Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:18]([CH3:35])[C:19](=[N:32][C:33]#[N:34])[N:20]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=5)[C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].[CH3:40]C(C)([O-])C.[K+].CI>C1COCC1>[C:30]([C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:20]2[C:11]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[N:7][C:2]([NH:1][CH3:40])=[C:3]([C:36]([F:38])([F:37])[F:39])[CH:4]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:18]([CH3:35])[C:19]2=[N:32][C:33]#[N:34])=[CH:26][CH:25]=1)([CH3:28])[CH3:29])#[N:31]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc(N)c(C(F)(F)F)c4)ccc3ncc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)cc2)c(=NC#N)n4C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the stirred solution of Example 6 (0.014 mmol) in dry THF was added potassium-t-butoxide (0.157 mmol) at 0° C. Reaction mixture was stirred further for 15 minutes, followed by addition of methyl iodide (0.125 mmol). Reaction mixture was warmed to RT and stirred overnight. Solvent was removed and diluted with EtOAc. Organic layer was washed with water, dried over anhydrous Na2SO4 and solvent was removed. Crude product was further purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.16-8.11 (m, 2H), 8.00-7.91 (m, 1H), 7.89 (s, 3H), 7.76 (brs, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.79 (q, J=4.5 Hz, 1H), 3.92 (s, 3H), 2.89 (d, J=4.2 Hz, 3H), 1.82 (s, 6H); MS (m/z): 541(M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)(=O)C.[Si](I)(C)(C)C>ClCCCl>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:43](=[O:44])[CH2:42][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:12]1[CH:11]=[C:10]([CH2:20][CH:21]([NH:22][C:43](=[O:44])[CH2:42][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1ccc(-c2cccc(C(N)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Agent: C[Si](C)(C)I
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3O)NC(=O)COc3ccccc3)c2)s1
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)NC(=O)COc3ccccc3)c2)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
N-{2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-[3-(5-methyl-thiophen-2-yl)-phenyl]-ethyl}-2-phenoxy-acetamide was prepared from 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-[3-(5-methyl-2-thienyl)phenyl]ethanamine (0.404 mmol) and phenoxyacetyl chloride (0.445 mmol, 1.1 eq.) according to the general procedure described above (Alternate General Procedure for N-Acylations). Ethyl acetate was used in place of dichloromethane in the workup procedure. Crude product obtained was a white foam that was subjected to the conditions described above for TMSI-mediated O-benzyl deprotection. After stirring 16 h at 70° C., 1,2-dichloroethane (5.6 mL) was added and the reaction was stirred 3 h at 70° C. after which time the reaction was quenched and worked up as described above. Crude product obtained was a brown oil that was purified by column chromatography using 10% acetone/dichloromethane followed by concentration and washing the solid with diethyl ether (3×5 mL) to give the title compound as a tan solid (0.171 mmol, 42% for 2 steps). MS (ESI) m/z 529.4.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11]>C1COCC1>[C:1]([NH:5][S:10]([CH2:9][CH2:8][CH2:7][Cl:6])(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: -20 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to −20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:34][CH3:35])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:19](=[O:20])[N:18]2[C@@H:12]1[CH2:13][C:14]([S:34][CH3:35])=[CH:15][CH:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)=[O:22])[CH3:10]
Reactant: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.5 %

Procedure:
To a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-5-methylthio-9-oxo-1-azabicyclo [5.2.0]non-2,4-diene-2-carboxylate (213 mg, 0.41 mmol) in anhydride THF (8 ml) was added acetic acid (0.35 ml) and a 1.1M solution in tetrahydrofuran of tetrabutylammonium fluoride (1.9 ml; 2.04 mmol). After stirring for 3 days at ambient temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and then washed with an 5% aqueous solution of NaHCO3 and water. After evaporation of the solvents, the residue was taken up with methylene chloride. The insoluble material was filtered off and identified as 4-nitrobenzyl (7R,8S)-8-[(1R)-1-hydroxyethyl]-5-methylthio-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate: The filtrate was concentrated and the residue was purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane 3:7 to give an other batch of the 4-nitrobenzyl (7R,8S)-8-[(1R)-1-hydroxyethyl]-5-methylthio-9-oxo-1-azabicyclo-[5.2.0]non-2,4-diene-2-carboxylate (total=102 mg, 62% overall yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][C:6]([C:13]([OH:15])=[O:14])=[N:7]2.[C:17]1([S:23]([N:26]=C=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:29](#N)[CH3:30]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:26][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH:5]=[C:6]([C:13]([O:15][CH2:29][CH3:30])=[O:14])[NH:7]2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: CC#N
Reactant: O=C(O)C1=Nc2cc(Cl)cc(Cl)c2C(=O)C1
Product: CCOC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 16 h

Procedure:
Combine 5,7-dichloro-quinolin-4-one-2-carboxylic acid, ethyl ester (0.59 g, 2.1 mmol) and benzenesulfonyl isocyanate (0.56 mL, 4.2 mmol) in acetonitrile (10 mL). Heat to reflux under an inert atmosphere. After 16 hours, quench with methanol (5 mL). Evaporate in vacuo. Chromatograph on silica gel eluting with 2% acetone/dichloromethane. Recrystallize from acetonitrile to give the title compound as a solid: TLC Rf =0.31 (silica gel, 2% acetone/dichloromethane); mp; 184°-185° C. Elem. Anal. calculated for C18H14Cl2N2O4S: C, 50.83; H, 3.32; N, 6.59. Found: C, 51.04; H, 3.33; N, 6.56.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 286.9 %

Procedure:
To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (102.9 g, 448.9 mmol) in EtOAc (1 L) at 10.9° C. was added a NaOH solution (2.5 M, 269 mL), and the biphasic reaction mixture warmed to 15.9 and then stabilized. Phenyl chloroformate (98.4 g, 156.5 mmol) was added in one portion and the temperature rose to 25.5 and then stabilized. The ice bath was removed and the reaction was monitored by HPLC. After 1 hour an additional 25 mL of 2.5 M NaOH was added. The reaction mixture was stirred overnight, and then diluted with EtOAc (200 mL). The organic layer was washed with brine (1 L), dried over Na2SO4 (200 g) and concentrated to about 400 to 500 mL of EtOAc. The concentrated solution was warmed to 60° C. After the solids had dissolved, heptane (2 L) was slowly added, during which solids formed. After stirring for 30 minutes the solid was collected via filtration and the cake was washed with 400-500 mL of heptane. The cake was dried in a vacuum oven at ambient temperature to yield 156.9 g (95.0%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (m, 6H), 7.26-7.225 (m, 2H), 7.13 (br s, 2H), 6.96 (br s, 1H), 6.47 (br s, 1H), 2.42 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:20][CH:22]4[CH2:23][O:24]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
4-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol (2 g, 6.89 mmol) was dissolved in DMF (200 ml) and sodium hydride (0.9 g, 20.67 mmol, 55% in oil) was added. The mixture was stirred at 50° C. for 1 h, and epibromohydrin (0.94 ml, 11.37 mmol) was added dropwise followed by stirring for one h at room temperature. Purification by flash chromatography on silica using ethyl acetate/heptane as eluent afforded the title compound (0.55 g, 23%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]3[CH:12]=[C:13]([I:16])[CH:14]=[N:15][C:8]=3[NH:7][C:6]2=[S:17])[CH2:3][CH2:2]1.[CH2:18](I)[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]3[CH:12]=[C:13]([I:16])[CH:14]=[N:15][C:8]=3[N:7]=[C:6]2[S:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3]1
Reactant: CCCI
Reactant: O=c1c2cc(I)cnc2[nH]c(=S)n1CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2ncc(I)cc2c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of the title compound of Step A (0.5 g, 1.39 mmol), n-propyl iodide (0.36 g, 2.09 mmol) and potassium carbonate (1.9 g, 13.9 mmol) in DMF (14 mL) were stirred at ambient temperature overnight. The reaction mixture was then concentrated to dryness in vacuo and the residue partitioned between 200 mL of ethyl acetate and 100 mL of H2O. The organic phase was separated, washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to provide 0.5 g of crude product. Purification of this crude product was achieved via column chromatography (silica gel, 70:30 hexanes:ethyl acetate eluent) to deliver 0.19 g of the title compound of Step B, a compound of the invention, as a solid melting at 159-161° C. 1H NMR (300 MHz, CDCl3): δ 0.50-0.62 (m,4H), 1.10 (t,3H), 1.31-1.43 (m,1H), 1.79-1.94 (m,2H), 3.41 (t,2H), 4.10 (d,2H), 8.82 (s,1H), 9.02 (d, 1H). Mass Spectrum: m/e 402 (protonated parent molecular ion measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+); the ion shown corresponds to the M+H+ ion calculated from the integral values of the atomic weights of the most abundant isotope of each element present).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(Oc2ccc(NC(=O)c3ccccc3)c(Oc3cccc(C#N)c3)n2)c1
Reaction time: 3 h

Procedure:
To 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (1.0 g, 2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirring for 3 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3) as eluent gave N-[2,6-bis(3-cyanophenoxy)-pyridin-3-yl]benzamide; NMR (CDCl3) 8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[S:35]>>[CH3:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)4-isobutyl-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[S:33][C:34]([C:38]([OH:42])([C:40]#[CH:41])[CH3:39])=[C:35]([CH3:37])[N:36]=1>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:41]#[C:40][C:38]([C:34]3[S:33][C:32]([CH3:31])=[N:36][C:35]=3[CH3:37])([OH:42])[CH3:39])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(O)c1sc(C)nc1C
Product: Cc1nc(C)c(C(C)(O)C#Cc2ccc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4ccc(Cl)cc4)c3c2)s1

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-(2,4-dimethylthiazol-5-yl)-3-hydroxybut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(2,4-dimethylthiazol-5-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (d, J=8 Hz, 1H), 7.70 (s, 1H), 7.58 (m, 3H), 7.43 (d, J=8 Hz, 1H), 7.32 (m, 2H), 5.18 (s, 1H), 2.64 (s, 3H), 2.61 (s, 3H), 2.47 (s, 3H), 1.82 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32ClNSO4: 562.2. found: 562.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]#[N:8].Cl.[NH2:10][OH:11].C(N(CC)CC)C>CO>[OH:11][N:10]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)[NH2:8]
Reactant: NO
Reactant: Cn1ccnc1C#N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cn1ccnc1C(N)=NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methyl-2-cyanoimidazole (0.85 g, 8.0 mmol) (J. Chem. Soc. Perkin Trans. I 1994, 239) was dissolved in methanol (20 mL), then hydroxylamine hydrochloride (0.66 g, 9.6 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added and the mixture was stirred at room temperature for 1 hour. The mixture was chilled in an ice-bath, then the solid was collected by filtration, washed with methanol and dried to give the title compound as a white crystalline solid which was contaminated with triethylamine hydrochloride (0.90 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](N1C=CN=C1)=[S:8].Cl.[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>CN(C)C=O>[CH3:15][O:16][C:17](=[O:27])[CH:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:8]
Reactant: S=C(Nc1nccs1)n1ccnc1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nccs1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (4.21 g, 20.0 mmol) and DL-phenylalanine methyl ester hydrochloride (4.31 g, 20.0 mmol) in N,N-dimethylformamide (150 mL) was heated at 90° C. for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ether-hexanes to provide 3.26 g (51%) of the titled product: IR (KBr, cm-1) 3184, 3029, 1735 1569, 1510, 1223, 1189; 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.40 (d, 1H), 7.20-7.38 (m, 5H), 7.17 (d, 1H), 5.30 (q, 1H), 3.63 (s, 3H), 3.02 -3.22 (m, 2H); MS (FD) m/e 321 (M+); UV (EtOH) 291 nm (ε=18235), 255 nm (ε=10773), 202 nm (ε=20575). Anal. Calcd for C14H15N3O2S2 : C, 52.31; H, 4.70; N, 13.07. Found: C, 52.24; H, 4.61; N, 13.18.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C(=O)=O.CC(O)C.[Li]CCCC.CN(/[CH:19]=[N:20]/[C:21]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:22]=1[C:23]([O:25]C)=O)C>C1COCC1.C(O)(=O)C>[OH:25][C:23]1[C:22]2[C:21](=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[CH:27]=2)[N:20]=[CH:19][C:2]=1[C:1]#[N:3]
Reactant: COC(=O)c1cc(OC)ccc1/N=C/N(C)C
Reactant: CC#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc2ncc(C#N)c(O)c2c1
Temperature: -72 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a cold solution of acetonitrile (2 mL, 38 mmol, 2.8 eq) in THF (30 mL) at −72° C. (Dry-ice/IPA) was added dropwise nBuLi (12 mL, 30 mmol, 2.2 eq) under argon atmosphere. The reaction mixture became an orange suspension after 1 h. A solution of methyl 2-{[(1E)-(dimethylamino)methylidene]amino}-5-(methyloxy)benzoate (3.2 g, 13.6 mmol, 1 eq) in THF (30 mL) was then added dropwise while the internal temperature was maintained at −72° C. The resulting mixture was slowly warmed to RT overnight. To the resulting light-brown suspension was added glacial acetic acid (6 mL) with slight cooling. After stirring for 1 h, the suspension was then quenched with water (60 mL) and filtered to give the titled compound (2.3 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:1].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][N:12]1[C:4]1[CH:3]=[C:2]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1cc(N2Cc3ccccc3C2)nc2ccccc12
Reactant: NCC(O)CO
Product: Cl
Product: OCC(O)CNc1cc(N2Cc3ccccc3C2)nc2ccccc12

Procedure:
The title compound, m.p. 295-301° C., and MS: m/e=336.2 (M+H+), was prepared from 4-chloro-2-(1,3-dihydro-isoindol-2-yl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [CH:1]([NH:4][C:5]([Cl:7])=[O:6])([CH3:3])[CH3:2]>ClC1C=CC=CC=1>[CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[C:5]([Cl:7])(=[O:6])[NH2:4]
Reactant: CC(C)NC(=O)Cl
Solvent: Clc1ccccc1
Product: CC(C)N=C=O
Product: NC(=O)Cl
Yield: 93 %

Procedure:
A solution of 970 parts of isopropylcarbamic acid chloride in 1,020 parts of chlorobenzene is inroduced into an apparatus analogous to that of Example 1 and is refluxed for 9 hours -- during which the reaction temperature rises from 77° to 88° C -- whilst passing 120,000 parts by volume of dry nitrogen per hour through the mixture. The subsequent distillation gives 630 parts of isopropyl isocyanate free from carbamic acid chloride (corresponding to 93% of theory, based on isopropylcarbamic acid chloride used), boiling at from 73.5° to 74.5° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Cl:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][Cl:12].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1COCC1>[Cl:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][Cl:12])[P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)N(CCCl)CCCl

Procedure:
Phosphorous oxychloride (0.15 mol) in 100 ml. THF are mixed dropwise at 10° C. with bis-chloroethylamine (0.1 mol) in 100 ml. THF and triethylamine (0.15 mol). After ending of the reaction (TLC verification), triethylamine hydrochloride is filtered off and the filtrate, after the addition of 50 ml. toluene, evaporated. The oily residue is immediately further reacted.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:34])[CH2:15][CH:16]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1)C1C=CC=C(OC)C=1>>[CH3:12][O:13][C:14](=[O:34])[CH2:15][CH:16]([C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)CC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1
Yield: 66 %

Procedure:
3-(1H-Indol-6-yl)-3-(4-methoxy-phenyl)-propionic acid methyl ester XXXIV (0.51 g, 66% yield) was prepared from 4-methoxy boronic acid using the procedure described for preparation of 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-propionic acid methyl ester XXXI (see Example 7).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Na+].[Cl:13][C:14]1[C:19]2[O:20][C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]=3[C:18]=2[CH:17]=[C:16](Br)[CH:15]=1>>[Cl:13][C:14]1[C:19]2[O:20][C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]=3[C:18]=2[CH:17]=[C:16]([S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)(=[O:11])=[O:10])[CH:15]=1
Reactant: N#Cc1cccc(S(=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4cccc(C#N)c4)cc3c2C1
Yield: 12 %

Procedure:
Sodium 3-cyanobenzenesulfinate was coupled with the product of Example 44, step B following the procedure of Example 29, step C. The crude product was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(3-cyanophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 12%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.22-8.17 (m, 2H), 7.98 (s, 1H), 7.86-7.83 (m, 2H), 7.70-7.64 (m, 1H), 4.59 (s, 2H), 3.85 (t, J=5.7 Hz, 2H), 2.92 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).