Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[CH3:10].Cl>CCO.O>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH2:9][CH3:10])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1ccc(Nc2ccnc(Nc3ccc(OCC)cc3)n2)cc1
Temperature: 75 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (0.015 g, 0.1 mmol) in EtOH (1 mL) was added 4-ethoxyaniline (0.034 g, 0.025 mmol) and heated in a sealed tube at 70-80° C. for 24 h. Upon cooling the reaction was diluted with H2O (10 mL), acidified with 2N HCl, the solid obtained was filtered, washed with H2O and dried to give N2,N4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (R926069). 1H NMR (CD3OD): δ 7.63 (d, 1H), 7.45 (d, 2H), J=9 Hz), 7.32 (d, 2H, J=9.3 Hz), 6.95 (d, 2H, J=6.9 Hz), 6.87 (d, 2H, J=8.7 Hz), 6.23 (d, 1H, J=7.2 Hz), 4.04 (m, 4H), 1.38 (m, 6H); LCMS: ret. time: 25.91 min.; purity: 99.5%; MS (m/e): 351 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1.S(Cl)(Cl)=O.Cl.CN.C[CH2:27][N:28](C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:28][CH3:27])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1cc(F)c(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Temperature: 65 °C
Reaction time: 7 h
Yield: 41.9 %

Procedure:
4-(4-chloro-2,5-difluorophenyl)nicotinic acid (170 mg, 0.630 mmol) was taken in thionyl chloride (0.14 mL, 1.89 mmol) and heated at 65° C. for 1 h. The solvent was evaporated under reduced pressure to afford a crude oil which was dissolved in dichloromethane and added to a mixture of methanamine hydrochloride (63.9 mg, 0.946 mmol) and DIEA (0.11 mL, 0.63 mmol) in DCM (8 mL) dropwise at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 7 h. The reaction mixture was diluted with DCM (5 mL) and washed with water (3×5 mL) followed by brine (1×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide the crude product which was purified by preparative thin layer chromatography (3:2 Ethyl acetate:hexane) to afford 4-(4-chloro-2,5-difluorophenyl)-N-methylnicotinamide (90 mg, 0.264 mmol, 42% yield) as a white solid. LC/MS (ESI) m/e 283.0 [(M+H)+, calcd for C13H10ClF2N2O 283.0]; LC/MS retention time (method A): tR=1.46 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][CH:13](Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:13]([O:12][CH3:11])=[C:6]([CH:7]=1)[CH:5]=[O:8]
Reactant: COc1ccc(Cl)cc1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)cc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 17.8 %

Procedure:
Titanium tetrachloride (24.3 g, 0.128 mole) is added to a solution of 4-chloro-2-methylanisole (10 g, 0.064 mol) in methylene chloride (150 ml) at 0° C. alpha,alpha-Dichloromethyl methyl ether (8.04 g, 0.070 mol) was then added dropwise with stirring over a three minute period at 0° C. The mixture was stirred for 30 minutes at 0° C. then poured into a saturated aqueous solution of sodium bicarbonate (700 ml). The organic layer was then separated and the aqueous phase extracted with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on a silica gel (300 g) column using hexane-ether (6-1) as eluent. Fractions of 15 ml each were collected. Fractions 21-50 were combined and evaporated in vacuo to a white solid (8.9 g). This solid was rechromatographed on silica gel (300 g), eluting with hexane (15 ml fractions). Fractions 174-215 were combined and evaporated in vacuo to give 2.1 g of the title product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[NH2:15])[C:4]([CH3:16])=[N:3]1.C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:15][C:9]1[CH:10]=[C:11]([NH:14][C:31]([C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:32])[CH:12]=[CH:13][C:8]=1[C:5]1[C:4]([CH3:16])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1nn(C)c(C)c1-c1ccc(N)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(C)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of 76 (119.4 mg, 0.55 mmol) in CH2Cl2 (20 ml) was added N,N-diisopropylethylamine (DIEA, 258 mg, 348 μL, 2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 4-chlorobenzoyl chloride (96 mg, 0.55 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (40 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 77 (49 mg, 25%) as yellow solid. LC-MS: calcd. for C19H19ClN4O: 355 (M+1).
Reaction SMILES: [CH3:1][C:2]1O[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:4](=[O:23])[CH:3]=1.[CH2:24]([NH2:31])[C:25]1C=C[CH:28]=[CH:27][CH:26]=1>C(O)C>[CH3:1][C:2]1[N:31]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:4](=[O:23])[CH:3]=1
Reactant: Cc1cc(=O)c(C(=O)Nc2ccccc2)c(-c2ccccc2)o1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCCCCn1c(C)cc(=O)c(C(=O)Nc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
1 g (3.23 mmol) of 6-methyl-4-oxo-N,2-diphenyl-4H-pyran-3-carboxamide and 590 mg (6.78 mmol) of benzylamine were dissolved in 10 ml of ethanol, and the resulted mixture was stirred over night at room temperature. Ethanol was removed under vacuo. The crystal residue was recrystallized from ethylacetate to afford 700 mg of the title compound having mp. 164°-165.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.[H+].[B-:28]([F:32])([F:31])([F:30])[F:29]>C(OCC)C.C(Cl)Cl>[F:29][B-:28]([F:32])([F:31])[F:30].[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][S+:7]([CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CO)cc1
Reactant: Cc1ccc(CSCc2ccc(C)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C[S+](Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1
Reaction time: 1 h

Procedure:
85.1 g (0.351 mol) of di-(p-methylbenzyl) sulfide and 51.5 g (0.421 mol) of p-methylbenzyl alcohol are initially introduced into 250 ml of methylene chloride under an N2 atmosphere in a reaction vessel (750 ml) provided with a stirrer and thermometer. 142.7 g of an approximately 54% by weight HBF4 solution in diethyl ether is added dropwise at an internal temperature of 20°-30° C. in the course of 40 min, while stirring. The reaction mixture is stirred at RT for 2 h. The reaction mixture is diluted with methylene chloride and extracted 4 times by shaking with deionized water (pH 5-6). The organic phase is dried with MgSO4 and the methylene chloride is removed on a rotary evaporator. The product, which has not been completely freed from methylene chloride, is stirred in 250 ml of toluene at RT for about 1 h and then at 0°-5° C. for 1 h. The crystals which have now precipitated are filtered off with suction and washed with a little toluene. The product is dried under a high vacuum at room temperature for 19 h. 118.6 g of tris-(p-methylbenzyl)-sulfonium tetrafluoroborate are obtained as white crystals of melting point 168°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(CC#N)cc1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
4-Hydroxybenzyl cyanide (5.0 g) and 1-bromobutane (5.7 g) were dissolved in dimethylformamide (100 mL), and potassium carbonate (6.2 g) was added to the resultant solution, followed by heating at 80° C. for one hour, to thereby allow reaction to proceed. After completion of reaction, the resultant reaction mixture was cooled, and then partitioned between brine and ethyl acetate. The resultant ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated. The thus-concentrated product was purified by use of a silica gel column employing hexane/ethyl acetate (4:1), to thereby produce 4-butoxybenzyl cyanide (5.1 g, yield: 70%). The thus-produced 4-butoxybenzyl cyanide (2.0 g) and the 4-methoxyethoxymethoxybenzaldehyde (2.2 g) produced in the production process for compound 1 were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (0.7 g, yield: 23%).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)([O-])=O.C1COCC1.[H][H]>[Pd].[C].C(O)C>[NH2:1][C:4]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1
Reactant: Cc1ccccc1NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1ccc(Oc2ccc(N)cc2N)cc1
Reaction time: 15 h
Yield: 96.9 %

Procedure:
1.55 g (3.90 mmol) of 4-(2,4-dinitrophenoxy)-2′-methylbenzanilide was dissolved into the solvent mixture with 70 ml THF and 30 ml of ethanol, and 0.166 g of 5% Pd-carbon powder was added into this solution. The solution was thoroughly deaerated under the reduced pressure at −78° C., and then stirred for 15 hours after the system was replaced with hydrogen gas and temperature was brought back to room temperature. The solution was concentrated after removing catalyst with Celite to yield 1.26 g of 4-(2,4-diaminophenoxy)-2′-methylbenzanilide shown in the structural formula (V) above in light brown solid (Yield: 96.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].Cl>C1COCC1.CCOCC>[CH2:11]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1)[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Mg (8.76 g, 360 mmol) is suspended in THF (90 mL) under nitrogen in a three-necked flask equipped with a condenser and a dropping funnel. The dropping funnel is filled with 1,4-dibromobenzene (77.3 g, 327 mmol) in THF (40 mL). About 5% of the 1,4-dibromobenzene sol. is added carefully to the Mg-suspension and the reaction is started with the help of a heat gun. When the reaction starts, the 1,4-dibromobenzene sol. is added to such a speed so that the reaction mixture is refluxing gently (about 20 min). The mixture is stirred for further 30 min, and is cooled to 0° C. THF (100 mL) is added and the dropping funnel is filled with a sol. of allyl bromide (30.5 mL, 360 mmol) in THF (50 mL). The allyl bromide sol. is added slowly, maintaining the reaction temperature below 20° C. When the addition is complete, the mixture is stirred for further 30 min, while being cooled to 0° C. Aq. 1M HCl is added. The mixture is diluted with Et2O, and washed with aq. 1M HCl and brine. The combined aq. extracts are extracted back with Et2O. The combined org. extracts are dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Distillation of the residue (11 mbar, 88-92° C.) yields the title compound (39.3 g, about 61%), together with another, unidentified impurity.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[O:14]=[S:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]3=[O:37])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.CN1CCOCC1>ClCCl>[O:14]=[S:15]1(=[O:4])[CH:16]=[CH:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]3=[O:37])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)CC3)cc2)C(=O)O1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic anhydride (2.98 mL, 21.1 mmol) is added dropwise at room temperature to a solution of N-[[(5S)-3-[4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.46 g, 7.02 mmol; prepared as described in International Publication WO 97/09328) and N-methylmorpholine (3.86 mL, 35.1 mmol) in dichloromethane (60 mL). The reaction mixture is stirred overnight at room temperature and then evaporated to dryness. The resulting crude N-[[(5S)-3-[4-(3,4-dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.77 g) is dissolved in tetrahydrofuran (100 mL) and peracetic acid (7.01 mL of a 32% solution in acetic acid) added dropwise at 0° C. The reaction mixture is allowed to warm to room temperature, stirred overnight, and then evaporated to dryness. The residue is purified by flash column chromatography (ethyl acetate) to give the title compound as white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15](B1OC(C)(C)C(C)(C)O1)=[CH2:16]>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[CH2:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Product: C=Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]

Procedure:
Following the general method as outlined in Intermediate 20, starting from 2-bromo-5-methylsulfonylnitrobenzene and vinylboronic acid pinacol ester, the title compound was obtained as a brown oil in quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:18]3[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 4-benzyloxyaniline (1 eq) and 4,6-dichloro-pyrido[3,4-d]pyrimidine (1 eq); δH (CDCl3) 9.11 (1H, s), 8.78 (1H, s), 7.75 (1H, d), 7.56 (2H, dd), 7.40 (5H, m), 7.15 (2H, d), 5.10 (2H, s); m/z (M+1 )+ 409.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1nccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
To a suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (900 mg, 5 mmol) in dichloromethane (25 mL) is added 4-fluorobenzoyl chloride (730 μL, 6.1 mmol) followed by DIPEA (2.0 mL, 11 mmol). After 1 day, the mixture is concentrated and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3×40 mL). The combined organic layers are washed with brine (3×25 mL), dried over magnesium sulfate, filtered and concentrated. The residue is passed through a pad of silica gel using dichloromethane-heptane (1:1) to load the sample and then eluting with dichloromethane to afford N-(3-chloro-pyrazin-2-ylmethyl)-4-fluoro-benzamide as an oil which partially solidified.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol), 4-chlorobenzyl bromide (1.0 eq, 2.68 mmol), and potassium carbonate (1.75 eq) were mixed in ethanol (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated. The crude product was purified by flash chromatography on silica using ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[CH2:23]=[C:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[F-].[K+].O>CS(C)=O>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29][C:24](=[CH2:23])[CH2:25][CH2:26]3)=[C:3]([C:21]#[N:22])[C:4]([C:17]([F:20])([F:19])[F:18])=[N:5]2)=[N:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Reactant: C=C1CCC(CO)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=C1CCC(COc2c(C#N)c(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)CC1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (351 mg, 1 mmol) and (4-methylene-cyclohexyl)-methanol (252 mg, 2 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (5 ml) and potassium fluoride (116 mg, 2 mmol) was added to the DMSO solution. The resulting mixture was stirred at 20° C. for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (15 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product was isolated by chromatography on silica gel column. MS: 441, r.t.: 3.0 min.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9](N)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.N(OC(C)(C)C)=O>CCCCCCC>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1ccsc1
Reactant: CC(=O)OC1CCc2c(N)cccc21
Agent: CC(C)(C)ON=O
Solvent: CCCCCCC
Product: CC(=O)OC1CCc2c(-c3cccs3)cccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 17.1 %

Procedure:
To a stirred solution of 15.0 g (0.079 mole) of 4-amino-1-indanyl acetate in 100 mL (1.25 moles) of thiophene was added dropwise 18.6 mL (0.157 mole) of tert-butyl nitrite. The addition caused an exothermic reaction, raising the temperature of the reaction mixture to 60° C. Upon complete addition, the reaction mixture was stirred for 1.5 hours while cooling to ambient temperature. The reaction mixture was dissolved in 350 mL of n-heptane, and the solution was dried over magnesium sulfate, filtered through a pad of magnesium sulfate, and the filtrate concentrated under reduced pressure to give an oil residue. The oil was purified by column chromatography on silica gel, eluting with hexane, then with 1% ethyl acetatehexane. The appropriate fractions were combined and concentrated under reduced pressure to give 3.5 g of 4-(2-thienyl)-1-indanyl acetate.
Reaction SMILES: CC1C(=O)[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2C1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[BH4-].[Na+].[CH2:49]1[CH2:53]O[CH2:51][CH2:50]1>C(O)C>[CH3:51][C:50]1[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:53][CH:49]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C(C)=CC3
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
In a 500 mL round flask, 2 methyl-9,9-ditetradecyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (20 g, 31.9 mmol) was dissolved in 150 mL of THF and 150 mL of ethanol, and then stirred. Sodium borohydride (NaBH4) (1.8 g, 47.8 mmol) was added to the reactant in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reactant was dissolved in 150 mL of toluene, and then inputted to a round flask. After that, p-toluene sulfonic acid (0.08 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (100 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 15.3 g of 2 methyl-9,9-ditetradecyl-3,9-dihydrocyclopenta[b]fluorene (yield: 78.5%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:11]=2[NH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:11]=2[N:10]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC1=Cc2[nH]nc(C(=O)OC(C)(C)C)c2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC1=Cc2c(c(C(=O)OC(C)(C)C)nn2S(=O)(=O)c2ccc(C)cc2)C1

Procedure:
To a solution of the pyrazole intermediate from step A (275 mg, 1.1 mmol) above in CH2Cl2 (5 mL) was added pyridine (178 μL, 2.2 mmol) and p-toluene sulfonyl chloride (230 mg, 1.21 mmol). After stirring the resulting reaction mixture at room temperature for 3 hours it was diluted with CH2Cl2, washed with 1N HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 10% ethyl acetate-hexanes.