Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)CCC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 24 h
Yield: 70.3 %

Procedure:
The intermediate (S)-ethyl 4-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-4-oxobutanoate (124 mg, 0.25 mmol) was dissolved in THF (4 mL) and treated with LiOH (12 mg, 0.5 mmol) in water (1 mL) and stirred for 24 h. The reaction mixture was evaporated to half-volume, diluted with water (5 mL) and the pH adjusted to pH ˜7 with a 1 N solution of hydrochloric acid. The resulting precipitate was filtered with the aid of water and air dried to afford the title compound as a solid (82 mg, 70%). LC/MS (Method A) 6.72 min, [M+1]+ 467.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[N+:29]([O-])=O)=[CH:17][CH:16]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[NH2:29])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)ccc1Nc1ccccc1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
Potassium carbonate (13 g) and sodium hydrosulphite (11.4 g) were added portionwise over 3 hour to a suspension of 4-chloro-2-nitrodiphenylamine (3.6 g) in 95% ethanol (100 ml) and water (100 ml). The mixture was stirred at 23° for 20 h. The reaction mixture was then acidified to pH=4 with conc. hydrochloric acid (20 ml); then 10% solution of sodium hydroxide (80 ml) was added until pH=10 and the solution extracted with ethyl acetate (2×150 ml). The combined organic extracts were washed with brine (2×150 ml), dried and concentrated in vacuo to give the crude compound as a yellow solid (7.8 g) which was purified by flash chromatography (eluting with CH-EA 90:10 then 70:30) to give the title compound as a yellow foam (2.37 g). T.l.c. CH-EA (1:1), Rf 0.66.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([NH2:15])=[CH:7][CH:6]=1.[N:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=2)[CH:20]=1>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]1[C:10]([C:11]([F:13])([F:14])[F:12])=[CH:9][C:8]([NH:15][C:35](=[O:36])[CH2:34][C:31]2[CH:30]=[CH:29][C:28]([N:21]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:27]4[N:19]=[CH:20]3)=[CH:33][CH:32]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 but using 3′-bromo-2-trifluoromethyl-biphen-4-ylamine and (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid. Title compound: ES-MS: 552.8 [M+H]+; tR=5.24 min (System 1); Rf=0.20 (CH2Cl2/MeOH, 96:4).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C-:13]#[N:14].[K+]>>[C:13]([C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([OH:4])[C:2]([F:11])([F:12])[F:1])#[N:14]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: [C-]#N
Agent: [K+]
Product: N#CC(O)(c1ccccc1)C(F)(F)F

Procedure:
1-Cyano-1-phenyl-2,2,2-trifluoroethanol was prepared from α,α,α-trifluoroacetophenone by a cyanohydrin reaction with potassium cyanide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][C:23]([CH:30]=O)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:24][C:23]([CH2:30][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1C(C)(C)C
Yield: 77.7 %

Procedure:
Compound 77 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(F)(F)F)C2=O)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2,2,2-trifluoroethyl trifluoromethanesulfonate, to give the title compound as a white solid (19%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C(Cl)Cl>[CH3:18][NH:19][C:15]([C@H:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:17]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To (R)-1-(4-Nitro-phenyl)-pyrrolidine-2-carboxylic acid (Method 55; 1.8 g, 7.6 mmol) in DCM (50 ml) was added HATU (3.2 g, 8.4 mmol) and DIPEA (2.0 ml, 11.4 mmol). The reaction was stirred for 10 minutes before the addition of methylamine (2.0 N in THF, 5.0 ml, 15 mmol); the reaction was stirred for 1 hour before being quenched with water (50 ml). The reaction was extracted with DCM (3×100 ml), dried and solvent removed in vacuo to yield a yellow gum. Purification was achieved via column chromatography eluting with 20% EtOAc/isohexane, 60% EtOAc/isohexane and finally 100% EtOAc. The title compound was obtained as an orange gum; (1.4 g, 74%). NMR (299.954 MHz, CDCl3) 8.10 (d, 2H), 6.56 (d, 2H), 6.24 (s, 1H), 4.20 (t, 1H), 3.75 (t, 1H), 3.40 (q, 1H), 2.80 (d, 3H), 2.36-2.29 (m, 2H), 2.13-2.05 (m, 2H); m/z 250.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: C/C=C/CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (77 mg, 75%), MS (ISP) m/z=411.4 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9]C(=O)OCC)=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[F:18].Br>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[F:18]
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c(F)c1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Product: Nc1c(F)cc(Cl)c(F)c1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Ethyl 4-chloro-3,6-difluoro-2-nitrophenylcarbamate (XLI) (0.9 g, 3.2 mmol) was mixed with acetic acid (30 ml) and hydrobromic acid (48%, 25 ml), the mixture was stirred at 150° C. for 4 hr and then the volume reduced to half by evaporation Ethyl acetate (50 ml) was added and the solution was washed with water (15 ml×3) and dried over sodium sulfate. The product was purified by column chromatography (silica gel, hexane) (0.56 g). 1H NMR (CDCl3, 300 MHz) 5.73 (2H, br), 7.24 (1H, dd, J=6.1, 6.1 Hz) ppm.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+:22].[Na+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O-:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[Na+:22]
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 5.00 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 4.00 g of sodium carbonate, 20 ml of water and 60 ml of methanol was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was recrystallized from water to obtain 5.10 g of sodium 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter referred to as “the present compound 5”).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH2:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46]1([S:52](Cl)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC#N>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:37][S:52]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:54])=[O:53])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (Example 132, step C) (10 mg, 0.249 mmol) and triethylamine (51 mg, 0.5 mmol) in MeCN (5 mL) is added benzenesulfonyl chloride (44 mg, 0.249 mmol) and the mixture is stirred at RT for 2 h. The solvent is removed under reduced pressure and the residue partitioned between methylene chloride and 1N HCl. The organic phase dried over sodium sulfate and the solvent removed under reduced pressure. The residue is purified by flash chromatography using a gradient of 0-40% EtOAc/hexane as eluent to give the title compound: (M−1)−=700.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)c(F)cc(C(=O)O)c1F
Product: COc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
A mixture of 2,4,5-trifluoro-3-methoxybenzoic acid (154 mg, 0.75 mmol) and thionyl chloride (8 mL) is refluxed for 4 h. Excess thionyl chloride is removed in vacuo, and the remaining residue is used directly in the next synthetic step.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: CCCCCSCCCCCCCCCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(9-pentylthiononyl)thiochroman (230 mg, 0.435 mmol) in dry dichloromethane (20 ml) was added dropwise 1M solution of boron tribromide in dichloromethane (3.04 ml, 3.04 mmol) at -78° C. and stirred at the same temperature for one hour. Then the reaction mixture was warmed to room temperature and stirring was continued for additional 10 hours. The reaction mixture was quenched with water and then diluted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen sulfide solution and water, dried over magnesium sulfate, filtered and evaporated. The concentrate was subjected to flash silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 178 mg (yield: 82%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([O:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH3:29].CO>O>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:45]2[CH2:46][CH2:47][CH:42]([C:34]3[N:33]([CH2:32][CH2:31][O:30][CH2:28][CH3:29])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)[CH2:43][CH2:44]2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Reactant: CCOCCn1c(C2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OCC)cc3)CC2)nc2ccccc21
Yield: 89.9 %

Procedure:
In a reaction vessel, 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (3.2 g) prepared in the Example 8, sodium carbonate (1.1 g), 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole (3.0 g) prepared in the Example 12 and methylalcohol (30 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition. Distilled water (50 mL) was added thereto, and the mixture was stirred and crystallized. The crystals were filtered under reduced pressure, and washed with distilled water, and then dried to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid ethylester (4.5 g, yield 90%, HPLC purity 98.5% or more).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13]Cl)[C:6]=2[CH:15]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:20][CH2:21]3)[C:6]=2[CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCCCl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 5.6 parts of 6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.34 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The undissolved product is filtered off and crystallized from a mixture of N,N-dimethylformamide and water. It is filtered off again, boiled in methanol, filtered off while hot and dried, yielding 5.1 parts of 6-chloro-1,3-dihydro-1-{3-[4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-2H-benzimidazol-2-one; mp. 273° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.ClCCl.Cl.[CH3:19][NH:20][O:21][CH3:22]>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:20]([O:21][CH3:22])[CH3:19])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
[Step 1] 5.0 g of 2-chloronicotinic acid and 2.8 mL of thionyl chloride were dissolved in 60 mL of benzene and then refluxed while heating. Three hours later, after adding the reaction liquid to 50 mL of a separately prepared dichloromethane solution containing 4.6 g of N,O-dimethylhydroxyamine hydrochloride and 20 mL of pyridine while cooling with ice, the solution was stirred overnight at room temperature. Following completion of the reaction, the solution was concentrated under reduced pressure, and the resulting residue was purified by recrystallization (with a mixture of ethyl acetate and hexane) to obtain 5.1 g of 2-chloro-N-methoxy-N-methylnicotinamide in the form of pale yellow crystals (79%).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)(C)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][CH:2]=1)([O-:14])=[O:13]
Reactant: NCCCCc1nc[nH]c1Br
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC(C)O
Product: CSC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1

Procedure:
Reaction of 5-bromo-4-(4-aminobutyl)imidazole with 1-nitro-2,2-bis-methylthioethylene in the procedure of Example 8(i) yields 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene, m.p. 157°-158°, (from isopropanol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.C[O:46][C:47]([C:49]1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.C(OC1C=CC(B(O)O)=CC=1)C>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH3:49])=[CH:2][CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2ccc(OC)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 16 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-ethoxyphenylboronic acid (44 mg, 0.2625 mmol) to produce the title compound (17 mg, 16% yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30].[OH-].[Na+:33]>>[Na+:33].[CH3:30][C:7]1[CH:8]=[C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([O-:31])=[O:2]
Reactant: COC(=O)CCc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCC(=O)[O-]
Yield: 16.9 %

Procedure:
A solution of 3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionic acid methyl ester (0.06 g, 0.13 mmol) and 5M NaOH (0.35 mL, 1.75 mmol) is heated to 70° C. for 14 h. Upon cooling, the solid is filtered and dried in vacuo to yield the title compound (10 mg, 17%) as the sodium salt. MS (ES): 435 (M+); the structure is also confirmed by 1H NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH:10]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:11]([C:14](=[O:15])[C:21]3[CH:20]=[CH:19][S:18][C:17]=32)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2ccsc2C2CN(Cc3ccccc3)CCC12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of the product from step d) (2.9 g, 8.15 mmol) in CH2Cl2 (12 ml) was added dropwise to a slurry of AlCl3 (3.26 g, 24.5 mmol) in CH2Cl2 (28 ml) at 22° C. After 45 minutes, the reaction mixture was poured into ice cold 2 M NaOH (100 ml) and extracted with CH2Cl2 (300 ml). The organic extract was dried (MgSO4), solvent evaporated in vacuo, and residue purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 50% ethyl acetate) to give the subtitle compound (1.32 g, 57%). MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH2:32][CH2:33]Cl)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].[OH-].[K+].[I-].[K+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:33][CH2:32][CH2:31][S:30][C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][CH:26]=3)[CH:12]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Reactant: CC(=O)Nc1ccc(SCCCCl)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCCSc1ccc(NC(C)=O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 3.6 g of 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride, 3.4 g of 3-(p-acetamidophenylthio)propyl chloride, 3.8 ml of methanol, 12 ml of an aqueous solution containing 0.027 mole of potassium hydroxide and 0.2 g of potassium iodide is heated at reflux for 20 hr. The mixture is cooled and filtered to remove a small amount of inorganic material. Water, (75 ml) is added to the filtrate, and the methanol is removed by vacuum distillation. After the addition of 50 ml of methylene chloride the mixture is stirred for 30 min. and then filtered to obtain a crystalline product. After twice recrystallizing from 50% aqueous ethanol the product 2,4-diamino-5-{3'-[3"-(p-acetamidophenylthio)propoxy]-4'-methoxybenzyl}pyrimidine, weighes 1.94 g and has m.p. 175°-177°.