Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[CH2:44][CH2:43][CH2:42][CH2:41][C:18]=2[C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)=[O:21])=[O:13])[CH:5]1[CH2:7][CH2:6]1.Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:5]1([N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=2)[C:12]([NH:14][C:15]2[S:16][C:17]3[CH2:44][CH2:43][CH2:42][CH2:41][C:18]=3[C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[CH:25][CH:24]=2)=[O:21])=[O:13])[CH2:3][CH2:2][NH:1][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CCN)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of methyl 4-(2-{4-[({2-[(3-{[(2-aminoethyl)(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.20 mL of ethyl bromoacetate, 212 mg of potassium carbonate, and 20 mL of DMF was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 140 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropyl {2-[(2-ethoxy-2-oxoethyl)amino]ethyl}amino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][N:26]2[CH:30]=[CH:29][CH:28]=[C:27]2[C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12])(C(C)(C)C)(C)C.O>C1COCC1>[OH:8][CH2:9][C@@H:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][N:26]2[CH:30]=[CH:29][CH:28]=[C:27]2[C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)OCc1ccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H](CO)OCc1ccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h

Procedure:
The compound of Example 68-4 (260 mg, 0.48 mmol) was dissolved in THF (5 ml), and thereto was added n-tetrabutylammonium fluoride (1 mol/liter in THF) (1.5 ml, 0.72 mmol) under ice-cooling. Under ice-cooling, the mixture was stirred for one hour, and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
In methylene chloride (200 ml) was dissolved 2,3-dimethylpyridine (9.50 g) and the resulting solution was. cooled to 0° C. Metachloroperbenzoic acid (21.9 g) was added to the reaction mixture, followed by heating to room temperature. Stirring was conducted for 3 days. An aqueous solution of sodium sulfite was added and the resulting mixture was separated using methylene chloride (200 ml). The organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated and the concentrate was purified by chromatography on a silica gel column (5% methanol—methylene chloride). Petroleum ether was added to the residue. Colorless powder so precipitated was collected by filtration, followed by drying, whereby the title compound (5.47 g) was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[C:9](=[O:20])[N:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][C:8]1[C:9](=[O:20])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Nc1cccn(CC(=O)OCC)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=CCOC(=O)Nc1cccn(CC(=O)O)c1=O

Procedure:
The compound of example 60 (1.00 g) is treated with 50% trifluoroacetic acid in dichloromethane (10 mL) for 1 hour at 0° C., and 3 hours at room temperature. The solution is diluted with toluene (50 mL) and the solvent is removed in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[O:23]1[C:34]2[C:35]3[C:30]([C:31](B(O)O)=[CH:32][CH:33]=2)=[N:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]1>>[O:23]1[C:34]2[C:35]3[C:30]([C:31]([C:2]4[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]5[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]5)[N:3]=4)=[CH:32][CH:33]=2)=[N:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c3c(ccnc13)CCO2

Procedure:
This compound is prepared according to general method E starting from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate and 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([C:10]([OH:12])=O)[CH2:9][CH:2]1[CH2:3][CH:4]3[CH2:5]2.S(Cl)([Cl:15])=O>>[CH2:5]1[CH:4]2[C:8]3([C:10]([Cl:15])=[O:12])[CH2:9][CH:2]([CH2:1][CH:6]1[CH2:7]3)[CH2:3]2
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Temperature: 25 °C

Procedure:
A solution of 3-noradamantanecarboxylic acid (Aldrich, 4.5 g, 26 mmol) in 40 mL of thionyl chloride was warmed to reflux for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 40 mL benzene and concentrated under reduced pressure (3×) to afford hexahydro-2,5-methano-pentalene-3a-carbonyl chloride.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:15]=2)[C:10]([Cl:35])=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[Cl:35][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[N:21][C:20]=3[CH3:34])=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH:9]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(Cl)cn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(Cl)cn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {3-chloro-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {3-chloro-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=3)=[N:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH2:26](I)[CH3:27]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[CH:18]=3)=[N:8][C:9]([N:12]([CH2:26][CH3:27])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)cn(C)c1=O
Reactant: CCI
Product: CCN(c1ncc(OCC2CC2)c(-c2cc(C)c(=O)n(C)c2)n1)S(C)(=O)=O

Procedure:
The title compound of Example 153 was treated with ethyl iodide in a manner similar to Example 161 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.36-0.42 (m, 2H) 0.60-0.66 (m, 2H) 1.25 (t, J=6.82 Hz, 3H) 1.29-1.40 (m, 1H) 2.09 (s, 3H) 3.48 (s, 3H) 3.56 (s, 3H) 3.88-4.20 (m, 4H) 8.13 (s, 1H) 8.49 (s, 1H) 8.69 (s, 1H).). LCMS: 393 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>Cl>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:28][CH:29]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCCc2c(-c3cccnc3)[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCc2c(-c3cccnc3)[nH]c3ccccc23)cc1

Procedure:
A mixture of 4.5 g of 3-[2-(4-ethoxycarbonylphenoxy)ethyl]-2-(3-pyridyl)-indole in 220 ml of 2N hydrochloric acid is heated under reflux for 6 hours. After cooling the solution is made basic with 3N NaOH and extracted with ethyl acetate. The basic solution is filtered and acidifed to pH 6-7 with 3N NCl. The solid is collected and dried to give 3-[2-(4-carboxyphenoxy)-ethyl]-2-(3-pyridyl)-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[NH:10][C:9]2=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]([CH3:27])[C:9]2=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2[N+](=O)[O-])c1=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 3-(4-chloro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (3 g), dimethyl sulfate (1.7 g) and potassium carbonate (1.85 g) in N,N-dimethylformamide (100 ml) was stirred at 55° C. overnight. The resulting mixture was allowed to cool to ambient temperature and filtered through Celite to remove unsoluble precipitate. The filtrate was diluted with a mixed solvent of ethyl acetate and hexane (1:1, 200 ml), washed with brine (×2) and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was solidified. The yellow solid was recrystallized from ethyl acetate and hexane to give desired compound (2.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[N:13]=[C:12](C=O)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:21]=1[NH2:22])([CH3:19])[CH3:18]>C(O)=O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[NH:13][C:12](=[N:22][C:21]3[C:23]([CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=[CH:26][C:20]=3[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(O)c(-c2cccc(C=O)n2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CO
Solvent: O=CO
Product: Cc1ccc(O)c(-c2cccc(=Nc3c(C(C)C)cccc3C(C)C)[nH]2)c1
Reaction time: 8 h

Procedure:
To a solution of 6-(5′-methyl-2′-hydroxyphenyl)-2-formyl-pyridine (4) (640 mg, 3.00 mmol) in the minimum volume of methanol was added 1.5 equivalents of 2,6-diisopropylaniline (780 mg, 4.50 mmol). After the addition of a few drops of formic acid, the solution was stirred overnight. The cloudy yellow reaction mixture was then filtered through a frit, and the solid washed with methanol (3×5 mL), giving 6-(5′-methyl-2′-hydroxyphenyl)-2-(N-(2,6-diisopropylphenyl) imino)pyridine (5) as a yellow solid. Yield: 1.06 g (95%).
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[C@@H:27]1[N+:28]([O-:30])=[O:29])=[O:9])[CH3:12]
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCC
Reactant: COc1ccccc1/C=C/[N+](=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCC)[C@@H](c2ccccc2OC)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq) and 1-methoxy-2-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.06 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:3) in 81% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-tert-butyl-1-fluoro-2-nitrobenzene in methanol was added a catalytic amount of palladium on carbon (10%). The mixture was allowed to stir for 1 h at room temperature under an atmosphere of hydrogen. Mixture was filtered though celite and concentrated to afford 5-tert-butyl-2-fluorobenzenamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:26][OH:27])=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:20]2[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1cnc(CO)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(COc2nc(N)nc(-n3cccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[CH:7]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:12][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][OH:3])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)Cc1ccnc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CCO)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
A solution of (2-methyl-pyridin-4-yl)-acetic acid ethyl ester (3.75 g, 20.2 mmol) in 100 mL of THF was cooled in an ice bath and a 1.0M solution of LAH in THF was added (15.7 mL, 15.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled in an ice bath and quenched with the successive addition of water, 15% aqueous sodium hydroxide solution and additional water. The resulting mixture was stirred at room temperature for 1 hour then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 2.8 g of the title compound as a light brown oil. MS(ES): m/e (EI*) 138.1 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16](=[O:28])/[C:17](/[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[N:18]\O)=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.Cl.CO>CO.[Pd]>[ClH:1].[NH2:18][CH:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[CH:16]([C:11]1[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:5]2[C:4]([CH3:29])=[CH:3][CH:2]=[CH:7][C:6]=2[CH3:8])[CH:10]=1)[OH:28]
Reactant: Cc1cc(Cl)cc(C)c1-n1cc(C(=O)/C(=N\O)c2ccc(F)cc2F)ccc1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cccc(C)c1-n1cc(C(O)C(N)c2ccc(F)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 115.1 %

Procedure:
To a solution of the compound prepared in Example 51 (250 mg) in methanol (12 mL) was added 10% hydrochloric acid-methanol solution (3 mL) and added 10% palladium/carbon (50 mg, 25% wt) subsequently. The mixture was stirred at room temperature for 5 hours under an atmosphere of hydrogen. The reaction mixture was filtered through Celite (trade name). The filtrate was concentrated and dried to give the title compound (281 mg) having the following physical data. MS (APCI, Pos, 20V): 371 (M+H)30.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5](OC2C=CC=CC=2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([NH:28][CH2:25][CH:26]=[CH2:27])=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1Oc1ccccc1
Reactant: C=CCN
Solvent: C1COCCO1
Product: C=CCNc1cc(Oc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 63.3 gm of 6-chloro-4-nitro-1,3-diphenoxy-benzene, 120 ml of dioxane and allylamine in substantial excess over the stoichiometrically required amount was heated for 12 hours at 60° C. Thereafter, the dioxane was distilled off, the residue was dissolved in methylene chloride, the resulting solution was washed with dilute sodium hydroxide, the organic phase was dried with sodium sulfate, and the methylene chloride was distilled off. The residue was recrystallized from a mixture of toluene and hexane and further purified on a silicagel column, yielding 51 gm (83.6% of theory) of the title compound, m.p. 81°-82° C.
Reaction SMILES: [F:1][CH:2]([F:29])[C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])([N:7]=[C:8]([NH:12]C(=O)C3C=CC=CC=3)[S:9][CH2:10]2)[CH2:5][O:4]1.N12CCCN=C1CCCCC2>CO>[F:29][CH:2]([F:1])[C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
N-((4aS,5S,7aS)-5-(difluoromethyl)-7a-(2,3-difluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide, obtained in Preparation Example 1-(8), (891 mg) was dissolved in methanol (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.02 g) was added, and the solution was heated to reflux (heating block temperature 70° C.). After 16 h, the reaction mixture was cooled, concentrated under reduced pressure, and the residue purified by silica gel column chromatography (0% to 80% EtOAc in hexanes) to afford the title compound (565 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.4, 4.0 Hz, 1H), 3.13 (dd, J=13.6, 3.3 Hz, 1H), 3.24 (dt, J=7.7, 3.7 Hz, 1H), 3.89 (d, J=8.3 Hz, 1H), 4.33-4.70 (m, 4H), 5.94 (td, J=56.3, 3.8 Hz, 1H), 7.05-7.25 (m, 3H)
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:2][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@@H]1CO
Reactant: C1CCNC1
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(R)-hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and pyrrolidine. MS (M+H) 403.2
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=C2C(=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C)CC3)C(OC)=O)C=1)NN=C2.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[C:47]([CH:49]([C:72]#[N:73])[O:50][CH2:51][C:52]3([C:65]4[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=4)[CH2:57][CH2:56][N:55]([C:58](OC(C)(C)C)=O)[CH2:54][CH2:53]3)[CH:48]=1)[NH:45][N:44]=[CH:43]2>>[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[C:47]([CH:49]([O:50][CH2:51][C:52]3([C:65]4[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=4)[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]3)[C:72]#[N:73])[CH:48]=1)[NH:45][N:44]=[CH:43]2
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C#N)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Agent: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COC(C#N)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare methyl 2-(5-chloro-1H-indazol-7-yl)-2-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)acetate trifluoroacetic acid salt using tert-butyl 4-(((5-chloro-1H-indazol-7-yl)(cyano)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. After preparative HPLC, the product was still impure. The product was re-purified by column chromatography (2M ammonia in methanol/dichloromethane) to give the title compound as the freebase. 1H-NMR (CDCl3, 500 MHz) δ 9.51 (bs, 1H), 7.97 (s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.34 (dd, J=8.9, 5.2 Hz, 2H), 7.31 (s, 1H), 7.14 (m, 2H), 5.43 (s, 1H), 3.84 (d, J=8.6 Hz, 1H), 3.68 (d, J=8.5 Hz, 1H), 2.56 (m, 2H), 2.22 (m, 8H), 1.99 (m, 3H), 1.67 (bs, 6H). Mass spec.: 413.22 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=2[N+:13]([O-:15])=[O:14])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
4.12 g of 2-chloro-6-methylquinoline (J. Med. Chem. 1992, pp. 2761-2768) is added at 0° C. to a solution that consists of 15 ml of 100% nitric acid and 2 ml of 96% sulfuric acid. After 4 hours at 0° C., it is added to water, and the product is filtered off. 4.66 g of 2-chloro-6-methyl-5-nitroquinoline is obtained as a beige solid. The latter is reacted for 80 hours at 100° C. in 46 ml of glacial acetic acid and 26 ml of water. The thus obtained 6-methyl-5-nitroquinolin-2(1H)-one is filtered off from the reaction solution. The 3.45 g of product that is obtained is reacted with hydrogen under normal pressure in methanol to palladium on activated carbon to form aniline. 2.89 g of the title compound is obtained as a beige solid.