Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH3:37])[C:22]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[O:23])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:37][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:39])[CH3:38])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[C:22](=[O:23])[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C(=O)N1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of tert-butyl 4-{2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoyl}piperazine-1-carboxylate (3.14 g, 5.65 mmol) in methylene chloride (20 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (7.06 mL, 28.2 mmol). The reaction mixture was stirred at RT for 1 h, then evaporated to dryness under reduced pressure. The residue was diluted with EtOAc and washed with 1 N NaOH, brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give the desired product (2.57 g, 99.8%). LCMS calculated for C22H34N7O2Si (M+H)+: m/z=456.3; Found: 456.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([C:17](=[O:34])[NH:18][CH:19]([C:30](=[O:33])[NH:31][CH3:32])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([C:17](=[O:34])[NH:18][CH:19]([C:30](=[O:33])[NH:31][CH3:32])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(=O)C(Cc1ccc(N)cc1)NC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
{2-(4-Hydroxy-phenyl)-1-[1-methylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl]-ethyl}carbamic acid tert-butyl ester (300, 0.617 mmol) is dissolved in methanol (10 mL). To this was added palladium on carbon (10% by weight, 100 mg). The reaction is placed under a hydrogen atmosphere until reaction is complete (tlc). The catalyst is removed by filtration and the filtrate is concentrated to provide the amine, which is used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][S:11][C:12]=1[C:13]([O:15]CC)=[O:14].C(O)C.[OH-].[Na+]>O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][S:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1snnc1-c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1snnc1-c1ccccc1O

Procedure:
To a solution of 10 g. of 4-(2-hydroxyphenyl)5-carboethoxy-1,2,3-thiadiazole in 500 ml. of ethanol is added a solution of 5 g. of sodium hydroxide in 25 ml. of water. The reaction mixture is refluxed for 4 hours and then evaporated to a small volume under vacuo. It is then cooled, diluted with water and extracted with ether to eliminate unsaponifiable products. The aqueous phase is acidified with 10% hydrochloric acid solution and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with sodium chloride solution, dried over sodium sulfate and evaporated to dryness under vacuo. Crystallization of the residue from ethyl acetate-methanol, affords the pure 4-(2-hydroxyphenyl)5-carboxy-1,2,3-thiadiazole.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:13]=[CH:14][C:15]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27]C)([CH3:19])[CH3:18])[N:4]=1)[CH3:2].B(Br)(Br)Br.CO>ClCCl>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH2:14][C:15]([C:30]([F:31])([F:32])[F:33])([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[OH:27])([CH3:19])[CH3:18])[N:4]=1)[CH3:2]
Reactant: CCc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
230 mg (0.49 mmol) of 1-(2-ethylquinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 4.5 ml of dichloromethane is mixed at 0° C. with 7.30 ml (7.30 mmol) of a 1 M boron tribromide solution. After 23 hours at room temperature, the reaction is brought to a halt by the addition of 30 ml of methanol. The reaction mixture is allowed to stir for one hour at room temperature, and then the solvent is removed in a vacuum. After chromatography on silica gel with ethyl acetate-methanol (0-10%), 60 mg (27% of theory) of the product is obtained.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].OS(O)(=O)=O>O>[CH2:14]([O:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCOC(=O)c1cccc2ccccc12
Temperature: 120 °C
Yield: 80.9 %

Procedure:
One mol (172 g) of α-naphthoic acid, 1.5 mol (195 g) of octyl alcohol and 3 ml of conc. H2SO4 were charged into a four-necked flask, and the whole was heated to 120° C. under agitation for 5 hours in a nitrogen atmosphere. After the end of the reaction, the resulting reaction mixture was cooled, freed from the water, sulfuric acid, unreacted naphthoic acid and alcohol by the use of a separating funnel and then distilled under a reduced pressure to obtain 230 g of octyl-1-naphthoate having a boiling point of 200°-202° C./4 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:13]([C:18]([O:20]C)=O)[C:14]([O:16][CH3:17])=[O:15])[CH:10]([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8].[F:22][C:23]1[C:24]([C:30](=[NH:32])[NH2:31])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=1>O1CCOCC1>[F:12][CH:10]([F:11])[C:9]1([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:18](=[O:20])[NH:32][C:30]([C:24]2[C:23]([F:22])=[CH:28][C:27]([F:29])=[CH:26][N:25]=2)=[N:31]1
Reactant: COC(=O)C(C(=O)OC)=C(c1ccc(F)c(F)c1)C(F)F
Reactant: N=C(N)c1ncc(F)cc1F
Solvent: C1COCCO1
Product: COC(=O)C1C(=O)NC(c2ncc(F)cc2F)=NC1(c1ccc(F)c(F)c1)C(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Titanium tetrachloride (11.4 mL, 104.1 mmol) in dichloromethane (28 mL) was added dropwise to a flask containing tetrahydrofuran (205 mL) under a nitrogen atmosphere, cooled in icebath. Then 1-(3,4-difluorophenyl)-2,2-difluoro-ethanone (10 g, 52 mmol) and dimethyl malonate (5.93 mL, 52 mmol) were added both at once. The resulting mixture was stirred under nitrogen atmosphere for 60 minutes while cooling was continued. Then, pyridine (16.8 mL, 208 mmol) in tetrahydrofuran (37 mL) was added to the mixture and this was allowed to warm to room temperature and stirred overnight. Next, distilled water (40 mL) and diethylether (40 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted with diethylether (2×40 mL). The combined organics were washed with brine (60 mL), NaHCO3 (60 mL) (aq/sat) and again with brine (60 mL). The organic layer was dried on MgSO4, filtered and concentrated under reduced pressure yielding dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (15.6 g) as a clear oil. Dimethyl 2-(1-(3,4-difluorophenyl)-2,2-difluoroethylidene)malonate (5 g) was dissolved in 1,4-dioxane (25 mL) and treated with 3,5-difluoropyridine-2-carboximidamide (3.1 g, 19.6 mmol). The resulting mixture was stirred at 40° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate-heptane 0:100 to 50:50) yielding methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate (5.45 g) as a yellow solid which was used as such. Methyl 4-(difluoromethyl)-4-(3,4-difluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate was treated with phosphorus oxychloride (10 mL, 107.6 mmol) and the mixture was stirred at reflux for 2 hours.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CNCCOC
Product: COCCN(C)C(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-methoxy-N-methylethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-:13])(=O)=O)=CC=1.[C:14]([O:22][CH3:23])(=[O:21])/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>CN(C=O)C>[NH:12]1[CH:13]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]([C:14]([O:22][CH3:23])=[O:21])=[CH:11]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]cc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
TOSMIC (1.5 g, 7.7 mmol) was added to a solution of dimethyl fumarate (1 g, 6.9 mmol) and sodium hydride (60%, 0.59, 12.5 mmol) in dry DMF (25 ml) at 0° C., and the solution stirred at 0° C. for 15 minutes. The reaction was poured onto ice-water and the product filtered and recrystallised from aqueous ethanol. 0.61 g, 48%. 1H-n.m.r. (DMSO-d6) δ (ppm) 3.68 (6H, s, 2×CH3), 7.39 (2H, s, 2×CH), 11.81 (1H, s, NH).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1>>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2ccccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1(c). 2-Naphthoyl chloride (200 mg, 1 mmol, Aldrich) reacted with 7-amino-quinoline (102 mg, 0.95 mmol, prepared according to the procedure described in WO03099284) to give the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 299 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:11][CH2:12][CH2:13][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCOCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
0.21 g (55%, 4.8 mmol) of sodium hydride was added to a solution of 0.44 g (4.8 mmol) of glycerol in dry N,N-dimethylformamide (5 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (4,8,12,16-tetramethylheptadec-3-enyl)tosylate was added dropwise with additional stirring for 12 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 44 mg of the title compound (4% yield in 2 steps) as a colorless transparent viscous product. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:15][CH:14]=2)=O)(C)(C)C>Cl.C(OCC)(=O)C>[ClH:26].[NH2:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Reaction time: 1 h
Yield: 179.2 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room,temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give (E)-3-[3-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide hydrochloride (0.12 g, 92.3%) as crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][N:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: N#CC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane (2 ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixture is stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-up in methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperature and stirred for a further 18 hours. The solvent is evaporated to afford crude azetidine-3-carbonitrile hydrochloride. The crude azetidine-3-carbonitrile is dissolved in dichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambient temperature for 2 hours, then washed with water, the organic phase dried over magnesium sulphate and evaporated. The crude product is purified by chromatography over flash silica using hexane:ethylacetate 2:1 as eluent to afford 1-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([O:3][C:16]([C:14]1[CH:15]=[C:8]2[C:7]([CH2:6][OH:5])=[CH:12][CH:11]=[CH:10][N:9]2[N:13]=1)=[O:17])[CH3:2]
Reactant: O=C(O)c1cc2c(CO)cccn2n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(CO)cccn2n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (9.5 mL, 130 mmol) is added to absolute ethanol (200 mL). After 30 min, the solution is poured into the flask containing 4-hydroxymethyl-pyrazolo[1,5-a]pyridine-2-carboxylic acid. The mixture is warmed to 50° C. for 3.5 h. After cooling to rt, the mixture is made basic with dropwise addition of sat. aq. NaHCO3. The volatiles are removed under reduced pressure. The aqueous solution is extracted with EtOAc. The organics are dried over Na2SO4, filtered, and concentrated to afford the title compound as a tan powder. LC-MS m/z (M+Na+): 242.98§.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH:21]([C:22]#[N:23])[C:20](OC)([O:24]C)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>C1COCC1.Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21]([C:22]#[N:23])=[C:20]([OH:24])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC1(OC)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2C1C#N
Agent: Cl
Solvent: C1CCOC1
Product: N#CC1=C(O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of 1-(4-fluorophenyl)-6,6-dimethoxy-1,5,6,7,8,9-hexahydrocyclohepta[f]indazole-5-carbonitrile (28, R1=4-Fluorophenyl) (54.8 g, 141 mmol) in THF (1000 mL) and 3N aq. HCl (170 mL) was heated at reflux for about 5 h. The reaction was cooled to rt and concentrated to about 200 mL volume. The product was extracted with ether (500 mL) and EtOAc (100 mL). The organic layer was washed with water (150 mL) and sat. aq. NaCl (150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to about 100 mL volume and diluted with heptane (about 100 mL). The product was filtered off and rinsed with 1:1/EtOAc:heptane (2×100 mL) and dried under vacuum at about 50° C. for about 18 h to yield 1-(4-fluorophenyl)-6-hydroxy-1,7,8,9-tetrahydrocyclohepta[f]indazole-5-carbonitrile (29, R1=4-Fluorophenyl) (23.1 g, 51%) as a solid: LC/MS, method 3, Rt=2.19 min, MS m/z 318 (M−H)—. 1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 8.34 (s, 1H), 7.85-7.77 (m, 2H), 7.76 (s, 1H), 7.71 (s, 1H), 7.47-7.38 (m, 2H), 2.82-2.74 (m, 2H), 2.31-2.22 (m, 2H), 2.19-2.07 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]([CH2:19][S:20][CH3:21])=[C:9]([C:11]2[C:12]([O:17]C)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br.CC(O)=O.C([O-])([O-])=O.[K+].[K+]>O>[C:1]([C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]([CH2:19][S:20][CH3:21])=[C:9]([C:11]2[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CSC)c(-c2cccnc2OC)cc1C(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CSC)c(-c2ccc[nH]c2=O)cc1C(C)(C)C
Temperature: 70 °C
Yield: 20.9 %

Procedure:
step 3—A mixture of 82 (30 mg), 48% HBr (50 μL) and HOAc (2 mL) in a sealed tube was heated overnight at 70° C. The reaction mixture was cooled to RT, carefully poured into water and neutralized with K2CO3 then extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC developed with 8% MeOH/DCM to afford 6 mg of 3-(5-tert-butyl-4-methoxy-2-methylsulfanylmethyl-phenyl)-1H-pyridin-2-one (84) as a white solid. The title compound can be prepared by oxidation of 84 with MCPBA which afford the sulfone I-15 directly.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:16][C:17]([F:31])([F:32])[C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2,4-bis(trifluoromethyl)phenylboronic acid (0.572 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 22 h to give 2-(2,4-bis(trifluoromethyl)phenyl)-4-chloro-5,7-difluoro-3-methylquinoline as a crystalline solid. Mass Spectrum (ESI) m/e=426.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C)c(C(F)(F)F)c4)nc23)cc(C)n1
Yield: 50.6 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (114 mg, 51%). MS (ISP) 451.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30](=[O:38])[CH2:31][CH2:32][C@H:33]([C:35](=[O:37])[NH2:36])[NH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][CH2:32][C@H:33]([C:35](=[O:37])[NH2:36])[NH:34][C:19](=[O:21])[C@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 15 h
Yield: 44.2 %

Procedure:
N-t-butyloxycarbonyl-O-benzyl-L-serine (4.43 g, 15 m mols) and D-isoglutamine benzyl ester (3.54 g, 15 m mols) were dissolved in acetonitrile (100 ml), and under ice-cooling, N,N'-dicyclohexylcarbodiimide (3.50 g, 17 m mols) was added. The mixture was stirred under ice-cooling for 3 hours and, then, at room temperature for 15 hours. The precipitate was filtered off, the solvent was distilled off and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with 1 N-hydrochloric acid, 5% aqueous sodium hydrogen carbonate and water in the order mentioned and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate-petroleum ether. By the above procedure there was obtained 3.40 g of N-t-butyloxycarbonyl-O-benzyl-L-seryl-D-isoglutamine benzyl ester. m.p. 65°-66° C.; [α]D23 +5.7° (c=0.5, ethanol); Rf1 -0.73.