Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].[CH:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([CH3:8])[CH3:7]>O>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([S:2]([OH:5])(=[O:3])=[O:1])=[CH:15][C:9]=1[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)c1ccccc1N
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1cc(S(=O)(=O)O)ccc1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
5.7 ml of H2SO4 are added to 10 ml of water, the mixture is heated to 80° C. and 13.5 g of 2-isopropylaniline are then added. The water is evaporated off by heating under vacuum, and the temperature is then gradually raised over one and a half hours to reach 260° C. After 3 hours with stirring and under vacuum at 260° C., the reaction medium is allowed to return to RT and to atmospheric pressure, and is then heated for 30 minutes in the presence of 15 ml of NaOH and 100 ml of water in order to dissolve the reaction medium. The insoluble matter is filtered off, and the mixture is cooled to 5° C. and then acidified to pH 1 by adding concentrated H2SO4. The precipitate formed is filtered off, washed with 5 ml of cold water and dried to obtain 20 g of the expected product.
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=O.[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11].N12CCN(CC1)CC2>C(O)C>[C:12]1([CH:10]2[O:3][N:1]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:11]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC1CCCCC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC(c2ccccc2)C1
Temperature: 80 °C
Reaction time: 60 h
Yield: 72.4 %

Procedure:
A mixture of ethyl 2-nitroacetate (0.96 mL; 8.70 mmol), vinylcyclohexane (0.6 mL; 4.35 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.050 mg, 0.438 mmol) and ethanol (2 mL) was stirred at 80° C. for 60 hrs. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate 0.690 g (63%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1
Reactant: COC(COc1ccc(O)cc1)OC
Reactant: CN=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(OCC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (5.0 grams) and benzene were charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (3.5 ml) and 4 drops of triethylamine were then added, and the reaction mixture was stirred at room temperature for a period of about 6 hours. After this time the reaction mixture was filtered, and the filtrate was concentrated to 10 ml by partially stripping the solvent under reduced pressure. Cyclohexane (10 ml) was then added to the concentrate, resulting in the formation of a precipitate. The precipitate was recovered by filtration to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-methylcarbamate as a slightly pink solid melting at 79° to 81° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: c1cnc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)nc1
Temperature: 180 °C
Yield: 17.7 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol), 2-chloropyrimidine (50 mg, 0.346 mmol) and N,N-diisopropylethylamine (112 μl, 0.629 mmol) in N-methylpyrrolidinone (0.5 ml) was heated at 180° C. in the microwave (Smith Personal Synthesiser) for 600 seconds. The reaction mixture was partitioned between ethyl acetate (10 ml) and saturated NaHCO3 (10 ml). The organic washings were dried over Na2SO4 and concentrated in vacuo to give an oil. The compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:ammonia, 100:0:0 to 88:12:1.2. Compound still impure so purified further on the Fraction Lynx automated LC system to give the title compound as a solid (22 mg, 17%) 1H NMR (400 MHz, CDCl3) δ 8.30 (brs, 2H), 7.34 (d, 2H), 6.92 (d, 2H), 6.70 (t, 1H), 4.10 (t, 2H), 3.78-3.84 (m, 2H), 3.62-3.72 (multiple peaks, 4H), 3.44-3.55 (m, 2H), 3.40 (m, 2H), 3.04-3.18 (m, 2H), 1.85-2.25 (multiple peaks, 10H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)C>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:15]=1
Reactant: NC(N)=S
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2csc(N)n2)cc1

Procedure:
At room temperature, methyl 4-bromoacetylbenzoate (1.00 g) and thiourea (296 mg) were dissolved in isopropanol (100 ml), followed by heating under reflux for 15 minutes. Under stirring at the same temperature, anhydrous sodium carbonate (206 mg) was added to the reaction mixture. The resulting mixture was heated under reflux for 20 minutes. After completion of the reaction, water (50 ml) was added under ice cooling and the solid so precipitated was collected by filtration. The solid was dissolved in water and dichloromethane. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was then distilled off. The pale yellow solid so precipitated was washed with ether, whereby the title compound (634 mg, 70%) was obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Si](Cl)(C)(C)C.[NH2:15][CH2:16][CH:17]([SH:20])[CH2:18][CH3:19].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]>CC#N>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([NH:15][CH2:16][CH:17]([SH:20])[CH2:18][CH3:19])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(S)CN
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N,N-Diisopropylethylamine (8.50 ml, 0.0488 mol) and Me3SiCl (3.50 ml, 0.0239 mol) were added to an ice-cold, stirring solution of 1-amino-2-butanethiol (3.00 g, 0.0212 mol) in MeCN (16.0 ml). The solution was stirred 10 minutes at 0°, then treated with more N,N-diisopropylethylamine (3.70 ml, 0.0212 mol) and with a solution of p-nitrobenzyl chloroformate (4.57 g, 0.0212 mol) in MeCN (5.0 ml). The resulting mixture was stirred for 30 minutes at 0° and 90 minutes at room temperature. The mixture was poured into ice-water (50 ml) and extracted with EtOAc (75 ml). The organic phase was separated, washed with 1.25N HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered and evaporated under vacuum to an oil (5.79 g).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([N:8]2[C:7]3[C:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1cc(-c2ccccc2)c2c(c1)ncn2-c1ccccc1
Yield: 47.3 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1 mmol), benzeneboronic acid (180 mg, 1.5 mmol), potassium carbonate (700 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) was stirred at reflux overnight. The cooled mixture was partitioned between water and ethyl acetate. The organic phase was collected, washed with brine, dried and concentrated under reduced pressure. Recrystallisation from methanol afforded the product as an off-white solid (160 mg, 47%), m/z, 339.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([O:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([O:30][C:31](=[O:32])[NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)Oc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)Oc4ccccc4)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid phenyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and phenylchloroformate (146 μl, 1.16 mmol). The title compound was obtained as brown powder (55 mg, 13%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH:19]1[CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C(O)C>[N:19]1([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[N:3]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(N2CCC2)nc2ccccc21
Temperature: 50 °C

Procedure:
2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (0.5 g) was placed in a flask with azetidine (0.48 mL), Hunig's base (iPr2Net, 1.5 mL) in 1 mL of ethanol. The reaction was heated to 50° C. overnight and then concentrated to dryness to get 0.55 g of crude 2-(azetidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(O)c2ccccc2n1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(O)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A slurry of 2,4-dihydroxyquinoline (20.7 g, 0.13 mol), potassium carbonate (35.5 g, 0.26 mol), and dimethyl sulfate (14.6 ml, 0.15 mol) in acetone (800 ml) was heated at reflux for 3 days. The reaction was cooled to ambient temperature then evaporated under reduced pressure. The residue was slurried in a system of water (1000 ml) and ethyl acetate (500 ml) for 1 hour. The solids were collected then rinsed with water (3×250 ml) and ethyl ether (3×250 ml). Vacuum dried over phosphorus pentoxide to give 2-hydroxy4-methoxyquinoline (16.3 g, 72%) as a tan powder. [M+H]+ 176, M+CH3CN=217.
Reaction SMILES: [N+:1]([C:4]1[C:5](NN)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(O)=O.C=O>CO.C([O-])(=O)C.[Ag+]>[N+:10]([C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([O-:12])=[O:11]
Reactant: NNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ag+]
Agent: C=O
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CO
Product: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Yield: 21.4 %

Procedure:
Silver acetate (2.0 g) was added to a solution of the crude 3,5-dinitro-pyridinyl-hydrazine (2.2 g) in a mixture of methanol:H2O (1:1,6 ml), and the mixture was stirred at reflux overnight. Solvent was evaporated, then water and conc. NH4OH were added. The mixture was extracted with ethyl ether, the combined extracts were dried over MgSO4, concentrated and purified by column chromatography (5:1 hexane: ethyl acetate) to give the title compound (400 mg) in 21.8% yield. MS (DCI/NH3) m/e: 124 (M-46+1). 1H NMR (CDCl3, 300MHz) δ: 9.77 (m, 2H), 9.27 (m, 1H).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[CH:32]([Si:25]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=2)=[CH:17]1)([CH3:33])[CH3:34]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)cc2)c2cccnc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(N)cc2)c2cccnc21

Procedure:
Benzyl-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amine (112, 210.0 mg, 0.447 mmol), methanol (15.0 mL) and palladium hydroxide (30.0 mg, 0.214 mmol) were combined. The reaction mixture was hydrogenated under under an atmosphere of hydrogen (1 atm) at room temperature for 2 hours. Filtration and concentration gave the compound (113, 154 mg, 91%).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[OH:30][CH2:31][CH2:32][NH:33][NH2:34].O>O1CCCC1>[OH:30][CH2:31][CH2:32][N:33]1[CH2:28][CH2:27][C:26]([CH2:25][CH:22]2[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)=[N:34]1
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: NNCCO
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CC4=NN(CCO)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 57.9 %

Procedure:
A solution of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (223 mg) and 2-hydroxyethylhydrazine (60 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (146 mg, yield 58%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 504 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[F:55])([OH:47])[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][C:43]1([OH:47])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1
Reactant: NC1CCCC(O)(Cc2ccccc2F)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(Cc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.05 mmol, 24.8 mg), HCl salt of 3-amino-1-(2-fluorobenzyl)cyclohexanol (0.05 mmol, 11 mg), HATU (0.05 mmol, 19 mg) and DIEA (80 μL) in DMA (300 μL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6].[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[CH2:28][C:27](=O)[CH2:26][CH2:25]2>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][CH:27]2[CH2:26][CH2:25][C:24]3[C:29](=[C:30]([F:32])[CH:31]=[C:22]([F:21])[CH:23]=3)[CH2:28]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)CC(=O)OC)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: MS m/z 449.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:34])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.2 %

Procedure:
A mixture of 32 mg (0.065 mmol) [(3S,4R)-4-(4-Chloro-3-fluoro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 57 uL (0.325 mmol) DIPEA and 11.2 mg (0.097 mmol) mesyl chloride in 1.5 mL DMF was shaken for 90 min at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 16 mg (43%) of the title compound as off-white solid. MS m/e: 570.4 [M+11]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:18]1[C:19]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2ccc(N)cc2)c1
Reactant: Clc1ncnc2cc(-c3ccccc3)sc12
Product: COc1cccc(Nc2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc2)c1
Yield: 17 %

Procedure:
Utilizing a procedure analogous to that described in Example 61, the title compound was prepared in 17% yield from added N-(3-methoxy-phenyl)-benzene-1,4-diamine (100 mg, 0.405 mmol) and 4-chloro-6-phenyl-thieno[3,2-d]pyrimidine (100 mg, 0.405 mmol). RP18-HPLC RT: 6.833 minutes; API MS: 425.53 (M+1); MP: 189-191° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])([F:7])[F:6].[CH:13]1[CH2:17][CH:16]=[CH:15][CH:14]=1>>[F:9][C:4]1([C:5]([F:8])([F:7])[F:6])[C:3]([F:10])([C:2]([F:11])([F:12])[F:1])[CH:16]2[CH2:17][CH:13]1[CH2:14][CH2:15]2
Reactant: FC(=C(F)C(F)(F)F)C(F)(F)F
Reactant: C1=CCC=C1
Product: FC(F)(F)C1(F)C2CCC(C2)C1(F)C(F)(F)F

Procedure:
In a like manner, octafluoro-but-2-ene and cyclopentadiene react to give 2,3-difluoro-2,3-bis(trifluoromethyl) bicyclo [2.2.1] heptane which, after hydrogenation over ruthenium gives 2,3-bis(trifluoromethyl)bicyclo [2.2.1] heptane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[CH2:39]([N:46]=[C:47]=[S:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([NH:46][C:47]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:20]=[C:19]([CH2:21][O:22][C:23]5[CH:24]=[CH:25][C:26]([CH2:27][CH:28]6[S:32][C:31](=[O:33])[NH:30][C:29]6=[O:34])=[CH:35][CH:36]=5)[N:18]([CH3:37])[C:17]=4[CH:38]=3)[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[S:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: S=C=NCc1ccccc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(NC(=S)NCc5ccccc5)c4c3)cc21
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) in anhydrous tetrahydrofuran (10 ml) was added benzyl isothiocyanate (0.24 g) and the mixture was stirred at room temperature for 5.5 hours and then at 50° C. for 9 hours. The reaction mixture was concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1→3:1 as the eluant to afford the title compound (0.36 g, Rf=0.53: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=3:1).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=399.1 (M+H)+