Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[CH2:59][CH2:58][NH:57][CH2:56]2)=[CH:51][CH:50]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[CH2:59][CH2:58][N:57]([C:20](=[O:21])[CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:2]3=[O:1])[CH2:56]2)=[CH:51][CH:50]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 3,3-bis(4-fluorophenyl)pyrrolidine from Example 203A for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-6.86 (m, 18H), 4.27-3.98 (m, 4H), 3.55 (dq, J=6.7, 9.6, 3H), 3.41 (t, J=6.7, 1H), 2.82 (q, J=6.5, 2H), 2.50 (dt, J=6.8, 21.3, 2H); MS (DCI) m/z 537.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[OH:17].[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C1COCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:18](=[O:19])[O:17][C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
A solution of 4-amino-3′-nitro-biphenyl-3-ol (0.115 g, 0.5 mmol) in dry THF (2.5 mL) was treated with a solution of 1,1′-carbonyldiimidazole (0.098 g, 0.6 mmol) in dry THF (2.5 mL). The reaction mixture was stirred at room temperature under a blanket of nitrogen for 6 hours. A precipitate formed, was collected and washed with methylene chloride (50 mL) to give 6-(3-nitro-phenyl)-3H-benzooxazol-2-one (0.095 g, 74%) as a white solid: mp 280-281° C.; 1H-NMR (DMSO-d6) δ 11.7 (s, 1H), 8.43 (t, 1H, J=1.15 Hz), 8.2-8.13 (nm, 21), 7.79-7.72 (m, 2H), 7.59 (dd, 1H, J=8.08, 2.31 Hz), 7.21 (d, 1H, J=8.08 Hz), MS (ES) m/z 255([M−H]−, 100%); Anal. Calc. For C13H8N2O4: C, 60.94, H, 3.15, N, 10.93. Found: C, 59.95, H, 3.17 N, 10.77.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>C(OCC)(=O)C.CO>[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:32]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 47 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 47%; MS: m/z=506 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:21]1([SH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(N(CC)CC)C.O1CCOCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH2:17][CH:16]([S:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: SC1CCCCC1
Reactant: CC(=O)Oc1cc(N2C(=O)CCC2=O)ccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Oc1cc(N2C(=O)CC(SC3CCCCC3)C2=O)ccc1C(=O)O
Reaction time: 4 h

Procedure:
8.24 g. (0.03 mole) of 1-(3-acetoxy-4-carboxyphenyl)-pyrroline-2,5-dione are dissolved in 80 ml. of dioxane and 3.6 ml. (0.03 mole) of cyclohexane-thiol are added. Two drops of triethylamine catalyst are then added dropwise to the reaction mixture and the mixture is kept at 80°-90° C. for 4 hours. The solvent is distilled off in vacuo. As a residue an oily 1-(3-acetoxy-4-carboxy-phenyl)-3-cyclohexylthio-pyrrolidine-2,5-dione is obtained. The product is dissolved in a mixture of 30 ml. of glacial acetic acid and 30 ml. of acetic anhydride and under cooling with icy water and stirring 14.4 ml. (0.15 mole) of a 30% hydrogen peroxide solution are added dropwise. The cooling is ceased and the reaction mixture is allowed to warm up to 30° C. The mixture is the cooled again with icy water to 0° to 5° C. and stirred at this temperature for 5 hours. The reaction mixture is allowed to stand overnight. The next day the pure solution is poured on ice and the precipitated product is filtered and washed with water to remove acid. M.p.: 155°-158° C. Yield: 6.7 g. (52.9%). After recrystallization from 50% ethanol the product melts at 160°-161° C.
Reaction SMILES: CN[C:3](=O)[CH2:4]CC1C=CC2C(=CC=CC=2)C=1.[CH3:17][N:18]([C@@H:29]([C:41](=[O:55])[N:42]([CH3:54])[C@@H:43]([C:50](=[O:53])[NH:51][CH3:52])[CH2:44][C:45]1S[CH:47]=[CH:48][CH:49]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:19](=[O:28])/[CH:20]=[C:21](\[CH3:27])/[CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24].NC(C)(C)CC=CC(N(C)[C@@H](C(=O)N(C)[C@@H](C(=O)NCC(F)(F)F)CC1C=CC=CC=1)CC1C=CC2C(=CC=CC=2)C=1)=O>>[CH3:17][N:18]([C@@H:29]([C:41](=[O:55])[N:42]([CH3:54])[C@@H:43]([C:50](=[O:53])[NH:51][CH3:52])[CH2:44][C:45]1[CH:4]=[CH:3][CH:47]=[CH:48][CH:49]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:19](=[O:28])/[CH:20]=[C:21](/[CH3:27])\[CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24]
Reactant: CNC(=O)CCc1ccc2ccccc2c1
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(\C)CC(C)(C)N
Agent: CN(C(=O)C=CCC(C)(C)N)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(/C)CC(C)(C)N

Procedure:
(2R)-2-(N-[{2-Amino-2-methylpropoxy}acetyl]-N-methylamino)-N-((1R)-1-dimethylcarbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)propionamide: ##STR93## 2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide, and its acetate salt;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].F[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C=O)C>[C:20]1([CH2:19][O:18][C:16]2[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 120 °C
Yield: 73.2 %

Procedure:
Potassium carbonate (3.21 g, 23.2 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in DMF (30 mL) followed by addition of 1-fluoro-4-(methylsulfonyl)benzene (2.02 g, 11.6 mmol) and the reaction was heated at 120° C. for 3 h. The solvent was then removed in vacuo and the residue was taken up in saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with 1M aqueous hydrochloric acid (50 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (3.50 g, 73%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>ClCCl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[C:27]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
To tert-butyl piperazine-1-carboxylate (1.39 g, 7.46 mmol) and diisopropylethylamine (1.955 mL, 11.19 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.196 mL, 7.46 mmol) dropwise. The reaction was stirred overnight. Thin layer chromatography indicated formation of a new product (hexanes/ethyl acetate 1:1). The reaction was diluted with dichloromethane (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[N:12]=[C:13]([C:17]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16].[H-].[Na+].Br[CH2:30][C:31]#[N:32]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[N:12]=[C:13]([C:17]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:30][C:31]#[N:32])[CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16]
Reactant: N#CCBr
Reactant: COc1cc(Cl)c(-c2nc(C3(c4ccccc4O)CC3)sc2C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nc(C3(c4ccccc4OCC#N)CC3)sc2C)cc1C
Reaction time: 0.5 h

Procedure:
2-{1-[4-(2-Chloro-4-methoxy-5-methyl-phenyl)-5-methyl-thiazol-2-yl]-cyclopropyl}-phenol (Example 126) (15 mg, 0.04 mmol) was dissolved in tetrahydrofuran (THF) (1 ml), treated with 1.1 mg NaH (0.044 mmol) at room temperature and stirred for 30 min. Bromoacetonitrile (5.5 mg, 0.044 mmol) was then added to the reaction vessel. The reaction mixtures was stirred overnight. The reaction mixture was quenched with 0.5 ml water and the THF removed in vacuo The residue was partitioned between ethyl acetate and water and the organic solution was separated and concentrated in vacuo then dissolved in methanol/dimethylsulfoxide (DMSO) 1:1 and purified via reversed phase HPLC chromatography (vide supra). Yield 11.5 mg (68%). [MH]+ 425.0, 427.0.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSC(=S)NCCO
Solvent: O
Solvent: c1ccncc1
Product: CSC(=S)NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (7.5 g) in pyridine (40 ml) is added triphenylmethyl chloride (15 g), and the mixture is left to stand overnight at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with diluted hydrochloric acid and water, dried and concentrated to remove the solvent. The residue is crystallized from a mixture of dichloromethane and ether to give N-(2-triphenylmethoxyethyl)dithiocarbamic acid methyl ester (14.73 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[S:16](Cl)(Cl)(=[O:18])=[O:17]>ClCCl>[S:16]1(=[O:18])(=[O:17])[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][O:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: OCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1(=O)OCC2CCCCN21
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a −78° C. hazy solution under a nitrogen atmosphere of racemic 2-piperidinemethanol (0.576 g, 5.00 mmol) and triethylamine (1.42 mL, 10.0 mmol) in anhydrous dichloromethane (30 mL) was added a solution of sulfuryl chloride (0.41 mL, 5.06 mmol) in anhydrous dichloromethane (30 mL) and the reaction was stirred for around 18 h from −78° C. to ambient temperature. The clear, yellow solution was washed with 1.0N HCl (2×25 mL) and brine (25 mL), dried over Na2SO4, concentrated in vacuo to a dark yellow oil, and purified by flash column chromatography (silica gel, ether) to afford the title product as a clear yellow oil (0.342 g, 39%). The proton NMR was identical to the desired product in procedure A, step 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:13][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([CH3:12])[CH:10]=2)[CH:5]=[CH:6][N:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(=O)[nH]ccc2cc1F
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(OCc3ccccc3)nccc2cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
6-Fluoro-7-methyl-2H-isoquinolin-1-one (prepared as described in WO2007012421, 13.2 g, mmol) was dissolved in tetrahydrofurane (175 mL). After addition of silver carbonate (41.2 g), benzyl bromide (15.3 g) was added dropwise. The mixture was stirred overnight. The mixture was heated to 70° C. and another 3 mL of benzyl bromide were added. Heating was continued until no further conversion was observed. The mixture was taken up in ethyl acetate, filtered over celite, evaporated and the residue was taken up in little ethyl acetate. The formed precipitate was filtered off to give 3.0 g of (2). The mother liquor was concentrated and chromatographed on silica gel to yield another 8.6 g of (2). Rt=4.00 min (Method 2). Detected mass: 268.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl.C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)ccc2o1

Procedure:
A solution of 2-amino-4-fluorophenol (4.0 g), carbonyldiimidazole (1.7 g) in DCM (100 ml) and acetonitrile (30 ml) was stirred at RT for 5 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 30% ethylacetate/isohexane, yield 4.0 g.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (315 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (717 mg, yield: 91%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:33]([CH3:36])=[C:34]=[O:35]>O1CCOCC1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:34]([NH:33][CH3:36])=[O:35])[C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN=C=O
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: C1COCCO1
Product: CNC(=O)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 1 part of isocyanatomethane and 25 parts of 1,4-dioxane is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-N-methyl-2-oxo-1H-benzimidazole-1-carboxamide; mp. 153.1° C.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C=NN2[CH2:27][CH2:26][N:25]([CH2:28]CCCI)[C:24]2=O)C=CC=CC=1.[H-].[Na+].CN(CCCl)C>CN(C)C=O.O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][N:25]([CH3:28])[CH3:24])[C:10]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Reactant: O=C1NCCN1N=Cc1ccccc1
Agent: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A solution of 1-phenylmethyleneamino-2-imidazolidinone (prepared as described in Part II of Example A (14.4 g, 0.076 mole) in dry dimethylformamide (338 ml) is stirred and treated portionwise over a 3 minute period with sodium hydride (60% dispersion in mineral oil) (3.0 g, 0.023 mole). During the addition, a nitrogen sweep is maintained. After the addition is complete, the reaction is heated on a steam bath for 15 minutes and then chilled to ambient temperature. The nitrogen sweep is discontinued and the reaction mixture is treated all at once with dimethylaminoethyl chloride (17.66 g, 0.16 mole), prepared as described in Part I herein. The reaction is stirred at ambient temperature for 15 minutes and then heated at 80° to 90° C. for 3 hours. The reaction is filtered hot, and the filtrate is chilled and concentrated under reduced pressure to leave an oily residue. The residue is treated with 300 ml of water and extracted with 3×300 ml portions of chloroform. The extracts are combined and dried over anhydrous MgSO4. The extract is filtered and the filtrate is concentrated under reduced pressure to leave a tan-colored semi-solid. The semi-solid is triturated with anhydrous ether to give the 1-phenylmethyleneamino-3-[2-(dimethylamino)ethyl]-2-imidazolidinone, weighing 6.17 g.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14][NH:15][CH3:16].C1COCC1>C(Cl)Cl>[CH3:14][N:15]([CH3:16])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of 3-(chlorosulfonyl)benzoic acid (152 mg, 0.689 mmol) in methylene chloride (2 mL) was treated with 2.0 M dimethylamine in THF (1.137 mL, 2.274 mmol), and the mixture was stirred overnight at room temperature. The reaction was quenched with 1 N HCl, and extracted 3× with EtOAc. The combined organic phases were washed with 1 N HCl followed by brine, then dried over sodium sulfate and concentrated in-vacuo to yield the title compound (138 mg, 0.602 mmol, 87% yield). MS (ESI+)=230.18, (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1>>[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Product: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1

Procedure:
The title compound was prepared following the procedure described in Step B of Example 3 from benzenesulfonyl chloride and 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, prepared of Preparation 44. 1H NMR (400 MHz, CDCl3)δ7.84 (d, 2H), 7.58-7.47 (m, 3H), 7.17 (m, 1H), 7.06 (m, 1H), 6.99 (m, 2H), 4.62 (m, 1H), 4.10 (d, 2H), 3.84 (s, 3H), 2.84 (t, 2H), 2.53 (t, 2H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12]1.Cl>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([CH3:14])[CH2:12][C:11]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC1CC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1ccc(Cl)cc1
Temperature: 23 °C

Procedure:
To a solution of 40 g (1 mol) sodium hydroxide in 400 ml water was added 128.6 g (1 mol) 4-chlorophenol and the reaction was heated at reflux for 15 minutes. To the refluxing solution was added 81.5 g (1 mol) of beta-butyrolactone dropwise over 1 hour. The reaction was cooled to 23° C., acidified with 100 ml concentrated hydrochloric acid and extracted with 2×500 ml diethyl ether. The ether layers were combined and extracted with 5×300 ml saturated aqueous sodium bicarbonate solution. The bicarbonate extracts were combined, acidified by slow dropwise addition of 160 ml concentrated hydrochloric acid and extracted with 250 ml diethyl ether. The latter ether extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the product as a white solid, 24 g (11%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.BrC1C=CC(CN)=CC=1.N.Cl>O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cccc2cnccc12
Agent: Cl
Agent: N
Agent: NCc1ccc(Br)cc1
Solvent: O
Product: CC(NC(=O)Cc1cccc2cnccc12)c1ccc(Br)cc1

Procedure:
The title compound was prepared using the procedure described in Example 132C using the product from Example 133B and 1-(4-bromophenyl)ethanamine instead of the product from Example 132B and 4-bromobenzylamine. 1H NMR (300 MHz, d6-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 840 (d, 1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d, 2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS (DCI/NH3) m/e 369 (M+H)+; Anal. Calcd. For C19H17N2OBr. 1.0 HCl. 1.0 H2O: C 53.86; H 4.76; N 6.61. Found: C 53.47; H 4.53; N 6.76.