(0) (14 mg, 0.03 mmol). The mixture was flushed with nitrogen three times and then stirred at rt overnight. The reaction was quenched by adding 5.0 mL of 1.0 N HCl solution and extracted with Et2O (3×20 mL). Organic layers were combined, washed with brine, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 1:99 v/v EtOAc/hexanes as the eluant afforded 243 mg (84%) of the title compound: 1H NMR δ 0.92 (d, J=6.6, 6H), 1.93 (m, 1H), 2.56 (d, J=6.1, 2H), 3.91 (s, 31H), 7.21 (t, J=7.6, 11H), 7.67 (dd, J=1.5, 10.2, 11H), 7.74 (dd, J=1.6, 7.8, 11H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:24][NH2:25]>C(O)(=O)C>[O:16]([C:13]1[N:12]=[CH:11][C:10]([C:9]2[NH:25][N:24]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)=[CH:15][N:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1cnc(Oc2ccccc2)nc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a mixture consisting of the solid comprising ethyl 2,4-dioxo-4-(2-phenoxypyrimidin-5-yl)butanoate (Step A, 1.00 mmol theory) in acetic acid (10 mL) was added hydrazine (0.40 mL, 410 mg, 13 mmol). The stirring mixture was heated to 60° C. for one hour and was subsequently cooled to room temperature and stirred overnight. The off-white solid which had precipitated was collected by filtration and washed with hexane. The solid was purified by silica gel flash chromatography using a 9:1 to 1:1 v/v hexane-ethyl acetate gradient through a 40-g Silicycle® flash silica cartridge to afford the title compound as a white solid (100 mg, 32% yield); Rf 0.50 with 1:1 v/v hexane-ethyl acetate; 1H-NMR (300 MHz; DMSO-d6) δ 9.12 (s, 2H), 7.50 (s, 1H), 7.43 (dd, 2H), 7.20-7.28 (m, 3H), 4.26 (q, 2H), 1.25 (t, 3H); MS (ESI−) m/z 309 (M−1); H-PGDS FPBA IC50: 1.3 μM; H-PGDS inhibitor EIA IC50: 0.13 μM.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([NH2:12])[C:2]1=2.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][C:22]=2[O:33][CH3:34])[C:17]([Cl:35])=[CH:16][N:15]=1>>[Cl:35][C:17]1[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][C:22]=2[O:33][CH3:34])=[N:19][C:14]([NH:12][C:11]2[C:2]3[O:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: Nc1cccc2c1OCCCC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2cccc3c2OCCCC3)ncc1Cl

Procedure:
The title compound was prepared from 2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 179. Product was isolated as a light brown solid (51 mg, 40%). LCMS (m/e) 482 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.88 (broad s, 1H), 8.43 (broad s, 1H), 8.28 (s, 1H), 7.66 (d, 1H, J=8 Hz), 7.37 (d, 1H, J=9 Hz), 6.80 (d, 1H, J=7.58 Hz), 6.71 (s, 1H), 6.67 (dd, 1H, J=7.58, 8 Hz), 6.54 (d, 1H, J=8 Hz), 3.94 (m, 2H), 3.78 (m, 6H), 3.18 (m, 5H), 2.70 (m, 2H), 1.89 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:17]O)[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[H][H]>N.[Ni]>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(=NO)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CC(N)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.35 g (4.60 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethanone-oxime were dissolved in 50 ml of 7M methanolic ammonia, then combined with 100 mg Raney nickel. The mixture was shaken overnight at RT and 50 psi hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated down.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].O.O.O.O.O.O.O.O.O.[S-2:16].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([S:16][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCBr
Reactant: [S-2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCSCCC(C)C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
Isoamyl bromide (21.88 g, 0.21 mol) and tetrabutylammonium bromide (1.61 g, 5 mmol) were added to a solution of sodium sulfide nonahydrate (24.02 g, 0.10 mol) in water (50 ml) and the mixture was refluxed with stirring for 6 h. The organic layer was separated, the aqueous layer was extracted with pentane (25 ml). The extract was combined with the organic layer and dried with anhydrous magnesium sulfate. Distillation gave 15.85 g, 91% of a colorless liquid, bp 49°-50° C./0.1 mm Hg, n20D=1.4514, >99% GC pure; 1H NMR (CDCl3) δ 0.95 (d, J=6 Hz, 12H, CH3), 1.47 (q, J=6 Hz, 4H, CH2), 1.68 (septet, J=6 Hz, 2H, CH), 2.51 (t, J=6 Hz, 4H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH3:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:23][C:21]1[S:22][C:18]([CH:17]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(C=O)s1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(C)s2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 5-methyl-2-thiophenecarboxaldehyde gave the cis and trans isomers of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH2:8]([N:17]1[C:22](=[O:23])[CH2:21][C:19](=[CH2:20])[C:18]1=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C([O-])(=O)C.[K+].CN(C)C=O.O.CO>[NH2:1][CH:2]([CH2:3][S:4][C:19]1([CH3:20])[CH2:21][C:22](=[O:23])[N:17]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1=[O:24])[C:5]([OH:7])=[O:6]
Reactant: C=C1CC(=O)N(CCCCCCCCC)C1=O
Reactant: NC(CS)C(=O)O
Agent: CC(=O)[O-]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCN1C(=O)CC(C)(SCC(N)C(=O)O)C1=O
Reaction time: 4 h

Procedure:
DL-Cysteine (0.0067 M) was dissolved in potassium acetate (50 mM) and the solution obtained was added slowly to N-nonyl itaconimide (0.004 M) prepared as described in Example 6 above. The reaction mixture was then dissolved in dimethylformamide with gentle stirring and triethylamine was added. Stirring was continued for a further four hours at room temperature. The progress of the reaction was monitored by reverse phase thin layer chromatography using 75% methanol in water system. The formation of the desired product was detected by the ninhydrin reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21](O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O.O>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([Cl:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(Cl)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.75 h

Procedure:
In a mixture of 120 ml of ethyl acetate and 13 g of pyridine is dissolved 12.8 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate, and 5.1 ml of thionyl chloride is added to the solution, followed by refluxing with stirring for 45 minutes. After cooling, 500 ml of water and 200 ml of ethyl acetate are added to the reaction solution, and extraction is carried out. The extract is washed with 0.1N hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 10 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate as a colorless oily material.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 40.6 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (25.0 mg, 0.063 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (19 mg, 0.075 mmol) and sodium carbonate (66 mg, 0.625 mmol), to obtain 12 mg of the title compound (41%) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:30][CH2:31][CH3:32])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:9]3[CH:29]=[CH:28][CH:12]=[CH:11][CH:10]=3)=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH2:31][CH3:32]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C

Procedure:
A solution of 4-[2-(4-benzyloxy-2-propylphenoxy)ethyl]-5-methyl-2-phenyloxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid.