Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[C:9](=[CH:12][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: C1COCCN1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Solvent: Cc1ccccc1
Product: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Yield: 89 %

Procedure:
To a solution of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (2.0 g, 10.2 mmol) in dry toluene (8.1 mL), morpholine (1.0 mL, 1.0 g, 11.3 mmol) was added. The reaction mixture was heated under reflux for 2 h. On cooling a brown precipitate formed. The solvent was removed under vacuum and the brown solid residue was fractionated by flash column chromatography (20% EtOAc:hexane) to leave a yellow solid that was purified further by crystallisation from EtOH to afford the pure title product as yellow crystals (2.4 g, 87%): mp 186-187° C. Anal. RP-HPLC: tR 12.7 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 7.50 (s, 1H, CH), 3.80 (t, 4H, J 4.6), 3.55 (t, 4H, J 4.6), 3.00 (m, 4H, CH2—CH2), 2.80 (s, 3H, CH3). 13C-NMR (CDCl3): δ 182.0, 171.6, 162.3, 147.9, 133.2, 103.3, 67.0, 51.4, 26.7, 24.9, 20.2. MS (ESI+): m/z 287.05 (M+Na)+, 265.07 (M+H)+. Anal. (C13H16N2O2S)C, H, N.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N+:19]([CH2:23][CH3:24])[C:18]=2[CH:25]=1.CC(C)=O.[C:32]([O:35][CH2:36][CH3:37])(=O)[CH3:33]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[F:27][C:13]([F:12])([F:26])[C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH:22]=[C:36]3[CH:37]=[C:5]([CH3:4])[C:6]4[C:32](=[CH:33][CH:3]=[CH:2][CH:1]=4)[O:35]3)=[N+:19]([CH2:23][CH3:24])[C:18]=2[CH:25]=1
Reactant: CCOC(C)=O
Reactant: CC[n+]1c(C)sc2ccc(C(F)(F)F)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(C)=O
Product: CC[n+]1c(C=C2C=C(C)c3ccccc3O2)sc2ccc(C(F)(F)F)cc21
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 46 %

Procedure:
2.37 g of 5-trifluoromethyl-3-ethyl-2-methylbenzothiazolium p-toluenesulfonate and 1.0 g of 4-methylcoumarin-2-thione were reacted under heat at 150° C. for 20 hours, and then 10 ml of metrhanol, 10 ml of acetone, and 20 ml of ethyl acetate were added to the reaction mixture in the order listed to obtain a uniform solution. After cooling to room temperature, crystals precipitated out therefrom. The crystals formed were separated by filtration and washed with a small amount of acetone, and thereafter the crystlas were placed in a mixed solvent comprising 10 ml of methanol, 10 ml of acetone, and 20 ml of ethyl acetate at room temperature, and stirred for 40 minutes. Then, the crystals were again taken out by filtration and washed with acetone, at last to obtain 1.47 g of the desired p-toluenesulfonate product. Yield: 46%. Appearance: brown crystal. M.P.: 272°-273° C. (decomposition).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.N1C=CC=CC=1.[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20]>CN(C)C=O>[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)=[O:20]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)Nc1nc(CCl)cs1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (5 g), anhydrous pyridine (5 ml) and anhydrous N,N-dimethylformamide (25 ml) was slowly added 3,3-dimethylbutyryl chloride (4.4 g) with stirring at 0° to 3° C. After an hour of stirring, the reaction mixture was poured into ice water. The resulting precipitate was collected, washed with water and dried to give 2-(3,3-dimethylbutyrylamino)-4-chloromethylthiazole (6.62 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)sc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (0.95 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.85 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.06 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.83 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[N:9]([CH2:27][CH2:28][CH2:29][C:30]#[N:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])=[CH:12][CH:11]=2)=[O:7])[CH:2]([CH3:4])[CH3:3].[N:32]([Si](C)(C)C)=[N+:33]=[N-:34].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:6]([C:8]1[N:9]([CH2:27][CH2:28][CH2:29][C:30]2[NH:34][N:33]=[N:32][N:31]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])=[CH:12][CH:11]=2)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)CNC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)CNC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 37.5 %

Procedure:
To a solution of 1-(3-cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid isobutyl amide (0.076 g, 0.17 mmol) in toluene (10 mL) was added azidotrimethylsilane (0.066 mL, 0.50 mmol) and dibutyltin oxide (0.012 g, 0.050 mmol). The reaction mixture was heated to reflux and stirred under argon at reflux temperature for 40 h. The solution was then cooled and the toluene removed under reduced pressure. Methanol was added and removed under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) yielded a white solid (0.032 g, 38%). MS(ES) m/e 501.2 [M +H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ncccc1CCOc1cccc2[nH]c(C(=O)O)cc12
Product: COc1ncccc1CCOc1cccc2[nH]c(C(=O)NC3CCC(O)(CCN4CC[C@H](O)[C@@H](C)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(2-methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid 16m and amine 14.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.CN1C(=O)CCC1.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][Mg]Cl)=[CH:28][CH:27]=1.[Cl-]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([CH2:25][C:26]3[CH:34]=[CH:33][C:29]([CH3:30])=[CH:28][CH:27]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
A 25-mL round bottom flask, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (318 mg, 1.20 mol, 1.0 eq.) and Fe(acac)3 (6.6 mg, 19 mol, 0.05 eq.), NMP (0.4 mL) and THF (4.0 mL). The mixture was cooled to 0° C. under nitrogen. A solution of 4-methylbenzylmagnesium chloride (0.83 mL, 0.5M in THF, 0.41 mmol, 1.1 eq.) was added dropwise over 2 minutes. The resulting mixture was stirred 0° C. for 1.5 hr until the starting chloride was consumed. The reaction was quenched with a 9:1 sat. NH4Cl/conc. NH4OH solution (10 mL) then diluted with ethyl acetate (75 mL). The organic layer was washed with sat. sodium chloride (3×5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (175 mg) was purified by chromatography on silica gel using dichloromethane as the eluent, to afford 2-(3-chlorophenyl)-4-(4-methylbenzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (65 mg, 52% yield) as a white solid. MW=334.84. 1H NMR (DMSO-d6, 500 MHz) δ 8.35-8.30 (m, 2H), 7.58-7.51 (m, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 2.06 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([OH:39])=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.40 g) and chloroform (10 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (20 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added ethyl acetate and water. The aqueous layer was separated, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and diethyl ether was added to the residue for solidification, followed by washing with diethyl ether and a 50% aqueous methanol solution. Further, it was purified by silica gel column chromatography (0→2% MeOH/chloroform), and the obtained solid was washed with a 50% aqueous methanol solution to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (0.25 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]4)[CH:24]=3)[CH2:20][C:19](=[O:38])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M19) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (34 mg).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:3](=[O:5])[O:4][C:14](=[O:16])[NH:1]2)=[CH:7][CH:8]=1
Reactant: NC(C(=O)O)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)cc2)C(=O)O1
Temperature: -20 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 2-amino-2-(4-fluorophenyl)acetic acid (5 g, 29.5 mmol) in THF (50 mL) at 50° C. was added triphosgene (8.77 g, 29.5 mmol), then heating was continued for 3 h. The reaction mixture was then filtered and evaporated to a volume of about 10 mL, followed by addition of 150 mL of hexanes. The mixture was heated slightly, and then cooled to −20° C. for 1 h. The crude slurry was filtered to give 4-(4-fluorophenyl)oxazolidine-2,5-dione (5.03 g, 87%) which was used without further purification.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[OH:6]>C(OCC)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[CH2:4][O:6]2)=[CH:8][CH:9]=1
Reactant: O[C@H](CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Brc1ccc([C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.5 %

Procedure:
Aqueous sodium hydroxide (1M, 400 ml) was added to 2-bromo-(1S)-1-(4-bromophenyl)ethanol (77.0 g) in diethyl ether (400 ml) and stirred at room temperature for 5 hours. The organic layer was separated and aqueous layer was extracted with ether. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent yielded (2S)-2-(4-bromophenyl) oxirane (55.0 g) as a pale brown oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH2:17]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH2:16][S:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCCCCSCCSCCCCCCCCCCCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCSCCSCCCCCCCCCCCCO
Temperature: 30 °C
Reaction time: 4 h

Procedure:
Ethylenedithio-bislauryl alcohol was prepared as the final intermediate as ethylenedithio-bislauric acid methyl ester (8 g) was dissolved in dry THF at 0° C. (ice bath). Lithium aluminum hydride (1.16 g) was added to the flask slowly. Hydrogen was generated, and the reaction temperature was gradually raised to 30° C. After stirring for 4 hours, the reaction was quenched by pouring the solution thus formed into ice water. The aqueous solution was neutralized by adding concentrated HCl, and the crude product was then extracted with ethyl acetate three times. After evaporating the solvents, the compound (7.0 gm) was dried under vacuum and analyzed by NMR. NMR data agrees with the expected structure of the final product as set forth in the reaction summary below.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:10]([NH:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600 mL of CH2Cl2 was added 2.0 eq. of phenethylamine (Aldrich) dropwise. The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory and extracted with CH2Cl2. The organic extracts were washed with water and 1N HCl, and then dried over Na2SO4, filtered and concentrated to give N-phenethyl benzamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:32][NH2:33]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:30][CH3:31])=[CH:19][C:20]([CH:27]4[CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:32][NH2:33])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: CCO
Product: CCc1cc(C2CC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a round-bottom flask was added a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate (compound 228.1, 830 mg, 1.99 mmol, 1.00 equiv) in ethanol (15 mL). Hydrazine (5 mL, 100 equiv) was added to the reaction. The resulting solution was stirred for 15 h at 100° C., then concentrated in vacuo. The residue was extracted with 100 mL of dichloromethane and the combined organic layers were washed with 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 0.800 g (96%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[S:20]1[C:24](B(O)O)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[S:20]1[C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=3)[N:4]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1ccc2c(c1)c(-c1cc3ccccc3s1)nn2C1CCCCO1
Yield: 25.5 %

Procedure:
A mixture of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (425 mg, 1.31 mmol), benzo[b]thiophene-2-boronic acid (348 mg, 1.95 mmol, 1.49 equiv.), [1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladium (II) complex with dichloromethane (107 mg, 0.131 mmol, 0.10 equiv.), potassium phosphate (K3PO4, 1.38 g, 6.50 mmol, 4.96 equiv.) and 6.5 mL of DME were refluxed for 18 h and concentrated. Purification by silica gel chromatography using 0–5% MeOH in EtOAc as eluent afforded the title compound (126 mg, 26% yield): ES-MS (m/z) 378 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[S:36][CH:37]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[N:39]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:35]2[S:36][CH:37]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[N:39]=2)[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1csc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of 136 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 64 mg of methyl 2-bromo-1,3-thiazole-4-carboxylate, and 38 mg of potassium carbonate was added 1.5 mL of DMSO at room temperature, and the mixed solution was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 113 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylate as a colorless foamy substance. ESI+: 586
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:37]1([CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:40]3[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47])[CH2:38][CH2:39]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and N-(2-piperazin-1-yl-ethyl)-acetamide hydrochloride (example 23) in an analogous manner as described in example 25. LR-MS: 664.5 [(M+H)+]
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:20][C:14]=2[N:13]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:30]1[CH:34]=[C:33]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:31]1>>[CH2:1]([O:8][CH2:9][C@H:10]([NH:11][C:36](=[O:37])[CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:20][C:14]=2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Yield: 39 %

Procedure:
Proceeding as in Example 1, but substituting (R)-2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethanamine and 4-imidazoleacetic acid hydrochloride gave Compound 59, (R)—N-(2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethyl)-2-(1H-imidazol-4-yl)acetamide (75 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.33-7.25 (m, 5H), 7.20-7.16 (m, 3H), 7.00-6.96 (m, 3H), 6.89 (dd, J=8.8, 2.0 Hz, 1H), 5.35-5.30 (m, 1H), 4.52 (s, 2H), 3.95-3.84 (m, 2H), 3.56-3.46 (m, 2H); ESI MS: m/z 486.2 (M+1).