Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([Mg]Cl)[CH2:26][CH3:27].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21]([CH2:25][CH2:26][CH3:27])([OH:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC[Mg]Cl
Reactant: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC1(O)CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone were dissolved at room temperature in 5 ml of tetrahydrofuran. A 2M solution of propylmagnesium chloride in diethyl ether (0.31 ml, 2 eq) was added, and stirring at room temperature was continued for 4 h. The reaction was stopped by careful addition of saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methyl tert-butyl ether. The organic layer was dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was chromatographed over silica gel using heptane/ethyl acetate 20:1 as the eluent. 54 mg of the title compound were isolated as a pale yellow oil (48%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1ccc2oc(S)nc2c1
Reactant: C1CNCCN1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(N3CCNCC3)nc2c1
Reaction time: 1 h

Procedure:
A 100 mg portion of 5-methyl-2-mercaptobenzoxazole was suspended in 20 ml of anhydrous toluene, and the suspension was mixed with 150 mg of phosphorus pentachloride and heated under reflux for 1 hour. The reaction solution was cooled in an ice bath and, with stirring, 500 mg of piperazine was added thereto. After 30 minutes of stirring, the ice bath was removed to carry out 1 hour of stirring at room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution, and then the water layer was washed with ethyl acetate and concentrated under a reduced pressure. Thereafter, the thus obtained mixture was purified by an LH-20 gel column chromatography (chloroform:methanol=1:1) to obtain the title compound (40 mg) in white color.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([NH:38][S:39]([C:42]1[S:46][C:45](Cl)=[N:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F-].[K+].O>C1(C)C=CC=CC=1>[C:34]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[N:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Yield: 47.2 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.55 g, 0.93 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.26 g, 1.0 mmol), tetrakis(triphenyl-phosphine)palladium (0.064 g, 0.055 mmol) in toluene (10 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (10 mL), water (40 mL) was added and the water layer was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.23 g) as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N:19]1([C:24]2[CH:30]=[CH:29][C:27](N)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[N:19]1([C:24]2[CH:30]=[CH:29][C:27]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCCC2)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(N5CCCC5)cc4)c3c2s1
Yield: 48 %

Procedure:
Prepared from VII and 4-(pyrrolidin-1-yl)aniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 48%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3303, 2842, 2233, 1709, 1629, 1613, 1583, 1522, 1466, 1388, 1347, 1275, 1219, 1185, 1166, 1060, 1014, 989, 828, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.88 (d, 1H, J=9.0 Hz), 7.35 (d, 2H, J=8.1 Hz), 6.73 (d, 2H, J=8.1 Hz), 3.17 (m, 4H), 1.99 (m, 4H); HRMS calcd for C20H17N6S (M+H+): 373.1235, found 373.1218.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[C:13]([CH:23]=O)=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[NH2:27]O.C(OC(=O)C)(=O)C.Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[C:13]([C:23]#[N:27])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1ccc(-n2cc(C=O)c3ccc([N+](=O)[O-])cc32)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc([N+](=O)[O-])cc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of 4-(6-nitroindol-1-yl)benzoic acid ethyl ester (0.53 g) in N,N-dimethylformamide (6 mL) was added phosphoryl chloride (0.31 g) under ice cooling and this mixture was stirred at 70° C. overnight. After cooling to ambient temperature, to this reaction mixture was added 2 mol/L aqueous sodium hydroxide solution and this mixture was stirred at 30 minutes. This reaction mixture was poured into 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give 4-(3-formyl-6-nitroindol-1-yl)benzoic acid ethyl ester (0.46 g). To a solution of this aldehyde (0.46 g) in tetrahydrofuran (10 mL) were added hydroxylamine hydrochloride (0.19 g) and pyridine (0.43 g) at room temperature, and this mixture was stirred at 80° C. for 8 hours. To this reaction mixture was added acetic anhydride (0.42 g) at 80° C., this mixture was stirred at same temperature overnight. After cooling to ambient temperature, to this reaction mixture was added 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration. This solid was washed with water, n-hexane and diethyl ether to give the title compound (0.13 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.Cl.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])(=O)C.[Na+]>C(O)CO.C(OC(=O)C)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:27]3[CH2:26][CH2:25][CH:24]([C:20]4[NH:21][CH:22]=[CH:23][N:19]=4)[CH2:29][CH2:28]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Reactant: c1c[nH]c(C2CCNCC2)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Fc1ccc(-c2cc(N3CCC(c4ncc[nH]4)CC3)c3sccc3n2)cc1
Temperature: 160 °C
Yield: 18 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (146 mg, 0.53 mmol), 4-(1H-imidazol-2-yl)piperidine. hydrochloride (U.S. Pat. No. 4,431,653) (100 mg, 0.53 mmole) and sodium acetate (50 mg) in ethylene glycol (10 mL) is stirred and heated at 160° C. for about 16 hours. It is then cooled, diluted with ethylacetate (15 mL), and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by preparative thin layer chromatography to give 5-(4-fluorophenyl)-7-(4-imidazol-2-ylpiperidyl)thiopheno[3,2-b]pyridine (36 mg, 18% yield) as a white solid, m.p. 95° C. (compound 1).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][C@@H:13]3[CH2:17][CH2:18][CH:19](P(=O)(OCC)OCC)[C:20](=[O:21])[N:12]23)=[CH:7][CH:6]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]1)[CH:35]=O.C(OCC)(=O)C>C1COCC1.C(O)C.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:16][O:15][CH2:14][C@@H:13]3[CH2:17][CH2:18]/[C:19](=[CH:35]\[C:34]4[CH:37]=[CH:38][C:39]([N:40]5[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]5)=[C:32]([O:31][CH3:30])[CH:33]=4)/[C:20](=[O:21])[N:12]23)=[CH:9][CH:10]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2COC[C@@H](c3ccc(Cl)cc3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C2\CC[C@H]3COC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.6 %

Procedure:
Lithium hydroxide monohydrate (13.1 mg) was added to a mixed solution of diethyl [(4R,9aS)-4-(4-chlorophenyl)-6-oxooctahydropyrido[2,1-c][1,4]oxazin-7-yl]phosphonate (73.5 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (47.5 mg) in THF (1.5 mL) and ethanol (0.5 mL) at room temperature, and the reaction solution was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 68.4 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].[NH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[Cl-]>ClCCl.O>[C:25]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][NH:30][CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:29])[CH2:8][C@@H:9]1[CH3:28])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see intermediate 36) (500 mg, 1.268 mmol) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (400 mg, 1.997 mmol) in dichloromethane (DCM) (15 ml) was stirred 45 min at room temperature under nitrogen before being treated portionwise with sodium triacetoxyborohydride (457 mg, 2.155 mmol). The resulting mixture was stirred at room temperature for 20 h then treated with a saturated NH4Cl aqueous solution (8 mL) and diluted with water (10 mL). The layers were separated and the aqueous phase was washed with DCM (2×10 mL). The combined organic layers were dried over Na2SO4 then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 1 to 10% MeOH in DCM) gave 1,1-dimethylethyl 4-[({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)amino]-1-piperidinecarboxylate (608 mg, 0.998 mmol, 79%) as a cream solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH2:12][OH:13])[CH:9]([F:11])[F:10])(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH:9]([F:10])[F:11])[CH2:12][OH:13]
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Solvent: C1COCCO1
Product: NC(CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C

Procedure:
A suspension of 10.22 g (26.6 mmol) [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester in 133 ml 4N HCl in dioxane was stirred for two h at rt. The mixture was evaporated to give the hydrochloride salt of 2-amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol.
Reaction SMILES: [H-].[Na+].CS(N=[N+:8]=[N-:9])(=O)=O.CS(Cl)(=O)=O.[N-]=[N+]=[N-].[Na+].[CH3:19][O:20][P:21]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[O:22][CH3:23]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:19][O:20][P:21]([C:25](=[N+:8]=[N-:9])[C:26](=[O:28])[CH3:27])(=[O:24])[O:22][CH3:23]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: CS(=O)(=O)N=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of sodium hydride in dry toluene, (2-oxo-propyl)-phosphonic acid dimethyl ester was added slowly. The solution mixture was stirred for 1 hour. Methanesulfonyl azide, prepared by the reaction of methanesulfonyl chloride and sodium azide, dissolved in dry toluene and dry tetrahydrofuran was added to a solution. The mixture was allowed to slowly warm up to the ambient temperature and stirred for additional 2 hours. Filtration through a celite filter cake gave yellowish oil of (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester, which was used for the next step without any further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]([PH:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@@H:21]([CH3:39])[C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]([PH:17]([O:18][CH:21]([CH3:39])[C:22]([N:24]2[CH2:38][CH2:37][CH2:36][C@H:25]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:23])=[O:19])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCCCC(NC(=O)OCc1ccccc1)[PH](=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCC(NC(=O)OCc1ccccc1)[PH](=O)OC(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-[[(phenylmethoxy)carbonyl]amino]pentylphosphinic acid (490 mg., 1.72 mmole) and 1-[(S)-2-hydroxy-1-oxopropyl]-L-proline, phenylmethyl ester (255 mg., 0.92 mmole) in dry tetrahydrofuran (5 ml.) is treated with dicyclohexylcarbodiimide (285 mg., 1.38 mmole) and dimethylaminopyridine (50 mg.) and stirred at room temperature for 2.5 hours. The mixture is filtered, diluted with ethyl acetate, and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride solutions, dried over sodium sulfate, and evaporated to give crude (S)-1-[2-[[[1-[[(phenylmethoxy)carbonyl]amino]pentyl]phosphinyl]oxy]-1-oxopropyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C1(C)C=CC=CC=1>[C:17]([C:16]1[CH:15]=[C:14]([NH:13][C:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])=[O:10])[CH:27]=[CH:26][CH:25]=1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: COc1ccc(Cl)cc1N=C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc(C(=O)c2ccccc2)c1
Yield: 92.4 %

Procedure:
A mixture of 5-chloro-2-methoxyphenyl isocyanate (1.00 g, 5.4 mmol) and 3-aminobenzophenone (1.29 g, 6.5 mmol) was stirred in toluene (20 ml) for two days. The reaction was filtered and the filter cake washed with toluene. 1.9 g of the title compound was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C2CCCN2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccc(Cl)c2)cc1

Procedure:
The title compound, off-white solid, m.p. 107° C. and MS: m/e=335 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2](=[S:15])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[S:6][C:7]=1[CH3:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)=O>>[OH:26][C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])[S:6][C:7]=3[CH3:8])[S:15][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(N)=S
Reactant: O=C(CBr)c1cccc(O)c1
Product: Cc1sc(C(=O)OC(C)C)cc1-c1nc(-c2cccc(O)c2)cs1

Procedure:
A solution of 1.97 g (8.1 mmol) of isopropyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 1.74 g (8.1 mmol) of 3′-hydroxy-2-bromoacetophenone (Example 40, step (a)) were reacted in a manner similar to Example 8, step (a) to give, after column chromatography on silica gel eluting with hexane:ethyl acetate 7/3 (v:v), crystallization from acetonitrile, and recrystallization from hexanes, isopropyl 4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate (1.4 g, 48%) as brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.57 (br s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.26 (m, 1H), ), 6.78 (m, 1H), 5.12 (septet, 1H, J=6.2 Hz), 2.85 (s, 3H), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C18H17NO3S2 360.1 (M+H), found 360.1.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]=[CH:10]2>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.COCCOC>[Cl:3][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([Cl:6])[CH:8]=2)[N:13]=1
Reactant: O=c1ccc2cc(Cl)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: COCCOC
Product: Clc1ccc2nc(Cl)ccc2c1
Reaction time: 6 h

Procedure:
Phosphorus oxychloride (16.72 Kg) was charged to a vessel containing 6-chloroquinolin-2(1H)-one (12.50 Kg) (Prepared according to method of Johnston K. M. et al., J. Chem. Soc. Perkin Trans. 1, 1972, 1648 and references therein), benzyltrimethylammonium chloride (1.575 Kg) and 1,2-dimethoxyethane (87.8 Kg) at 70° C. 1,2-dimethoxyethane (22.5 Kg) was charged as a line rinse. The reaction was stirred at 70° C. to 75° C. for ca. 6 hours before the batch was concentrated to ca. 44 L by vacuum distillation (<40° C.). The concentrate was diluted with dichloromethane (253.1 Kg), adjusted to 38° C. to 45° C. and quenched by the addition of water (37.5 Kg) whilst maintaining the temperature at 38° C. to 45° C. After 70 minutes the batch was cooled to 25° C. to 30° C. and treated with Celite (1.30 Kg) for 40 minutes. The slurry was pressure filtered via a 1 μm filter membrane and the filtrates diluted with dichloromethane (87.5 Kg). The phases were separated and the aqueous phase extracted twice with dichloromethane (82 Kg). The combined organic extracts were washed sequentially with 5% w/w sodium hydrogen carbonate solution (37 L), water (37 Kg) and then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (96.5 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. Isopropanol (95.4 Kg) was charged and the batch then concentrated to ca. 75 L at 25° C. to 40° C. The resultant slurry was stirred at 16° C. to 18° C. for 2 hours and then filtered. The filter cake was washed with isopropanol (19.7 Kg) at ca. 20° C. and then dried at up to 50° C. in vacuo to provide the subtitle compound as an off white solid (12.04 Kg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(P(CCCC)(CCCC)=CC#N)CCC.[CH3:49][C:50]([O:53][C:54]([NH:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:55])([CH3:52])[CH3:51]>C1(C)C=CC=CC=1>[C:60]([O:59][C:57]([N:56]([C:54]([O:53][C:50]([CH3:52])([CH3:51])[CH3:49])=[O:55])[CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][C@@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])=[O:58])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC[C@@H](CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (282 mg, 0.589 mmol; Example 186, Step A), 2-(tributylphosphoranylidene)acetonitrile (171 mg, 0.707 mmol) and di-tert-butyl iminodicarbonate (256 mg, 1.179 mmol) in toluene (3 mL) under argon was stirred at 110° C. for 2 h. Flash column purification on silica gel (0 to 60% EtOAc in hexanes) gave the title compound. Mass Spectrum (ESI) m/z=677 (M+1).