Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[N+:14]([C:10]1[C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cccc([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a suspension of 7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (1.0 g) in THF/MeOH (40 mL/40 mL) was added 8.4 mL (2.0 eq) of 1N NaOH. The reaction was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was diluted with H2O/EtOAc, acidified with 3N HCl and extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated to give 7-nitro-benzo[b]thiophene-2-carboxylic acid as a light yellow solid (928 mg, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)=[O:18]
Reactant: COC(=O)c1cscc1N
Reactant: O=C=NCCCCBr
Solvent: Cc1ccccc1
Product: COC(=O)c1cscc1NC(=O)NCCCCBr

Procedure:
Methyl 4-aminothiophene-3-carboxylate was reacted with one equivalent of 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl] urea as a tan solid, mp 85°-86° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)[CH:9]=1)=[O:4].[OH-].[Na+]>CS(C)=O.O>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=[C:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:25])[N:7]=1
Reactant: COC(=O)c1cc(-c2ccccc2-c2cc3ccccc3o2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)O
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A suspension of 0.90 g (2.71 mmol) of 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (6′A) in 8.50 ml of DMSO was treated at RT with 1.35 ml (5.42 mmol) of aqueous 1N NaOH. After 2 h, reaction was diluted with chilled water and extracted 1× with Et2O. The water phase was acidified with aqueous 10% KHSO4 and extracted with Et2O (2×). These organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.84 g (97%) of the title compound as white powder. MS: 317.1 (M−H−).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:10]=[CH:9][O:8][N:7]=1)[OH:5].[F:11][C:12]1[C:13]([CH3:21])=[CH:14][C:15](O)=[C:16]([CH:19]=1)[C:17]#[N:18]>>[Cl:1][CH2:2][CH2:3][C@@H:4]([O:5][C:15]1[CH:14]=[C:13]([CH3:21])[C:12]([F:11])=[CH:19][C:16]=1[C:17]#[N:18])[C:6]1[CH:10]=[CH:9][O:8][N:7]=1
Reactant: Cc1cc(O)c(C#N)cc1F
Reactant: O[C@@H](CCCl)c1ccon1
Product: Cc1cc(O[C@H](CCCl)c2ccon2)c(C#N)cc1F

Procedure:
The product of step (d) (0.47 g) was reacted with 5-fluoro-2-hydroxy-4-methylbenzonitrile using the procedure described for Example 5(a) to afford the product as a white solid (0.4 g).
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[N:20]=[C:19]([C:21]([O:23]C)=O)[C:18](=[O:25])[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[C:16]=3[CH3:36])=[CH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1)#[N:3]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[N:20]=[C:19]([C:21]([NH2:1])=[O:23])[C:18](=[O:25])[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)[C:16]=3[CH3:36])=[CH:13][CH:12]=[N:11]2)=[CH:8][CH:9]=1)#[N:3]
Reactant: N
Reactant: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)nc(C(N)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 87 %

Procedure:
Ammonia solution (1.12 L, 7M in MeOH, 10 eq) was added to methyl 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (377 g) and MeOH (3.8 L, 10 vols) under nitrogen. The suspension was stirred at ambient temperature for 36 h. The mixture was then filtered, washed with MeOH (2×754 ml) and dried under vacuum. The crude material was dissolved in acetone (10.7 L) at 45° C., and filtered to remove particulates. The filtrate was is concentrated to a volume of about 3.8 L. The resulting slurry was diluted by the addition of methyl isobutyl ketone (10 L), and a further 3.2 L of solvent were removed by distillation. Further methyl isobutyl ketone (7.8 L) was added to achieve a total of about 53 relative volumes (with respect to substrate). The resulting slurry was heated to 53-60° C. and held within this temperature range until in-processes testing (DSC) showed that the desired polymorph had been achieved (62 hours for this particular batch). The slurry was cooled to 25° C. over 4 hours, and then held at 20-25° C. for 36 hours. The product was collected by filtration, and the cake washed with methyl isobutyl ketone (1.9 L). The cake was dried in a vacuum oven at 55° C. until constant weight was achieved. After drying, the title compound (310.8 g, 87%) was obtained as a pale yellow crystalline solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:8][CH2:7]1)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:31][S:28]([CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:39])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1)(=[O:29])=[O:30]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(CS(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a solution of ethyl{2-[5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (1.0 g) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 1N hydrochloric acid (5 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.95 g, yield 100%) as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.BrC1C=C[C:16]([OH:19])=[C:15](CC)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16](=[O:19])[CH3:15])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CC(C)c1cc(Br)ccc1O
Product: CC(=O)Oc1ccc(Br)cc1C(C)C

Procedure:
The title compound was prepared as described in Step 2 of Example A(22) where 4-Bromo-2-isopropyl-phenol from step 1, was substituted in place of 4-Bromo-2-ethyl-phenol.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH2:35][CH2:36][CH3:37]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH2:35][CH2:36][CH3:37])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCOC([O-])([O-])[O-]
Solvent: CC(=O)O
Product: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (0.9 g) in propyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.72 g, 68%), m.p. 90°-92° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O>[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:20][CH2:19]1
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
Fluoronitrobenzene (10.3 g, 0.073 mol) is dissolved in water and then potassium carbonate (12.1 g, 0.0876 mol) is added. 1-Methyl[1,4]diazepane (10 g, 0.0876 mol) is introduced and then the reaction medium is heated under reflux (≅100° C.) for 5 hours. The medium is cooled. A precipitate forms, which is filtered and washed with water. A yellow solid is recovered, which is dried at 45° C. in a vacuum oven (16.21 g, yield=94.5%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@:28]([OH:43])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@@H:29]([CH3:36])[CH2:30][CH:31]([CH2:34]O)[CH2:32][OH:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:33][CH2:32][C@H:31]([CH2:30][C@H:29]([CH3:36])[C@:28]([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[F:20])([OH:43])[CH2:37][N:38]4[CH:42]=[N:41][CH:40]=[N:39]4)[CH2:34][O:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](CC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](C[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as described in Example 1(2), a reaction was carried out using 4′-cyano-4-formylbenzanilide (78 mg, 0.31 mmol) obtained in Example 2(1), (4S,5R)-5-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-methyl-6-(1H-1,2,4-triazol-1-yl)-1,5-hexanediol (disclosed in Japanese Patent Application Publication No. Hei-11-80135: 100 mg, 0.29 mmol) and p-toluenesulfonic acid monohydrate (99 mg, 0.52 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to give the trans isomer of the title compound (100 mg, yield 59%) as a white solid and the cis isomer (23 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:2][NH2:3])=[O:17]
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Temperature: 60 °C
Yield: 92 %

Procedure:
Hydrazine hydrate (2 ml) is added dropwise to a suspension of methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate (227.1 mg, 0.73 mmol) in 10 ml of methanol. The reaction mixture is heated at 60° C. for seven hours under an atmosphere of nitrogen and then allowed to cool to room temperature overnight. The now clear colorless solution is concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (gradient of 1:2 to 1:1), providing 208.6 mg (92%) of a white solid, mp 158°-160° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Cl:13][CH2:14][C:15]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To an ice-cooled solution of pyrrolidine (0.4 g, 5.62 mmol) in dichloromethane (4 mL), triethylamine (1.176 mL, 8.44 mmol) and chloroacetyl chloride (0.451 mL, 5.62 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was concentrated in vacuo and residue was purified by column chromatography to give title compound (0.5 g, 60.2%); MS: 147.10 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].Cl[CH2:27][C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH2:7][CH:6]([CH2:27][C:28]2[CH:32]=[C:31]([CH3:33])[O:30][N:29]=2)[C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17]
Reactant: Cc1cc(CCl)no1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(Cc2cc(C)on2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (230 mg, 1 mmol), purged with nitrogen and anhydrous THF (5 ml) added. The resulting solution is cooled to −78° C. and lithium diisopropylamide (1.8M solution in hexane/THF/ethyl benzene) (0.61 ml, 1.1 mmol) is added dropwise and the reaction stirred at −78° C. for a further 30 minutes. A solution of 3-chloromethyl-5-methyl isoxazole in THF (1 ml) is then added in one portion, and the reaction is allowed to warm to ambient temperature and stirred for a further 2 hours. The reaction is quenched by the addition of saturated ammonium chloride solution (20 ml), and extracted with ethyl acetate (2×20 ml). The combined organics are evaporated under reduced pressure and the residue is purified by flash chromatography to give 3-methoxy-5-(5-methyl-isoxazol-3-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (132 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[CH2:21](O)[CH2:22][CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])(=[O:10])=[O:11]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Reactant: OCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCCO)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A solution of 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (177 mg, 0.60 mmol, as prepared in step b of example 8), 1,4-butanediol (0.53 mL, 6.0 mmol), triphenylphosphine (316 mg, 1.2 mmol), and anhydrous tetrahydrofuran (4 mL) was cooled to 0° C., then diethyl azodicarboxylate (0.20 mL, 1.2 mmol) was added dropwise over 5 minutes. The solution was stirred at 0° C. for 15 min and then at ambient temperature overnight. Additional triphenylphosphine (3×320 mg) and diethyl azodicarboxylate (3×0.20 mL) were added over the next 3 days. The mixture was filtered, and the filtrate was concentrated. The residue was triturated with 40% ethyl acetate in hexane, then the mixture was filtered and the filtrate was concentrated. Crude product was purified by flash column chromatography through silica gel (40% to 70% ethyl acetate in hexane, then 0% to 2% acetone in dichloromethane in a separate chromatographic separation) to give the title compound as a colorless oil (85.4 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 7.83 (dd, 1H, J=1.8, 7.9 Hz), 7.61 (ddd, 1H, J=1.7, 7.4, 8.4 Hz), 7.08 (d, 1H, J=8 Hz), 6.99-7.04 (m, 1H), 6.57 (br s, 1H), 6.50 (br s, 1H), 6.44 (t, 1H, J=2.2 Hz), 4.02 (s, 3H), 3.88 (t, 2H, J=6.0 Hz), 3.70 (q, 2H, J=6 Hz), 2.24 (s, 3H), 1.65-1.87 (m, 4H), 1.45 (t, 1H, J=6 Hz).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CS(O[CH2:24][C:25]1([CH2:28][N:29]2[C:34](=[O:35])[C:33]([CH3:36])=[CH:32][N:31]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:30]2=[O:44])[CH2:27][CH2:26]1)(=O)=O>>[CH2:37]([N:31]1[CH:32]=[C:33]([CH3:36])[C:34](=[O:35])[N:29]([CH2:28][C:25]2([CH2:24][N:14]3[CH2:15][CH2:16][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]3)[CH2:27][CH2:26]2)[C:30]1=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CC2(COS(C)(=O)=O)CC2)c1=O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC2(CN3CCN(c4ccccc4OCC(F)(F)F)CC3)CC2)c1=O

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethyl methanesulfonate gave 1-benzyl-3-(1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-ylmethyl}cycloprop-1-ylmethyl)-5-methyl-2,4(1H,3H)-pyrimidinedione as an oil;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:16]2[CH:17]=[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:19](COCC[Si](C)(C)C)[C:15]=2[C:14](=[O:33])[N:13]([CH3:34])[N:12]=1.[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:34][N:13]1[C:14](=[O:33])[C:15]2[NH:19][C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:17][C:16]=2[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[O:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:12]1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cc2c(-c3cc([N+](=O)[O-])ccc3F)nn(C)c(=O)c2n1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccccc3)nn(C)c(=O)c2[nH]1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A mixture of Example 74f (0.26 g, 0.53 mmol), phenol (0.060 g, 0.64 mmol) and cesium carbonate (0.21 g, 0.63 mmol) in dimethylsulfoxide (5 mL) was heated at 110° C. for 6 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was then treated with 15 mL of ethanol and 1 mL of concentrated H2SO4. The mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40-80% ethyl acetate to afford 0.14 g (61%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[S:65][C:64]([NH2:66])=[N:63][C:62]=2[CH3:67])=[CH:57][C:56]=1[S:68]([CH3:71])(=[O:70])=[O:69]>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23](=[O:25])[NH:66][C:64]1[S:65][C:61]([C:58]2[CH:59]=[CH:60][C:55]([Cl:54])=[C:56]([S:68]([CH3:71])(=[O:70])=[O:69])[CH:57]=2)=[C:62]([CH3:67])[N:63]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCOCCOCCOCCOCCNC(=O)OC(C)(C)C)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
3-(2-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid (690 mg 1.9 mmol), EDAC (403 mg 2.1 mmol), HOBT (284 mg 2.1 mmol), NMM (420 uL 3.8 mmol) and 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (520 mg 1.7 mmol) were combined in dimethylformamide (16 ml) and stirred over night at room temperature. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (150 ml), washed with 1M HCl aqueous solution (50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml), dried (Magnesium sulphate), filtered and evaporated. The residue was purified by flash chromatography using 50 g IST silica flash cartridge eluting with 0-2% methanol/dichloromethane to yield (2-{2-[2-(2-{2[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylcarbamoyl]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl)-carbamic acid tert-butyl ester as an oil (1.1 g residual solvent present) 1H NMR (400 MHz CDCl3) 10.3 (br s, 1H), 8.2 (s, 1H), 7.6 (m, 2H), 7.2 (br s, 1H), 3.9 (t, 2H) 3.8-3.5 (br m, 14H), 3.3 (br m, 5H), 2.8 (t, 2H), 2.4 (s, 3H), 1.4 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@H:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C@H:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36]
Reactant: CC(=O)OCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Temperature: 70 °C
Yield: 89.5 %

Procedure:
A mixture of (3S)-1-(2-acetoxyethyl)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (1.80 g) and potassium carbonate (0.30 g) in 85% aqueous ethanol (30 ml) was heated at to 70° C. for 1 hour under stirring. After cooling, ethanol was removed under reduced pressure, and to the residue was added water. The aqueous mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Removal of the solvent afforded a light yellow amorphous powder, which was chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (3:1). The fractions containing the desired product were combined and evaporated to give (3S)-1-(2-hydroxyethyl)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (1.47 g) as a colorless amorphous powder.
Reaction SMILES: C(Cl)(=O)C.[C:5]1([CH2:15][C:16]([OH:18])=[O:17])([CH2:11][C:12]([OH:14])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[C:5]12([CH2:11][C:12](=[O:14])[O:18][C:16](=[O:17])[CH2:15]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Solvent: CC(=O)Cl
Product: O=C1CC2(CCCCC2)CC(=O)O1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Acetyl chloride (35 ml, 492 mmol) was added to 1,1-cyclohexanediacetic acid (25 g, 125 mmol) in a round bottom flask and the suspension was heated for 3 hrs. at 0° C. using an oil bath. After about 15 min. the suspension became clear. The reaction was attached to a short path condenser and was heated to 100° C. under vacuum to remove volatile by products. 1HNMR indicated no starting diacid and GC indicated >99% purity. Upon cooling to room temperature the anhydride solidified. 1H-NMR (CDCl3): δ62.65(s,4H); 1.45(m,10H).