Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.CO.[OH:6][CH:7]([CH2:14][C:15](=[O:40])/[CH:16]=[CH:17]/[C:18]1[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]2[C:30]=1[CH:31]([CH3:33])[CH3:32])[CH2:8][C:9]([O:11]CC)=[O:10]>C(O)(=O)C>[OH:6][CH:7]([CH2:14][C:15](=[O:40])/[CH:16]=[CH:17]/[C:18]1[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]2[C:30]=1[CH:31]([CH3:33])[CH3:32])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(O)CC(=O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)c1c(/C=C/C(=O)CC(O)CC(=O)O)c(-c2ccccc2)c2c3ccccc3ccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of sodium hydroxide (120 mg), water (2 ml), methanol (10 ml) and ethyl (E)-3-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-5-oxohept-6-enoate (230 mg; prepared as described in Example 4) was stirred under an argon atmosphere at the ambient temperature for 5 hours. Water (10 ml) was added and the solution was acidified to pH 5 by treatment with glacial acetic acid. The milky solution was extracted with diethyl ether (4×50 ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give (E-3-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-5-oxohept-6-enoic acid, (80 mg) in the form of a buff foam, m.p. 95°-100° C. [Elemental analysis: C 76.7; H, 6.57; N, 3.02%; Calculated: C, 76.2; H, 6.16; N, 3.2%. N.M.R. (in CDCl3 and D2O): 1.56 (6H, d, J=7 Hz), 2.54 (2H, d, J=7 Hz), 2.55 (2H, d, J=7 Hz), 3.76 (1H, septet, J=7 Hz), 4.42 (1H, quintet, J=7 Hz), 5.68 (1H, d, J=16 Hz), 6.75 (1H, d, J=8 Hz), 7.03-7.57 (9H, m), 7.84 (1H, d, J=8 Hz), 7.86 (1H, d, J=16 Hz)].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.I[CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].[NH2-].[Na+].BrN1C(=O)CCC1=O.[CH2:29]([O:31][P:32]([O:36]CC)[O:33][CH2:34][CH3:35])[CH3:30]>C(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH2:13]([O:12][P:11]([CH:10]([NH:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[P:32](=[O:36])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: CCOP(=O)(CI)OCC
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOP(OCC)OCC
Agent: O=C1CCC(=O)N1Br
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)C(Nc1ccc(Cl)nc1)P(=O)(OCC)OCC

Procedure:
6-Chloro-3-aminopyridine was alkylated with diethyl iodomethylphosphonate, sodium amide as base, with known methods. The obtained 6-chloro-3-pyridinylamino-methylphosphonic acid diethylester (0.5 mol) and N-bromosuccinimid (0.5 mol) in anhydrous carbontetrachloride is irradiated 2 hours with a 200 W lamp. The solid is filtered off, washed with carbontetrachloride and the solution is concentrated in vacuo. The obtained 6-chloro-3-pyridinylamino(bromomethyl)-phosphonic acid diethylester (0.1 mol) is warmed in tetrahydrofuran with triethylphosphite (0.1 mol) in 50° C. for 4 hours. The reaction mixture is concentrated in vacuo. The product is purified chromatographically (eluent dichloromethane: methanol 9:1). Yield 5.1 g.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([SH:11])[CH2:7][CH2:6]1.Br[CH2:13][CH:14]=[O:15].[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH2:14]([O:15][CH:17]([O:16][CH2:20][CH3:19])[CH2:18][S:11][CH:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]1)[CH3:13]
Reactant: C1CCOC1
Reactant: CN1CCC(S)CC1
Reactant: O=CCBr
Agent: C[O-]
Agent: [Na+]
Product: CCOC(CSC1CCN(C)CC1)OCC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Sodium methylate (18.1 g) is added in portions to a solution of 1-methylpiperidine-4-thiol (22 g) in anhydrous tetrahydrofuran (200 ml). After one hour, the diethyl acetal of bromoacetaldehyde (30.3 ml) is added. After 4 hours at room temperature, the solution is heated for 2 hours at 40° C. The insoluble material is filtered off and rinsed with THF. The filtrate is concentrated and then distilled under reduced pressure to give 4-[(2,2-diethoxyethyl)thio]-1-methylpiperidine (36 g; b.p.=104°-108° C. under 0.05 atm) in the form of an oil.
Reaction SMILES: [BH3-]C#N.[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[C:14]2[C:15]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=3[NH:17][C:18]=2[CH:19]=[CH:20][CH:21]=1>C(C(O)=O)(F)(F)F>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[C:14]2[CH:15]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][CH:16]3[NH:17][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(F)c1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1-c1cccc2c1C1CCNCCC1N2
Reaction time: 4 h
Yield: 68.4 %

Procedure:
NaCNBH3 (0.223 g, 3.54 mmol) was added to a solution of 10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.336 g, 1.13 mmol) in CF3CO2H (6 mL), which was cooled in an ice-water bath. After stirring for 4 h, the reaction mixture was quenched by adding 6N HCl (6 mL). The resulting mixture was refluxed for 0.45 h. The mixture was cooled and made basic by the addition of 6 N NaOH (25 mL). The basic mixture was combined with CHCl3 (30 mL) and H2O (5 mL) and the layers were separated. The aqueous layer was extracted with CHCl3 (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product (0.78 g) was chromatographed (SiO2 35 g, eluted with 90:10:2 CH2Cl2:CH3OH:conc. NH4OH) to yield 10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (0.232 g) in 69% yield. 1H NMR (400 MHz, CD3OD) δ 1.37, 1.61, 1.94, 2.05, 2.44, 2.65-2.73, 3.05, 3.54, 4.19, 6.52, 6.63, 7.03-7.09, 7.41; MS (ESI+) for C18H18F2N2 m/z 301.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)=[CH:4][C:3]([O:2][CH3:1])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: COC(=O)C#Cc1ccc(F)cc1
Product: COC(=O)C=C(c1ccc(F)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 73 %

Procedure:
The title compound was synthesized from (4-fluoro-phenyl)-propynoic acid methyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 17, step (a), in 73% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.43 (m, 1H), 7.30 (m, 2H), 7.00-7.20 (m, 3), 6.94 (m, 1H), 6.50-6.90 (m, 3H), 6.12 (s, 1H), 4.36 (m, 2H), 3.75 (m, 2H), 3.7 and 3.6 (s, 3H), 3.20 (m, 2H), 2.75 (m, 2H), 1.90 (m, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI) calculated for C33H35FN3O5 572.3 (M+H); found 472.3 (M-Boc+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:26][CH:27]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H:28]1O>>[OH:26][CH:27]([C:23]1[CH:24]=[CH:25][C:20]([N:14]2[CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: CS(=O)(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C(N)=O)cc1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: CC(O)c1ccc(-n2cc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1

Procedure:
As a specific embodiment of this invention, 100 mg of 3-{[4-(methylsulfonyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carboxamide is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.
Reaction SMILES: [F:1][C:2]([F:24])([C:10]([F:23])([F:22])[CH2:11][O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].FC(F)(C1C=CC=CC=1)CCC(OCC)=O>>[F:1][C:2]([F:24])([C:10]([F:22])([F:23])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)C(F)(F)COC/C=C/c1ccccc1
Agent: CCOC(=O)CCC(F)(F)c1ccccc1
Product: CCOC(=O)CCC(F)(F)C(F)(F)COCCCc1ccccc1

Procedure:
Obtained from Intermediate 39 (1.2 g, 3.46 mmol) by the procedure described in Intermediate 21. Ethyl 4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexanoate was obtained (1.0 g, 82%) as oil.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1.Cl.[NH2:14][CH2:15][CH2:16][SH:17].[BrH:18]>>[BrH:18].[BrH:18].[BrH:18].[CH3:3][NH:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:17][CH2:16][CH2:15][NH2:14])[N:10]=1
Reactant: NCCS
Reactant: CNCc1nc(CO)cs1
Agent: Br
Agent: Cl
Product: CNCc1nc(CSCCN)cs1

Procedure:
Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics:
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:14](Cl)[C:15](=[CH2:17])[CH3:16].C(N(CC)CC)C>O>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[C:1]([C:4]1([CH2:16][C:15]([CH3:17])=[CH2:14])[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH3:10][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][CH2:16][C:15]([CH3:17])=[CH2:14])[CH2:5]1
Reactant: C=C(C)CCl
Agent: CC(=O)C1CCCC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)CC1(C(C)=O)CCCC(C)(C)C1
Product: C=C(C)CCC(=O)C1CCCC(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 1-acetyl-3,3-dimethylcyclohexane (156 grams, 1 mole), sodium hydroxide (60 grams, 1.5 moles), methallyl chloride (135 grams, 1.5 moles) and triethylamine (10 grams) is stirred and heated at 80°-84° C. for 12 hours. The reaction mass is cooled to room temperature. Water is added with stirring, and the aqueous layer is discarded. The organic layer is distilled to afford 1-acetyl-3,3-dimethylcyclohexane (62.4 gm), 1-acetyl-3,3-dimethyl-1-(2-methyl-2-propenyl) cyclohexane (80 gm) (NMR spectrum, FIG. 1; IR spectrum, FIG. 2) and 3,3-dimethyl-1-(4-methyl-4-pentenoyl) cyclohexane (8 gm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH3:13])[CH2:11][O:10]1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C@H:12]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:13])[CH2:11][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (1.7 g) and imidazole (0.49 g) in N,N-dimethylformamide (17 ml) was added 60% oily sodium hydride in mineral oil (0.29 g) by portions at 20° C. with constant stirring. After 5 minutes, the mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled, then poured into water (50 ml) and extracted with ethyl acetate (20 ml×3). The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×15 cm) using methanol-ethyl acetate (5:95) as the eluent. The desired fraction was concentrated under reduced pressure to give (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-2-butanol (1.8 g) as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:25][CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: COCCBr
Reactant: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(OCCOC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300 mg, 0.797 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium hydride (60% in oil, 35.0 mg, 0.877 mmol), and the mixture was stirred at room temperature for 10 min. To the mixture was added 2-bromoethyl methyl ether (166 mg, 1.19 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (218 mg, 0.502 mmol, 63%).
Reaction SMILES: [H][H].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:28]=[CH:27][C:8]2[NH:9][C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[N:25]O)[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1>C(O)C.O1CCCC1.[Ni]>[F:30][C:4]([F:3])([F:29])[C:5]1[CH:28]=[CH:27][C:8]2[NH:9][C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]([NH2:25])[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(C(F)(F)F)ccc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cccc21
Yield: 81.6 %

Procedure:
The procedure used in Example 6 is followed. In a 528 ml autoclave, dissolve 2.2 g of 4-(5-trifluoromethyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 80 ml of ethanol and 80 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 600 for 4 hours. After cooling, the volume of hydrogen absorbed is 412 ml. After filtration of the catalyst over Celite, concentrate under reduced pressure. In this way, we obtain 1.73 g of 4-(5-trifluoromethyl-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a grey foam with the following characteristics:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][Si](C(C)(C)C)(C)C)[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+:32](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[NH2:32][C:15]1([OH:18])[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1.[CH2:1]([O:8][C:9](=[O:26])[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](O)CC1
Product: NC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3.1 g (8 mmol) trans-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-methyl-carbamic acid benzyl ester in 20 ml THF, 10.3 ml (1M, 10.3 mmol, 1.3 eq) Tetrabutylammonium fluoride in THF were added at 6° C. and the mixture was stirred at RT for 2 days. Water was added and the phases were separated and the inorganic phase was extracted with ether and EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with a gradient EtOAc:hexane 1:4-EtOAc yielded 1.9 g 1.9 g (92%) trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid benzyl ester as orange oil, MS: 263 (M).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:19])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>ClCCl>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:19][S:1](=[O:2])[O:5][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: NC(CC1=Cc2ccccc2CC1)=NO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S1NC(CC2=Cc3ccccc3CC2)=NO1
Yield: 14.3 %

Procedure:
Thionyl chloride (2.55 ml, 0.035 mol) was added dropwise to a mixture of N'-hydroxy-(3,4-dihydro-2-naphthalenyl)ethanimidamide (6.5 g, 0.032 mol) and pyridine (5.18 ml, 0.064 mol) in dry dichloromethane (100 ml) at 0° C. Upon completion of the addition, the reaction mixture was concentrated under reduced pressure, placed in an ice bath, diluted with deionized water (50 ml), extracted with diethyl ether (3×50 ml), filtered, dried over MgSO4 and concentrated under reduced pressure to give the crude title compound as a red-brown solid. The solid was triturated with diethyl ether (3×50 ml), dissolved in boiling diethyl ether (100 ml), vacuum filtered and recrystallized from diethyl ether (75 ml) to yield 1.14 g (14.4% yield) of pure product, m.p. 118°-120.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[N:29]1([C:25]2[CH:24]=[C:23]([NH:22][C:20]([C:19]3[CH:35]=[C:36]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:4][C:3]=4[CH3:14])[C:16]([CH3:15])=[CH:17][CH:18]=3)=[O:21])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Solvent: CC(C)O
Product: Cc1nc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)c(C)c2)no1

Procedure:
Example 32 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and 4-methyl-N-(3-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -benzamide (Intermediate 5) with propan-2-ol as the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH3:23])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccn(C)c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=325.2, 327.1 (M+H+), was prepared in accordance with the general method of example 2 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one and methyl iodide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([OH:22])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.C(OCC)(=O)C>[CH2:23]([O:22][C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 64.4 %

Procedure:
To a solution of (1) (1.07 g, 3.44 mmol) and benzyl chloride (0.43 mL, 3.78 mmol) in THF (100 mL) was added potassium carbonate (1.57 g, 11 mmol), then the reaction was heated to 90° C. for 18 h. After cooling to room temperature, water (200 mL) and ethyl acetate (200 mL) were added; the organic layer was separated and washed with water (2×200 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by silcagel column chromatography eluting with a gradient from 10%-50% ethyl acetate in hexane. Fractions containing the pure desired product were combined and solvent was removed under reduced pressure to produce a colorless oil (890 mg, 64%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ICCC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCC3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 2-iodoethylcyclohexane.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](=[O:7])[CH3:6].[CH2:11](O)[CH2:12][CH2:13][OH:14].C(OC)(OC)OC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:8]1([CH3:9])[O:14][CH2:13][CH2:12][CH2:11][O:10]1)\[C:5](=[O:7])[CH3:6]
Reactant: CON=C(C(C)=O)C(C)=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CO/N=C(\C(C)=O)C1(C)OCCCO1
Yield: 94.6 %

Procedure:
Starting from 103 g (0.72 mol) of pentane-2,3,4-trione 3-(O-methyloxime), 275 g (3.62 mol) of 1,3-propanediol, 80 g (0.76 mol) of trimethyl orthoformate and 1.6 g of p-toluenesulfonic acid (9 mmol) and using the procedure of Example 2, 137 g (94% yield) of a reddish oil were obtained which, according to HPLC, had a purity of 70% (phys. data see Tab. 1).