Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10](=[O:30])[NH:11][C:12]([C:15]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)=[CH:16][C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:13][CH:14]=1.[C:31](Cl)(=[O:33])[CH3:32].O>C(Cl)Cl>[C:31]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1/[CH:16]=[C:15](/[C:12]1[NH:11][C:10](=[O:30])[C:9]([Cl:8])=[CH:14][CH:13]=1)\[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CCc1ccc(C(=C[C@H]2CCCN2)c2ccc(Cl)c(=O)[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(/C(=C\[C@H]2CCCN2C(C)=O)c2ccc(Cl)c(=O)[nH]2)cc1
Yield: 23 %

Procedure:
Triethylamine (15.3 μL) was added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (32.9 mg) in methylene chloride (1 mL) at room temperature, and acetyl chloride (7.8 μL) was added under ice-cooling, after which the mixture was stirred under ice-cooling for 30 minutes. Triethylamine (15.3 μL) and acetyl chloride (7.8 μL) were added under ice-cooling and the mixture was stirred under ice-cooling for further 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. Acetonitrile (329 μL) and 48% hydrobromic acid (329 μL) were added to the resulting residue, and the mixture was stirred at 50° C. for one hour. Separately, triethylamine (121 μL) and acetyl chloride (61.6 μL) were added to a solution of 3-chloro-6-{1-(4-ethylphenyl)-2-[(2R)-pyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (E:Z=1:3 mixture) (190 mg) in methylene chloride (2 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. Acetonitrile (1.9 mL) and 48% hydrobromic acid (1.9 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. The reaction solutions were neutralized respectively with saturated aqueous sodium bicarbonate at room temperature, combined and extracted with ethyl acetate. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate:methanol=4:1) to give a yellow oil. This was powdered with acetonitrile, and filtration operation gave the title compound as a colorless solid (49 mg, 23%).
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([NH2:10])[C:4]=1[CH3:11].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl-:1].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:2][N+:3]2[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([N:10]=[CH:18][C:17]3[CH:20]=[CH:21][C:14]([N:13]([CH3:22])[CH3:12])=[CH:15][CH:16]=3)[C:4]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1n(N)c(CO)c[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc(N(C)C)cc2)c(CO)c[n+]1N=Cc1ccc(N(C)C)cc1

Procedure:
0.89 g (5 mmol) of 1,3-diamino-4-(hydroxymethyl)-2-methylimidazolium chloride and 1.49 g (10 mmol) of 4-dimethylaminobenzaldehyde are dissolved in 20 ml of glacial acetic acid. After 22 hours the precipitated product is filtered off and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-4-(hydroxymethyl)-2-methylimidazolium chloride of melting point 237° (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:21]([O:23]C)=[O:22])[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[K+].O.[ClH:28]>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[ClH:28]
Reactant: COC(=O)c1cc(-c2cc(C)cc(C)c2)cnc1-c1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(-c2cnc(-c3cccnc3)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.3 g, 1.20 mmol) in dioxane (6 mL) was added 3,5-dimethylphenyl boronic acid (0.452 g, 3.01 mmol), cesium carbonate (1.17 g, 3.61 mmol), tricyclohexylphosphine (0.101 g, 0.362 mmol), and tris(dibenzylideneacetone)-dipalladium (0.166 g, 0.181 mmol), and stirred at 95° C. overnight. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and filtered, concentrated and purified via normal phase chromatography (0->5% MeOH in DCM) afforded methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate as a yellow foam. ESI+ MS [MH]+ C20H18N2O2=319.25. To a solution of methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate (0.385 g, 1.20 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added potassium hydroxide (0.122 g, 2.17 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+ C19H16N2O2=305.0. To a solution of the bis HCl salt form of 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid (0.390 g, 1.03 mmol) and 3,4-dimethoxybenzylamine (0.173 g, 1.03 mmol) in dimethylformamide (5 mL) was added EDC (0.029 g, 0.191 mmol), HOBt (0.317 g, 2.06 mmol) and triethylamine (0.720 mL, 5.16 mmol) and the system was stirred in the microwave at 100° C. for 15 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was purified using normal phase chromatography (0->10% MeOH in DCM) to afford the title compound (1-3) as a white powder. 1H NMR (500 MHz, CDCl3) δ 8.98-9.00 (m, 2H), 8.65-8.66 (m, 1H), 8.17 (d, J=2 Hz, 1H), 7.98-8.00 (m, 1H), 7.28-7.30 (m, 3H), 7.11 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.41-6.67 (m, 2H), 5.72 (br s, 1H), 4.42 (d, J=6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 (s, 6H). HRMS [M+H] C28H27N3O3 calc'd 454.2125, found 454.2107.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:34]1([C:40](=[S:42])[NH2:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl.CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:41][C:9]=2[C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)N1CCOCC1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 2-propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (30 g, 82.9 mmol) in DCM (300 mL), NBS (14.8 g, 82.9 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated on the rotovap and the resulting oil was diluted with DMSO (240 mL) and 4-morpholinecarbothioamide (14.8 g 101 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the product of Step A (40 g, 98.8% yield) which was used directly in the next step.
Reaction SMILES: [CH2:1]([CH:8]([N:12]1[CH2:16][CH2:15][O:14][C:13]1=[O:17])[C:9]([O-:11])=[O:10])C1C=CC=CC=1.[CH:18]([N-]C(C)C)([CH3:20])[CH3:19].[Li+].IC.[CH2:28]1[CH2:32]O[CH2:30][CH2:29]1>>[O:17]=[C:13]1[N:12]([CH:8]([CH3:1])[C:9]([O:11][CH2:30][C:29]2[CH:20]=[CH:18][CH:19]=[CH:32][CH:28]=2)=[O:10])[CH2:16][CH2:15][O:14]1
Reactant: C1CCOC1
Reactant: O=C([O-])C(Cc1ccccc1)N1CCOC1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Product: CC(C(=O)OCc1ccccc1)N1CCOC1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of 0.50 g (2.1 mmol) of benzyl(2-oxo-1,3-oxazolidin-3-yl)acetate from step A in 15 mL of anhydrous THF at −78° C. under an atmosphere of nitrogen was added 1.2 mL (2.4 mmol) of a 2.0 M solution of lithium diisopropylamide in anhydrous THF. The resulting yellow solution was stirred for 15 min at −78° C. and then 0.0360 g (2.55 mmol) of iodomethane was added. The resulting mixture was stirred for 2 h with gradual warming to ambient temperature then quenched with a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a clear gum 0.37 g (70%). LC-MS: m/z (ES) 250 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:40][OH:41]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:40][OH:41])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NO
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Intermediate (17b) (4.3 g, 10 mmol) was dissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride (1.7 g, 25 mmol) was added, followed by the addition of water (20 mL, 1000 mmol). The mixture was stirred at room temperature overnight. Water (30 mL) was added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (17c) (3.5 g). MS m/z: [M+H+] calcd for C26H29N3O4, 448.2. found 448.3.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CC(C)=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:24])[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:8]3[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)CBr
Reactant: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(3-benzyl-1-methyl-2-phenyl-1H-indol-5-yl)-phenol (0.140 g, 0.359 mmol) was reacted with K2CO3 (0.065 g, 0.467 mmol) and methyl bromoacetate (0.071 g, 0.467 mmol) in acetone (5 ml) to give the product (0.141 g, 0.305 mmol, 85%) as a glass-like solid. 1H NMR (DMSO-d6) δ 3.62 (s, 3H), 3.70 (s, 3H), 4.04 (s, 2H), 4.81 (s, 2H), 6.97 (d, J=8.9 Hz, 2H), 7.07-7.11 (m, 3H), 7.18 (t, J=7.6 Hz, 2H), 7.41-7.57 (m, 10H); [ESI(+)], m/z 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:41]1([C:37]2[CH:36]=[C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:44])[NH:24][C:9]5[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)[CH:40]=[CH:39][N:38]=2)[CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(C4CC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M269) (349 mg, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 81%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([CH2:23][CH2:24][CH2:25][NH2:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.[H-].[Na+]>CN(C)C=O.O.ClCCl>[CH2:16]([O:15][C:11]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:23][CH2:24][CH2:25][NH:26][C:4](=[O:5])[C:6]3=[CH:14][C:13]=2[CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CCCN
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCCn2c1cc1cc(OCc3ccccc3)ccc12
Yield: 67 %

Procedure:
To the solution of 0.6 g (1.70 mmol) 1-(3-amino-propyl)-5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester in 6 mL N,N-dimethylformamide, 85 μg (1.95 mmol; 55% dispersion in mineral oil) sodium hydride was added. After 2 hours the reaction mixture was diluted with water and dichloromethane, the phases were separated and the aqueous phase was washed three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give the desired compound as a light yellow solid (67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH:16]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:17]=O>C(O)(CC)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]3[N:10]([C:16]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[CH:17][N:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Reactant: Nc1ncc(-c2ccc(F)cc2)cn1
Solvent: CCC(C)(C)O
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)cn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 5-(4-fluorophenyl)pyrimidin-2-amine (50 mg, 0.3 mmol), 2-chloro-3-(4-methoxyphenyl)propanal (52 mg, 0.26 mmol) in tert-amyl alcohol (1.0 mL) in a sealed reaction vial was heated at 130° C. for 3 hours. After cooling, the mixture was purified by preparative HPLC to afford the desired product. LCMS: (M+H)=334.0.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]([OH:17])=O)(=[O:4])=[O:3].C([N:20]([CH2:23][CH3:24])CC)C.[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])[CH3:26]>ClCCl>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][CH:33]([NH:36][S:2]([C:5]2[C:6]3[C:11](=[C:10]([C:15](=[O:17])[NH:20][CH:23]4[CH2:24][CH2:13][CH2:14][CH2:5][CH:6]4[CH3:7])[CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:3])=[O:4])[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)NC4CCCCC4C)cccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chlorosulfonyl-naphthalene-1-carboxylic acid 45 (100 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (110 mg, 0.15 mL, 1.11 mmol) was added followed by 4-amino-piperidine-1-carboxylic acid ethyl ester (76 mg, 0.44 mmol). The reaction was stirred for 1 hour at room temperature then diluted with dichloromethane (15 mL). The mixture was charged to a separatory funnel and washed with water, brine and dried over Na2SO4. Flash column chromatography (95:5 dichloromethane:methanol) afforded the title compound as a white solid. Wt.: 20 mg (13%)
Reaction SMILES: FC1C(F)=C(C)C=CC=1CBr.O[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:17]1(=[O:18])[NH:13][C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cc1ccc(CBr)c(F)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 180 %

Procedure:
To a stirred solution of 2,3-difluoro-4-methylbenzyl bromide (Matrix, 10.47 g) and N-hydroxyphthalimide (7.73 g) in DMF (100 ml) was added drop-wise triethylamine (Et3N) (7.3 ml) (DBU may be used as an alternative to Et3N). The red reaction mixture was stirred at room temperature for 2 hours. On addition of 1 M HClaq. a white precipitate formed, that was isolated by filtration and washed with water and dried in vacuo affording a phthalimide intermediate (12.55 g, white shiny material). This compound (6.07 g) was dissolved in dichloromethane and methyl-hydrazine (1.16 ml) was added drop-wise. The reaction mixture was stirred at room temperature for 30 min. and the solid material was removed by filtration. The filtrate was evaporated under reduced pressure and purified by chromatography on silica gel (EtOAc/petroleum ether as eluent) and gave the title amine as a clear colourless oil (3.34 g). Alternatively the phthalimide intermediate can be treated with hydrazine monohydrate (1.0 eq.) in refluxing ethanol for 2-3 hours and the title compound obtained as the hydrochloride salt by treatment with 4M HCl in dioxane as described above for preparation 14. HCl salt: 13C-NMR (DMSO-d6) δ 150.0, 146.8, 128.4, 126.2, 126.1, 120.3, 68.9, 13.9. Free amine: 13C-NMR (CDCl3) δ149.2, 149.3, 127.0, 125.4, 124.5, 124.0, 70.9, 14.3
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:40]([O:42][CH3:43])=[O:41].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:40](=[O:41])[O:42][CH3:43])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(C)CNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)N(CC(C)C)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(isobutylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (25.6 mg, 0.0502 mmol) in CH2Cl2 (0.5 mL) was added methyl chloroformate (7.7 μL, 0.100 mmol), followed by EtN(i—Pr)2 (70 μL, 0.402 mmol) The reaction was stirred at room temperature for 24 hours, and then methyl chloroformate (7.7 μL, 0.100) and EtN(i—Pr)2 (70 μL, 0.402 mmol) were added. The reaction was stirred for 96 hours and then diluted with EtOAc (20 mL), and washed with saturated NaHCO3 solution, brine, and 1 N HCl (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded methyl [2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]isobutylcarbamate. Rf=0.29 (25% EtOAc/hexanes). LCMS=617.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.87 (m, 1H), 7.78-7.76 (m, 2H), 7.24-7.17 (m, 3H), 5.73-5.71 (m, 1H), 5.01-4.75 (m, 2H), 4.07-3.06 (m, 3H), 1.83-1.75 (m, 1H), 1.27-1.21 (m, 3H), 0.99-0.91 (m, 6H), 0.70-0.68 (m, 3H).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O.[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][NH2:20].O.N1C=CC(=O)N=1>C(O)(=O)C>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]1[C:4](=[O:14])[CH2:5][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:20]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNCC(F)(F)F
Agent: O=C1C=CN=N1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1CC(F)(F)F

Procedure:
0.75 Mole (144 g) of benzoylacetic acid ethyl ester and 0.75 mole (126 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred for 3 hours in 900 ml of boiling acetic acid. The reaction mixture was poured out on 9 l of water. After 1 hour of stirring at room temperature the pyrazolone derivative was filtered and recrystallized from methanol.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].N([O-])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[OH:13]
Reactant: Nc1cnccc1C(F)(F)F
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cnccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 2 g (12.34 mmol) of 3-amino-4-(trifluoromethyl)pyridine in 28 ml of 50% sulfuric acid is cooled to −5° C. and a solution of 1.03 g (14.8 mmol) of sodium nitrite in 10 ml of water is added slowly. The mixture is left to return to room temperature and stirring is continued for 30 min. 25 ml of concentrated sulfuric acid are then added and the reaction mixture is stirred at 100-110° C. for 2 hours. After cooling, the reaction medium is neutralized by adding saturated sodium bicarbonate solution to pH 6-7, and the mixture is extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 1.92 g of the expected compound in the form of a brown powder (yield=95%).
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1.I[CH2:13]C>>[CH2:1]([CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1)[CH3:13]
Reactant: CC1CCc2sccc2C1=O
Reactant: CCI
Product: CCC1CCc2sccc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting iodoethane and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.40, 7.07, 3.18-2.96, 2.43-2.27, 2.09-1.94, 1.59, 1.02. HRMS (FAB) calcd for C10H12OS+H 181.0687, found 181.0684. Anal. Calcd for C10H12OS: C, 66.63; H, 6.71. Found: C, 66.50; H, 6.75.