Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[F:34][C:33]([F:35])([F:36])[C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37])=[CH:13][CH:12]=3)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=2)=[CH:32][CH:31]=1
Reactant: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a mixture of 3-{4-[1-(4′-trifluoromethyl-biphenyl-4-yl)-hept-1-enyl]-benzoylamino}-propionic acid methyl ester (40 mg) in methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by 5 NHCl (0.5 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (30 mg). MS (ES): 508.3 [M+H]−.
Reaction SMILES: [CH3:1][C:2]([C@:4]1([OH:25])[C@@:8]2([CH3:24])[CH2:9][C@H:10]([OH:23])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:26]([O:23][C@H:10]1[CH2:9][C@@:8]2([CH3:24])[C@@H:7]([CH2:6][CH2:5][C@:4]2([OH:25])[C:2](=[O:3])[CH3:1])[C@H:12]2[C@H:11]1[C@:21]1([CH3:22])[C:15]([CH2:14][CH2:13]2)=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@]2(O)C(C)=O)[C@@H]2CCC3=CC(=O)CC[C@]3(C)[C@H]21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 4-pregnene-11β,17α-diol-3,20-dione (2) (2 g), acetic anhydride (10 ml), pyridine (20 ml) and 4-dimethylaminopyridine (20 mg) was stirred for 6 hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with chloroform. The chloroform layer was sequentially washed with 10% HCl, a 5% aqueous NaHCO3 solution, and brine, dried over Na2SO4, and concentrated. The residue was subjected to column chromatography (silica gel, 150 g) using 70% chloroform/hexane as eluant, thereby obtaining an acetylated derivative (3) (2.24 g, 100%). Recrystallization from ethyl acetate/hexane afforded white crystals having a melting point of 159.5°-160° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CO.C([BH3-])#N.[Na+]>C1COCC1>[CH:12]1([NH:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][O:3][CH3:2])[CH2:6][CH2:7]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC[C@H]1CC[C@H](N)CC1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H]1CC[C@H](NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of trans-4-methoxymethyl-cyclohexylamine hydrochloride (0.7 g), cyclohexanone (0.4 g), diisoropylethylamine (0.5 g) and molecular sieves (3 g) in THF (5 mL) and methanol (5 mL) was added sodium cyanoborohydride (0.49 g) and the mixture stirred overnight at room temperature. Insoluble material was removed by filtration and the crude product purified by flash chromatography to give cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine (0.29 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:47])([F:46])[C:9]1[CH:10]=[C:11]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[C:29]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=2)[N:15]=[N:14]1.O>C1COCC1>[F:47][C:8]([F:7])([F:46])[C:9]1[CH:10]=[C:11]([CH:39]=[C:40]([C:42]([F:43])([F:45])[F:44])[CH:41]=1)[CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[C:29]([CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[OH:31])=[CH:28][CH:27]=[CH:26][N:25]=2)[N:15]=[N:14]1
Reactant: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Add LiAlH4 (2.6 mL, 2.6 mmol, 1.0 M in THF) dropwise to a stirred solution of {2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanone (1.28 g, 2.18 mmol) in THF (20 mL, anhydrous) at RT. After 15 min, add water (2.6 mL) dropwise with rapid stirring to quench. Add 1N NaOH solution (2.6 mL) dropwise, followed by dropwise addition of water (7.8 mL). Filter out solids and rinse with THF. Concentrate, dissolve in CH2Cl2, wash with saturated NaHCO3 solution (2×), dry over MgSO4 and concentrate. Purify the solid by flash chromatography on silica gel eluting with 0-15% ACN/Et2O to afford the title compound (882 mg, 69%); MS(IS) 590 (M+1); TLC: Rf=0.32 (7.5% EtOH/CHCl3).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35]C)[C:6]([NH:8][C:9]1[S:10][C:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[N:13]=1)=[O:7].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[OH:35])[C:6]([NH:8][C:9]1[S:10][C:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)=[O:7]
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1ccc(O)c(O)c1
Yield: 66.7 %

Procedure:
A procedure similar to that in Example 7 was used. 3,4-dimethoxy-N-[4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-yl]-benzamide prepared in Example 28 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 66.7%, mp: 195-196 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.33 (2H, s, CH2), 6.74˜6.81 (3H, m, ArH), 7.37˜7.50 (6H, m, ArH), 8.16 (2H, d, J=8.80 Hz, ArH), 9.30 (1H, br, OH), 9.59 (1H, br, OH), 9.77 (1H, br, OH), 12.30 (1H, br, CONH); EI-MS m/e (%): 463.1 (M+, 1), 327.1 (100); HREI-MS Calcd. for C23H17N3O6S: 463.0838. found: 463.0822.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[CH2:9]([O:11][C:12](=[O:18])[CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[CH3:10].C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH2:13][C:14]([N:17]=[C:2]=[O:3])([CH3:16])[CH3:15])=[O:18])[CH3:10]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)N=C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of trichloromethyl chloroformate (4.1 g) in methylene chloride (15 ml) is slowly added to a stirred mixture of ethyl-3-amino-3-methylbutanoate (3 g), triethylamine (6.6 g) and methylene chloride (30 ml) at 5° C. The mixture is stirred overnight at room temperature, refluxed for 3 hours, cooled and anhydrous ether added thereto. The precipitated triethylamine hydrochloride is filtered and the filtrate evaporated to yield 2-ethoxycarbonyl-1,1-dimethylethylisocyanate as an oil (3.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:5]=[CH:6][CH:7]=[O:8]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C=CC=O)cc1O
Solvent: CO
Product: COc1ccc(CCC=O)cc1O
Temperature: 35 °C
Reaction time: 7 h
Yield: 78.4 %

Procedure:
3-Hydroxy-4-methoxycinnamaldehyde (8.66 g, 48.6 mmol) and 5% palladium-alumina (aluminum oxide) (0.540 g) were added to methanol (144 ml), and the mixture was stirred under hydrogen atmosphere of normal pressure (0.1 MPa) at 35° C. for 7 hours for reaction. The reaction solution was filtrated to remove the catalyst, and further the catalyst was washed with methanol (40 ml). The filtrate and the wash solution were combined together, and then concentrated. Thus concentrated solution was subjected to a purification process with a silica gel column chromatography (eluting solvent: toluene/ethyl acetate=4/1). The thus eluted fractions containing the object compound were concentrated under reduced pressure to obtain crude 3-(3-hydroxy-4-methoxyphenyl) propionaldehyde (6.86 g, 38.1 mmol, yield: 78%) in the slightly yellow coloured solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[C@@H:17]1([NH2:21])[CH2:19][C@@H:18]1[NH2:20]>>[C@@H:17]1([NH:21][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[C:4]([OH:3])=[O:5])[CH2:19][C@@H:18]1[NH:20][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: N[C@@H]1C[C@@H]1N
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Product: O=C(COc1cccc(C(=O)O)c1)N[C@H]1C[C@H]1NC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R36 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with 1,2-cis-cyclopropanediamine (CAS 365996-16-3). A white powder is obtained.
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[ClH:10]>CCCCCCC>[ClH:10].[CH3:1][NH+:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3]
Reactant: CN(C)C1CCCCC1
Agent: Cl
Solvent: CCCCCCC
Product: C[NH+](C)C1CCCCC1

Procedure:
15.08 g of N,N-dimethylcyclohexylamine and 700 ml of heptane were placed under argon in a 500 ml three-necked flask fitted with internal thermometer and gas inlet stopcock. HCl gas from a gas generation apparatus was passed into this reaction mixture for 1 hour. The N,N-dimethylcyclohexylammonium hydrochloride formed was separated off via a G4 frit, washed with 100 ml of heptane and dried in an oil pump vacuum. 19.0 g (98%) of the desired product were isolated.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:17][CH2:16][C:10]3([C:14](=[O:15])[NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(S(N2CCC3(C(=O)N(C4C=CC(C(O)C(F)(F)F)=CC=4)CC3)CC2)(=O)=O)CC1.[F:47][C:48]([F:60])([F:59])[C:49]([C:52]1[CH:57]=[CH:56][C:55](I)=[CH:54][CH:53]=1)([OH:51])[CH3:50]>>[CH:1]1([S:4]([N:7]2[CH2:17][CH2:16][C:10]3([C:14](=[O:15])[N:13]([C:55]4[CH:56]=[CH:57][C:52]([C:49]([OH:51])([CH3:50])[C:48]([F:59])([F:60])[F:47])=[CH:53][CH:54]=4)[CH2:12][CH2:11]3)[CH2:9][CH2:8]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C1NCCC12CCN(S(=O)(=O)C1CC1)CC2
Reactant: CC(O)(c1ccc(I)cc1)C(F)(F)F
Agent: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)C1CC1)CC2
Product: CC(O)(c1ccc(N2CCC3(CCN(S(=O)(=O)C4CC4)CC3)C2=O)cc1)C(F)(F)F

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(cyclopropylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one, product of example 170 A) and 1,1,1-trifluoro-2-(4-iodo-phenyl)-propan-2-ol). Pink crystalline solid. MS (ESI): 447.15 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[N:19]=1)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:20]2[N:19]=[C:18]([C:16]([OH:17])=[O:15])[CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3)cc2)n1

Procedure:
6-(Biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure B from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (intermediate 2). Yield: 68 mg. Mass spectrum (ES) MH+=306.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([OH:17])=[C:13]([C:18]([NH:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:19])[C:12]3=[O:27])=[CH:8][C:7]=2[CH3:30])[CH2:3][CH2:2]1.[OH-].[Na+:32]>C(O)C>[Na+:32].[CH:1]1([CH2:4][O:5][C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([OH:17])=[C:13]([C:18]([NH:20][CH2:21][C:22]([O-:24])=[O:23])=[O:19])[C:12]3=[O:27])=[CH:8][C:7]=2[CH3:30])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)C1=C(O)CCN(Cc2ccc(OCC3CC3)c(C)c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN2CCC(O)=C(C(=O)NCC(=O)[O-])C2=O)ccc1OCC1CC1
Reaction time: 0.25 h

Procedure:
To a solution in ethanol (37.8 mL) of the compound (1.97 g) obtained in step (1) above, 0.5 mol/L sodium hydroxide in aqueous solution (18.9 mL) was added under cooling with ice and the mixture was brought to room temperature at which it was stirred for 15 minutes. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by DIAION (registered trademark) HP20 column chromatography (with elution by methanol). The eluted fraction was concentrated under reduced pressure and to a solution of the resulting compound in water (2 mL), acetone (100 mL) was added and the mixture was stirred at room temperature for an hour. The precipitate was recovered by filtration to give the titled compound as a colorless solid (1.60 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:11]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Br-].[Li+].CCN(CC)CC.CC(OC)(C)C>C(#N)C.O>[CH3:23][O:22][C:20]([N:11]1[CH2:12][CH2:13][CH:14]([C:16]([OH:18])=[O:17])[CH2:15][CH:10]1[C:4]1[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:21]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1cc(F)c(F)c(F)c1
Yield: 84.1 %

Procedure:
Dimethyl 2-(3,4,5-trifluorophenyl)piperidine-1,4-dicarboxylate (2.77 g, 8.36 mmol) was dissolved in acetonitrile (35 mL) and water (0.700 mL), then lithium bromide (5.81 g, 66.89 mmol) was added. Et3N (4.66 mL, 33.45 mmol) was added and the resulting yellow suspension was heated under reflux for 2 h. Water (50 mL) and MTBE (150 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled aqueous layers were acidified to pH 1 with 3.8 M HCl and with MTBE (2 times). The combined organic layer was dried over Na2SO4, filtered and evaporated yielding 1-(methoxycarbonyl)-2-(3,4,5-trifluorophenyl)piperidine-4-carboxylic acid (2.23 g, 84%) as a slightly yellow semi-solid. MS m/z 316 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Br[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:7]=[O:8])[CH3:2]
Reactant: CCC(Br)CC
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC(CC)CC

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMF using K2CO3 as base. MS (ISP): 237.1 [M+H]+.
Reaction SMILES: C(SC1SC2=NC(C3C=CC=CC=3)=CN2N=1)C1C=CC=CC=1.[NH2:23][N:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]=[C:25]1[SH:35].[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>>[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH:23][N:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]=[C:25]1[SH:35])=[O:40]
Reactant: Nn1cc(-c2ccccc2)nc1S
Reactant: Cc1ccccc1C(=O)Cl
Agent: c1ccc(CSc2nn3cc(-c4ccccc4)nc3s2)cc1
Product: Cc1ccccc1C(=O)Nn1cc(-c2ccccc2)nc1S

Procedure:
4.4 g of 1-(2-methylbenzoylamino)-2-mercapto-4-phenylimidazole (obtained by hydrazinolysis of 2-benzylmercapto-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole and subsequent acylation of the 1-amino-2-mercapto-4-phenyl-imidazole with 2-methylbenzoyl chloride), melting point 268°-270° C., were heated to the boil in 30 ml of POCl3 for 20 minutes. The mixture is cooled and mixed with ice and the product is filtered off and then recrystallised from alcohol. 2.6 g, corresponding to 67% of theory, of colourless crystals of melting point 159°-160° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.I[CH3:28].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:28])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Reaction time: 48 h

Procedure:
To a solution of 3.45 g (8.47 mmol) of 2-[4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile (Example 1h), 1.8 g (12.7 mmol) of iodomethane (Fluka, Buchs, Switzerland) and 273 mg (0.847 mmol) of tetrabutylammonium bromide (Fluka, Buchs, Switzerland) in 170 ml of CH2Cl2 is added a solution of 508 mg (12.7 mmol) of NaOH (Fluka, Buchs, Switzerland) in 85 ml of H2O. The reaction mixture is stirred for 2 days and 900 mg (6.35 mmol) of iodomethane and 254 mg (6.35 mmol) of NaOH in 5 ml of H2O are added. The reaction mixture is stirred for 1 day at rt. After this time, the reaction is quenched with H2O and extracted with CH2Cl2 (2×). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound as a beige solid. ES-MS: 421, 423 (M+H)+, Br pattern; analytical HPLC: tret=3.15 min (Grad 1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH2:40]([S:41]([NH:44][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)(=[O:42])=[O:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)Cc1ccccc1)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a mixture of 3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (250 mg, 0.575 mmol) and α-toluenesulfonamide (98 mg, 0.575 mmol) in DMF (6 ml) was added 4-dimethylaminopyridine (105 mg, 0.863 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol). After stirring the resulting mixture at room temperature for 16 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water and brine successively, dried over dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1 elution) to give N-benzylsulfonyl-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (216.4 mg, 64%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O)C.O.[NH2:13][NH2:14]>C(O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[N:11][C:6]=1[C:4]([NH:13][NH2:14])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ncccn1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ncccn1
Yield: 68.8 %

Procedure:
A mixture of pyrimidine-2-carboxylic acid ethyl ester (Ann. Chim., 5, 351 (1960)) (0.866 g, 5.7 mmol) and hydrazine hydrate (0.332 mL, 6.8 mmol) in ethanol (20 mL) was heated under reflux for 3 hours, then concentrated under reduced pressure. The residue was triturated with diethyl ether, collected by filtration and washed with ethyl acetate to give the title compound (0.542 g, 69%) as a yellow solid, mp 173-175° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[OH:11][CH:12]1[CH2:15][NH:14][CH2:13]1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:19]=1[C:20]#[N:21]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]([CH2:17][N:14]2[CH2:15][CH:12]([OH:11])[CH2:13]2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: N#Cc1cc(Cl)ccc1CBr
Reactant: OC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1CN1CC(O)C1
Yield: 82.3 %

Procedure:
DIEA (3.57 mL, 20.50 mmol) was added to a stirred mixture of 3-hydroxyazetidine hydrochloride (1.00 g, 9.11 mmol) and 2-bromomethyl-5-chlorobenzonitrile (2.10 g, 9.11 mmol) in CH2Cl2 (75 mL). After 16 h the reaction mixture was concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was washed with ether, made neutral with NaHCO3, saturated with NaCl and extracted into CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 3.03 (m, 2H), 3.68 (m, 2H), 4.49 (t, J=6.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.53 (d,d, J=2.2, 6.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H).
Reaction SMILES: CC1C=CC(S(OCC2CC3C(C(F)(F)F)=CC=C(Cl)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:31]([CH2:34][CH:35]1[CH2:39][C:38]2[C:40]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:42]=[C:43]([Cl:44])[C:37]=2[O:36]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[Cl:44][C:43]1[C:37]2[O:36][CH:35]([CH2:34][NH2:31])[CH2:39][C:38]=2[C:40]([C:45]([F:48])([F:46])[F:47])=[CH:41][CH:42]=1
Reactant: [N-]=[N+]=NCC1Cc2c(C(F)(F)F)ccc(Cl)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3c(C(F)(F)F)ccc(Cl)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2c(C(F)(F)F)ccc(Cl)c2O1
Yield: 64 %

Procedure:
Treatment of (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.0 g, 2.46 mmol) with sodium azide (0.64 g, 9.83 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.060 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.350 g (64%) of (±)-1-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C10H9F3ClNOHCl: C, 41.69; H, 3.5; N, 4.86. Found: C, 41.78; H, 3.43; N, 4.77.