Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([OH:46])[CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)[O:46][C:2]3[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (427 mg, 1.31 mmol) synthesized in Example (121b) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (568 mg, 1.64 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (361 mg, 2.61 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-3.5%) to afford the desired compound (228 mg, yield 27%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:4])=[O:3]
Reactant: CCOC(=O)Nc1cc(N)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(NS(C)(=O)=O)ccc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
61.1 g (533 mmol) of methanesulfonyl chloride was added dropwise to a mixture of 96.0 g (485 mmol) of ethyl 5-amino-2-fluorocarbanilate, 46.0 g (582 mmol) of pyridine and 700 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the solvent was distilled off, the resultant product was dissolved in ethyl acetate and washed with diluted hydrochloric acid twice, then with water, and with saturated saline solution. The resultant solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude procut (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 126 g of the objective product (yield: 94%) in the form of light brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (39.1 g, 119 mmol) in CH2Cl2 (400 mL) and AcOH (40 mL) was added acetaldehyde (24.7 g, 476 mmol) and sodium triacetoxyborohydride (79.6 g, 357 mmol). The reaction mixture was stirred at RT for 24 hours. Then saturated NaHCO3 aq. was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2Heptane/EtOAc=3/1) to give the titled compound as a viscous oil (44.1 g, quantitative yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm; 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (m, 5H), 3.31 (m, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: COc1ccccc1N=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2OC)n1

Procedure:
Following a procedure similar to that described in preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5 g of o-methoxyphenyl isocyanate and 40 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:41])([F:40])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[C:35](=O)[CH2:34][CH2:33]4)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[F:41][C:16]([F:15])([F:40])[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][CH:26]([O:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[CH:35]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH2:34][CH2:33]4)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1
Reactant: O=C1CCc2cc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NC2CCc3cc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Tert-butyl 4-aminopiperidine-1-carboxylate (0.48 g, 2.4 mmol) and 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-one (0.75 g, 2.0 mmol) were mixed in neat titanium(IV) isopropoxide (2.85 g, 10.0 mmol) and stirred at room temperature overnight. Methanol (10 mL) was added followed by addition of sodium borohydride (0.12 g, 3.2 mmol). The reaction was stirred at room temperature for 3 h and then quenched by adding 0.1N aqueous sodium hydroxide. The resulting mixture was filtered through celite, and the residue was washed with ethyl acetate (2×10 mL) and with dichloromethane (10 mL). The organic layer was separated and dried over sodium sulfate. The drying agent was filtered off, and the filtrate concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/4) to afford the title compound as a off-white solid (0.73 g, 65%). 1H NMR (CDCl3, 300 MHz) 7.64 (m, 1H), 7.48 (m, 2H), 6.95 (m, 2H), 6.76 (m, 2H), 4.68 (m, 1H), 4.44 (m, 1H), 3.53 (m, 2H), 3.18 (m, 2H), 2.85 (m, 4H), 2.47 (m, 2H), 2.24-1.79 (m, 12H), 1.46 (s, 9H) ppm; MS (ES) 560.6 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:21]([OH:36])[CH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([NH:19][C@@H:20]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C@H:21]([OH:36])[CH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:18])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@@H](N)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Yield: 47.6 %

Procedure:
In a manner analogous to that described in Example 6, 73 mg (0.29 mmol) of N-benzyloxycarbonyl-L-valine were coupled with 100 mg (0.29 mmol) of 2(S)-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide to give 80 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid; MS m/e 580 [M+H]+.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[O:18][CH3:19])C(=O)C2=CC=CC=C12.Cl>C1COCC1.CC(OC)(C)C>[NH2:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(C#N)ccc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1cc(C#N)ccc1CN
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.6 %

Procedure:
10.6 ml of hydrazine hydrate were added to 21.2 g (73 mmol) of 4-phthalimidomethyl-3-methoxybenzonitrile dissolved in 290 ml of THF, and the mixture was stirred at room temperature for 20 h. Then 180 ml of 2H [sic] HCl were added dropwise and, after 1.5 h, the solvent was completely stripped off. The residue was taken up in MTBE, extracted with 1N HCl, adjusted to pH 9-10 with 2N NaOH and extracted with methylene chloride. 8.0 g (68%) of product were obtained. 1H-NMR (DMSO-d6 ; δ in ppm): 7.55 (dd, 1H); 7.40 (dd, 1H; 7.37 (d, 1); 3.85 (s, 3H); 3.70 (s, 2H); 2.5-1.6 (NH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([C:8](=[CH:21][N:22]([CH3:24])[CH3:23])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(OC)c(OC)c1

Procedure:
A solution of ethyl 2-(3,4-dimethoxybenzoyl)-acetate (25.2 g) and N,N-dimethylformamide dimethyl acetal (17.9 g) in tetrahydrofuran (100 ml) was refluxed for 18 hours under stirring. The reaction mixture was evaporated in vacuo to give ethyl 2-(3,4-dimethoxybenzoyl)-2-(dimethylaminomethylene)acetate (31.09) as an oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([NH2:17])=[C:9]([Cl:18])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:19][CH2:20]O>Cl>[NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[C:10]([NH2:17])=[C:9]([Cl:18])[CH:8]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CCO
Reactant: Nc1c(Cl)cc(C[C@@H](N)C(=O)O)cc1C(F)(F)F
Agent: Cl
Product: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
A solution of 3.5 g (10.97 mmol) (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 100 mL EtOH and 70 mL ethanolic hydrochloric acid solution (11.5 M) was stirred overnight at RT. The mixture was evaporated down i. vac., the residue was taken up in 150 mL water, combined with 30 mL 15% K2CO3 solution, extracted with 150 mL EtOAc, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the desired product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([P:16]1(=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1)=[O:7]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c1
Temperature: 115 °C

Procedure:
35.1 g (0.175 mol) of 3,5-dimethoxybenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 40.3 g (0.175 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise over the course of one hour while stirring. At the same time, the temperature was gradually increased to 115° C. When the reaction was complete, 60 ml of toluene were added at 80° C. After crystallization, 49 g (74% of theory) of the abovementioned compound of melting point 140° to 142° C. were obtained.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:30])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]3CCC#N)=[CH:15][C:14]=2[F:31])[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH:9]1[CH2:12][N:11]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:30])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][NH:20]3)=[CH:15][C:14]=2[F:31])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCC#N)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)C1

Procedure:
A solution of EXAMPLE 20B (0.12 g) in trifluoroacetic acid (6 mL) was stirred for 10 minutes and concentrated; and the concentrate was azeotroped with toluene to provide the desired product. NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.03 (m, 1H), 4.58 (m, 2H), 4.26 (m, 2H), 4.16 (br s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:19][CH2:20]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCCn2cnc3ccccc32)CC1

Procedure:
A mixture of 6.7 parts of 1-(4-chlorobutyl)-1H-benzimidazole, 5.5 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1.8 parts of 1-{1-[4-(1H-benzimidazol-1-yl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 157.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[CH:32][C:33]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[CH:32][C:33]([C:34]([F:36])([F:37])[F:35])=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Product: COCCOc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)ccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
The title compound was prepared according to the procedure described in Example 147B by using 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (95 mg, 0.3 mmol) and phenyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate described in Example 147A (161 mg, 0.45 mmol). The reaction was stirred at 50° C. overnight. After removal of the solvent, dichloromethane was added and the precipitating solid filtered off, washed with DCM and dried to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea (78 mg, 45%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.55-7.42 (m, 4H), 7.35 (d, 2H), 7.28 (d, 1H), 7.05 (d, 1H), 4.18-4.15 (m, 2H), 4.00 (s, 6H), 3.69-3.68 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40](O)=[O:41]>>[C:25]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:40](=[O:41])[CH2:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O[C@H]1CC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]2[C@]1(O)c1ccccc1
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Product: COc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)C[C@H](O)[C@@]2(O)c1ccccc1
Yield: 63.3 %

Procedure:
By working in accordance with Use Example 18, starting from 0.5 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-phenyl-perhydroisoindole-4,5-diol hydrochloride and 0.39 g of (2-methoxyphenyl)-acetic acid, 0.4 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-phenyl-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindole-4,5-diol is obtained in the form of a white solid which melts with decomposition at 150° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1cccs1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccs3)c(=O)n(C3CCCC3)c12
Yield: 48.3 %

Procedure:
1-Cyclopentyl-7-methoxy-3-thiophen-2-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and 2-isocyanatothiophene (0.4 mmol) following general procedure C. LCMS: m/z 394 [M+1]+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:35]I>C1COCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:34])[C@H:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH3:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
As shown in step 5-ii of Scheme 5, to a solution of sodium hexamethyldisilazide (NaHMDS, 5.06 g, 26.2 mmol) in THF (100 mL) under an atmosphere of nitrogen at −78° C. was added (4S)-4-benzyl-3-[2-(2-methoxyphenyl)acetyl]oxazolidin-2-one (7.11 g, 21.9 mmol) and the reaction was stirred for 1.5 hours. Methyl iodide (3.08 g, 1.35 mL, 21.7 mmol) was then added dropwise and stirring continued at −78° C. for 4 hours, then the reaction was warmed to room temperature over 18 hours. The reaction was cooled to −20° C. and quenched with NH4Cl (sat). The organics were removed under reduced pressure and the aqueous layer was extracted with DCM (3×). The organic extracts were combined and washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (5 to 25% EtOAc in hexanes) to give (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one as a white solid with a de of 9:1 (SIR). The solid was then purified via supercritical fluid chromatography (SFC) on an IC column (10% MeOH/CO2 isocratic gradient) to give (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one (Compound 2015, 3.14 g, 41.8% yield) with an enantiomeric excess of 99.9% by analytical SFC: 1H NMR (300 MHz, CDCl3) δ 7.41-7.20 (m, 7H), 6.96 (dd, J=13.8, 6.6 Hz, 1H), 6.93-6.84 (m, 1H), 5.30 (q, J=7.1 Hz, 1H), 4.68 (qd, J=6.7, 3.5 Hz, 1H), 4.22-4.11 (m, 2H), 3.84 (s, 3H), 3.35 (dd, J=13.3, 3.2 Hz, 1H), 2.82 (dd, J=13.3, 9.7 Hz, 1H), 1.64-1.46 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].Br[CH:25]([CH3:31])[C:26](OCC)=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:9][C:6]1[C:7]2[O:8][CH:25]([CH3:31])[C:26](=[O:27])[NH:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1Oc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluromethyl-2,4(1H,3H)-pyrimidinedione (1.07 g), ethyl bromopropionate (0.61 g) and potassium carbonate (0.414 g) in acetonitrile (30 ml) was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to give an amorphous (0.95 g). The amorphous was purified on a silica gel column, eluted with methylene chloride-ethyl acetate (19:1 and 9:1) to give the title compound (0.86 g) as white crystals.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH3:29])[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>>[Cl:27][C:25]1[CH:26]=[C:21]([S:20][C:14]2[N:13]([CH3:29])[C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[N:16][C:15]=2[CH:17]([CH3:19])[CH3:18])[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Yield: 64.5 %

Procedure:
To 3.1 g (6.9 mmol) of the above oil (136a) was added 13 ml of concentrated hydrochloric acid and the mixture was heated at 110° C. for 2 hours. After cooling, the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol-ethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide 1.6 g (yield 39%) of 3-(5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl)-propan-1-ol (137a) as crystals. mp 124-125° C.