Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])/[CH:20]=[C:21](/[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)\[C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:35]([CH3:38])([O-:37])=[O:36].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])[CH2:20][C:21]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)([CH2:38][N+:35]([O-:37])=[O:36])[C:22]([F:23])([F:25])[F:24])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To the stirred solution of 3-{4-[(Z)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.315 mmol, 1 eq.) in acetonitrile (10 mL) was added nitro methane (1.24 mL, 23.152 mmol, 10 eq) and DBU (0.33 mL, 2.246 mmol, 0.97 eq) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine (60 mL), dried over sodium sulphate and concentrated to get crude compound semi solid (1.37 g, crude). Crude compound was purified by column chromatography on silica gel using 230-400 mesh. Desired compound was eluted in 10% ethyl acetate in n-hexane to give product as light yellow sticky liquid (1.09 g, 81.34%). LC-MS (m/z): 576.8 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH:13]12[CH2:18][CH:17]1[C:16](=[O:19])[O:15][C:14]2=O>C(O)(=O)C>[O:12]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:1]3[C:14](=[O:15])[C@@H:13]4[C@@H:17]([CH2:18]4)[C:16]3=[O:19])[CH:4]=2)[NH:8]1
Reactant: NCc1ccc2c(c1)CC(=O)N2
Reactant: O=C1OC(=O)C2CC12
Solvent: CC(=O)O
Product: O=C1Cc2cc(CN3C(=O)[C@H]4C[C@H]4C3=O)ccc2N1

Procedure:
A solution of the compound obtained in Step C (15 mmoles) and 3-oxa-bicyclo[3.1.0]-hexane-2,4-dione (22.5 mmoles) in acetic acid (60 ml) is heated at reflux for 48 hours. The mixture is brought to ambient temperature and the solid formed is filtered off to yield the title product, which is used directly in the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:18][OH:19]>CC(O)C.C(OCC)(=O)C>[OH:19]/[N:18]=[C:8](\[NH2:9])/[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: N/C(=N\O)c1ccc(CCO)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a mixture of 4-(2-hydroxyethyl)benzonitrile (500mg, 3.40 mmol) and sodium bicarbonate (1427 mg, 16.99 mmol) in 2-propanol (50 mL) was added hydroxylamine hydrochloride (472 mg, 6.79 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4, filtered, and concentrated to yield 300 mg of (Z)—N′-hydroxy-4-(2-hydroxyethyl)benzimidamide. MS (m+1)=181. HPLC Peak RT=0.13 minutes. (Analytical Method B).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([CH2:14][N:5]2[CH:6]=[C:2]([I:1])[N:3]=[CH:4]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Ic1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cn(CC2CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a solution of 4-iodo-1H-imidazole (800 mg, 4.12 mmol) in DMF (50 mL) was added cesium carbonate (5.37 g, 16.5 mmol) and (bromomethyl)cyclopropane (1.6 mL, 16.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially with water, sat'd LiCl and sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/heptane) to isolate first 590 mg (58%) of 1-cyclopropylmethyl-4-iodo-1H-imidazole as a pale yellow oil followed by 227 mg (22%) of 1-cyclopropylmethyl-5-iodo-1H-imidazole as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=[O:9].Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CN1C(=O)CCC1.[OH-].[K+:29]>O>[OH-:9].[K+:29].[Br:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]2[N:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[N:20]=[CH:8][C:7]=12
Reactant: O=Cc1c(Br)cncc1Br
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 1 L flask was charged 3,5-dibromopyridine-4-carboxaldehyde (50.0 g, 188.7 mmol, 1.0 eq) and 4-fluorophenylhydrazine hydrochloride (31.0 g, 190.7 mmol, 1.01 eq). NMP (250 mL) was charged, and the resulting slurry was stirred at ambient temperature for 2 hours. A solution of aqueous KOH was prepared from 85% KOH pellets (27.4 g, 415.2 mmol, 2.2 eq) and water (27.4 mL), and this KOH solution was charged to the reaction mixture. The batch was heated to 80° C. and held at this temperature for 30-60 minutes. Water (250 mL) was then charged at 80° C., and the resulting slurry was cooled to ambient temperature over 4-16 hours. The slurry was filtered, the solid was washed with water, and oven dried under vacuum to afford 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine as a tan colored solid, 51.5 g, 99.3 area % purity by HPLC, 93% yield.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][CH2:8][CH:7]2[CH2:15][O:16][CH3:17])(=[O:3])[CH3:2].OO.[S:21](S([O-])=O)([O-:23])=[O:22].[Na+].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:21](=[O:23])(=[O:22])[CH2:9][CH2:8][CH:7]2[CH2:15][O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=S([O-])S(=O)[O-]
Reactant: COCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC1CCS(=O)(=O)c2c(C)cc(C(C)=O)c(C)c21
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture containing 0.30 g (1.1 mmol) of 6-acetyl-4-methoxymethyl-5,8-dimethylthiochroman, 0.39 ml of a30 wt % hydrogen peroxide aqueous solution and 0.3 ml of acetic acid was allowed to react at 60° C. for 2 hours, and further allowed to react at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and a 2 wt % sodium hydrosulfite aqueous solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off to give 0.32 g (yield 94%) of the titled compound as a crude product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC(C)=O>[C:25]([O:24][C:22]([CH2:21][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COC(=O)CCc1ccc(O)cc1

Procedure:
To a mixture of 3-(4-hydroxy phenyl) propionic acid (20 grams, 120.35 mmol) and triethyl amine (30 grams, 296.47 mmol) in acetone (150 mL) is added t-butyl chloroacetate (19.6 grams, 130 mmol) drop wise, later it is stirred under reflux for 10 hours. The resulting solids are filtered off, acetone is distilled off, and water (100 mL) is added. The crude 4 is extracted into chloroform, and is washed with 5% sodium bicarbonate (2×25 mL), water (2×25 mL), and the product is dried over sodium sulphate, and is distilled to give crude 4 which can be purified from an appropriate solvent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[C@H:16]1[CH2:20][CH2:19][O:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:8]([C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:5]=1)[O:1][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1)([O-:10])=[O:9]
Reactant: O[C@H]1CCOC1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(OC2CCOC2)cc(C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 72 h

Procedure:
3-Hydroxy-5-nitrobenzotrifluoride (5 g, 24.1 mmol, 1 eq), (S)-3-hydroxytetrahydrofuran (1.9 mL, 24.1 mmol, 1 eq), PPh3 (6.3 g, 24.1 mmol, 1 eq) were dissolved in 43 mL of THF. The solution was cooled to −20° C. DIAD (4.8 mL, 24.6 mmol, 1.02 eq) was added in 22 mL of THF over the course of 2 h while the temperature was maintained between −10 and −20° C. After the addition was complete the reaction was stirred for 3 days at RT. The solvent was removed in vacuo. The residue was stirred with ˜250 mL of hexane for 45 min during which time triphenylphosphine oxide precipitated as a white solid. The solid was removed by filtration and the filtrate was washed twice with 2 N NaOH and once with brine. After drying over Na2SO4 the solution was filtered and the solvent removed under reduced pressure. The crude material was purified by chromatography on a Biotage system eluting with a gradient of 5 to 15% EtOAc:hexane to yield the desired compound.
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:38][CH2:39][CH2:40][CH2-].ICCC>C1COCC1>[Si:1]([C:8]1[S:9][C:10]([CH2:38][CH2:39][CH3:40])=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:23])[CH3:22])[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: [CH2-]CCC
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2csc([Si](C)(C)C(C)(C)C)n2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCc1sc([Si](C)(C)C(C)(C)C)nc1C[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.150 g, 0.269 mmol) in THF (3 mL) was cooled to −78° C. when N-BUTYLLITHIUM (2.5 M in hexanes) (0.1 19 ml, 0.296 mmol) was added dropwise. The solution was warmed to −50° C. for 40 minutes and then cooled to −78° C. 1-Iodopropane (0.0549 g, 0.323 mmol) was added dropwise and the solution was allowed to slowly warm to −50° C. and stirred for 1 hr. The reaction was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification for the next step.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]([CH3:16])[C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NC2CC2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CC1
Temperature: 200 °C

Procedure:
The intermediate, cyclopropyl-(5-nitro-pyridin-2-yl)-amine, from the above procedure, was methylated with methyl iodide. To a 2 mL microwave vial was added cyclopropyl-(5-nitro-pyridin-2-yl)-amine (146 mg, 0.812 mmol), DMF (2 mL), potassium carbonate (224 mg, 1.62 mmol), and the MeI (56 μl, 0.893 mmol). The mixture was heated by microwave for two 10 min increments at 200° C. using a Personal Chemistry, Emrys Optimizer. Then followed addition of another portion of MeI (56 μL, 0.893 mmol) microwave at 200° C. for 10 min and then conventional heating at 70° C. for 15 hr. At the end of this period a third addition of MeI (56 μL, 0.893 mmol) took place and the mixture was heated by microwave once more for 10 min at 200° C. The reaction mixture was then concentrated to dryness, suspended in ethyl acetate (100 mL) and washed with water (100 mL) two times and one time with brine. The aqueous layers were combined and extracted once with ethyl acetate (50 mL). The combined organic layer was washed once with brine (100 mL), concentrated, supported onto silica gel, and purified by flash chromatography using the Analogix system with a 12 g Silicycle silica gel column with increasing concentrations of ethyl acetate in hexanes (20 mL/min, equilibrate with 0%, 0 to 5 min: 0%; 5 to 25 min: 0 to 30%; 25-45 min: 30%). The appropriate fractions were collected and dried to afford 90 mg of cyclopropyl-methyl-(5-nitro-pyridin-2-yl)-amine, a yellow solid (yield 57%). LCMS calcd. for C9H11N3O2 (m/e) 193, observed 194 (M+H). This intermediate nitropyridyl compound was then reduced, as described in the preparation of cyclopentyl-pyridine-2,5-diamine above, to afford N2-cyclopropyl-N2-methyl pyridine-2,5-diamine. LCMS calcd. for C9H13N3 (m/e) 163, observed 164 (M+H).
Reaction SMILES: FC1C=[C:4](C=C(F)C=1)[CH2:5][N:6]1C=CN=C1S.[C:16]1([CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[SH:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:6][CH2:5][CH2:4][S:29][C:25]1[N:24]([CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Sc1nccn1CCc1ccccc1
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Product: NCCSc1nccn1CCc1ccccc1

Procedure:
The Example 1 process wherein 1-(3,5-difluorobenzyl)-2-mercaptoimidazole is replaced by 1-(phenylethyl)-2-mercaptoimidazole yields 2-(2-aminoethylthio)-1-(phenylethyl)imidazole.
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:13][O:14][C:15]([N:17]1[CH:22]=[C:21]([O:23]C(=O)C)[CH:20]([CH3:27])[CH2:19][CH2:18]1)=[O:16]>CO>[CH3:13][O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([CH3:27])[C:21](=[O:23])[CH2:22]1)=[O:16]
Reactant: COC(=O)N1C=C(OC(C)=O)C(C)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)N1CCC(C)C(=O)C1
Yield: 32 %

Procedure:
In a 1000 ml round bottom flask, 50 g of crude 5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methyl ester was dissolved in 200 ml of methanol. To 300 ml water was added 30 g of sodium carbonate and 30 g sodium bicarbonate (pH=10). The aqueous buffer was added to the methanol solution. Methanol was added to the mixture until it stirred easily, and stirred at room temperature for 18 hours. The mixture was then concentrated to remove methanol. Water was added to the mixture to dissolve all salts. This was then extracted with ethyl acetate three times. The organic extracts were combined, dried over magnesium sulfate, filtered, and evaporated to furnish the crude compound 4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl ester as oil, which was then purified as described below.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (74 mg, 0.94 mmol) and dichloromethane (2 mL) at 0° C. was added dropwise a solution of ethanesulfonyl chloride (90 mg, 0.70 mol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford ethanesulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (143 mg, 74.1%) as a white solid. MS (ESI+APCI) M+1=413.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]3)[CH2:7][CH2:6]1.[CH:30]1([CH2:36][S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]3)[S:37]([CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:39])=[O:38])[CH2:9][CH2:10]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: COCOC1CCN(CCNCCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOC1CCN(CCN(CCCCOc2ccc3[nH]c(=O)ccc3c2)S(=O)(=O)CC2CCCCC2)CC1
Yield: 17.8 %

Procedure:
A solution of 2.5 g of 6-{4-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminobutoxy}carbostyril, 1.5 g of cyclohexylmethanesulfonyl chloride and 1.35 ml of triethylamine in 30 ml of dichloromethane was stirred at room temperature for 16 hours. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/chloroform)-to obtain 620 mg of 6-[4-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-cyclohexylmethylsulfonylamino}butoxy]carbostyril.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>CCCCCC.O1CCCC1>[C:9]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([Si:21]([Cl:20])([CH3:23])[CH3:22])[CH:7]=[C:6]([CH3:8])[CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1c(Br)cc(C)cc1C(C)(C)C
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution composed of tetrahydrofuran (31.5 ml), hexane (139 ml) and 1-bromo-3-tert-butyl-2-methoxy-5-methylbenzene (45 g) synthesized in the above-described procedure (2) was added a 1.6 mol/liter hexane solution (115 ml) of n-butyllithium dropwise at −40° C. over 20 minutes. The resultant mixture was kept at −40° C. for 1 hour, and tetrahydrofuran (31.5 ml) was then added dropwise. To a solution composed of dichlorodimethylsilane (131 g) and hexane (306 ml) was added the above-described mixture dropwise at −40° C. The resultant mixture was allowed to warm to room temperature over 2 hours, and further stirred at room temperature for 12 hours. The solvent and excess dichlorodimethylsilane were removed under reduced pressure from the reaction mixture, hexane-soluble components were extracted from the residue with hexane, and the solvent was distilled off from the resultant hexane solution to obtain 41.9 g of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane as a pale yellow oil. Yield was 84%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH2:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:31](=[O:34])[CH2:32][CH3:33])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine (example 89) (40 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.071 mL, 0.41 mmol) in DMF (0.5 mL) was treated with propionyl chloride (0.018 mL, 0.20 mmol) and the reaction mixture stirred at room temperature overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (7%) of the title compound as a light brown oil. MS: 353.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]([NH:33][CH3:34])[CH:30]=[CH:31][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[C:29]([N:33]([CH3:34])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=3)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cccc(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (3-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (3-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 521.9.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:15]=[C:16]2[N:26]([C:27]([C:29]3[NH:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([O:38][CH3:39])=[CH:33][CH:32]=4)=[O:28])[CH2:25][CH:24]([CH2:40][Cl:41])[C:17]2=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)C1C=CC=CC=1>O.[Pd]>[Cl:41][CH2:40][CH:24]1[C:17]2=[C:18]3[C:23](=[C:14]([OH:13])[CH:15]=[C:16]2[N:26]([C:27]([C:29]2[NH:30][C:31]4[C:36]([CH:37]=2)=[CH:35][C:34]([O:38][CH3:39])=[CH:33][CH:32]=4)=[O:28])[CH2:25]1)[N:22]=[CH:21][CH:20]=[CH:19]3
Reactant: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(O)c3ncccc43)cc2c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
THF (6 mL) then HCO2NH4 (0.14 g, 2.21 mmol) in H2O (0.7 mL) were added to cooled (0° C.) mixture of 17d (0.11 g, 0.22 mmol) and 10% Pd/C (0.05 g) under N2. The mixture was stirred at 0° C. for 5 h, and was then filtered through Celite. The Celite was washed with CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4) and CH2Cl2 evaporated. Precipitation from CH2Cl2/MeOH gave 18d (0.077 g, 89%) as a grey solid: mp 224–227° C.; 1H NMR [(CD3)2SO]δ 11.66 (s, 1 H), 10.02 (bs, 1 H), 8.77 (dd, J=4.1, 1.3, 1 H), 8.41 (dd, J=8.4, 1.4, 1 H), 8.07 (s, 1 H), 7.57 (dd, J=8.4, 4.1, 1 H), 7.40 (d, J=9.0, 1 H), 7.16 (d, J=2.4, 1 H), 7.12 (d, J=1.6, 1 H), 6.92 (dd, J=8.9, 2.3, 1 H), 4.82 (dd, J=10.8, 9.4, 1 H), 4.57 (dd, J=11.0, 2.3, 1 H), 4.30 (m, 1 H), 4.04 (dd, J=11.1, 3.3, 1 H), 3.91 (dd; J=11.1, 7.2, 1 H), 3.78 (s, 3 H).