Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].Cl>O1CCCC1>[C:2]([CH:3]([CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH3:9]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A 6.214 g portion of sodium hydride (55% dispersion in oil) was washed with hexane, 150 ml of tetrahydrofuran was added thereto and, under ice-cooling, a solution prepared by dissolving 18.534 g of ethyl 3-oxobutanoate in 75 ml of tetrahydrofuran was added dropwise thereto. After stirring at room temperature for 30 minutes, this solution was added dropwise, under ice-cooling, to a solution prepared by dissolving 25.500 g of 1-bromo-3,3-dimethyl-2-butanone in 150 ml of tetrahydrofuran, followed by stirring overnight at room temperature. After adding 171 ml of 1 M hydrochloric acid to the reaction liquid, tetrahydrofuran was evaporated under a reduced pressure. The residue was extracted with diethyl ether, and the organic layer was washed with water (twice) and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, 30.51 g of ethyl 2-acetyl-5,5-dimethyl-4-oxohexanoate was obtained as yellow oil. A 15.00 g portion of this product was dissolved in 250 ml of acetic acid, and 9.48 ml of 4-fluorophenethylamine was added thereto, followed by stirring at 100° C. for 4 hours. The solvent was evaporated under a reduced pressure. The residue was dissolved in ethyl acetate and washed with water, a 1 M sodium hydroxide aqueous solution (twice) and saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:15-1:10) to obtain 15.91 g of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:25][N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:25][N:26]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:29][CH:28]=[N:27]1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: COCCOC
Product: Cn1nccc1-c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 100 mg, 0.26 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59.7 mg, 0.29 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.52 ml, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.09 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated and water (5 ml) was added to the residue, the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated in vacuo and the residue was purified using the MDAP to yield the title compound. 22 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O)(=O)C.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([F:29])[CH:23]=3)[C:14]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:14]3[C:15](=[N:16][CH:17]=[N:18][C:13]=3[NH2:12])[N:19]([CH:30]3[CH2:35][CH2:34][CH:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:32][CH2:31]3)[N:20]=2)=[CH:23][C:24]=1[F:29]
Reactant: CN1CCNCC1
Reactant: Nc1ccc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 283.3 %

Procedure:
N-methylpiperazine (3.6 g, 0.036 mol) and acetic acid (2.17 g, 0.036 mol) were added to a suspension of 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (Intermediate R) (4.1 g, 0.012 mol) in dichloroethane (200 mL). Sodium triacetoxyborohydride (3.32 g, 0.016 mol) was then added portionwise to the reaction suspension. The reaction mixture was stirred at room temperature for 18 h. Additional sodium triacetoxyborohydride (1.79 g, 0.084 mol and 1.28 g, 0.06 mol) was added in two batches over 5 days. The reaction mixture was filtered, washed with dichloroethane (100 mL) and the filtrate was concentrated under reduced pressure to give 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (14.5 g, 0.034 mol). The yellow solid was purified and the cis/trans isomers were separated by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (93:5:2) as the eluent to give trans 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (lower running component) as a white solid (115 mg, 0.27 mmol). 1H NMR (DMSO-d6, 400 MHz) 8.19 (s, 1H), 7.18 (m, 2H), 6.88 (m, 1H), 5.46 (s, 2H), 4.60 (m, 1H), 2.35 (br m, 4H), 2.14 (s, 3H), 1.95 (br m, 6H), 1.44 (m, 2H), 1.26 (m, 4H), 0.86 (m, 2H). TLC (dichloromethane/methanol/ammonium hydroxide=95:5) Rf 0.31.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The product from Example 109 was converted to the title sulfonamide according to the method of Example 384 (yield: 110 mg, 45.7%). mp 224-226° C. 1H NMR (300 MHz, CDCl3) δ 4.86 (br s, 2H), 6.89-7.03 (m, 4H), 7.19-7.30 (m, 1H), 7.45-7.52 (m, 1H), 7.56-7.66 (m, 1H), 7.79 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 1H), 8.08 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F3N3O4S.0.25H2O: C, 55.32; H, 2.93; N, 8.80. Found: C, 55.26; H, 3.11; N, 8.58.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cccnc2Br)cc1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cccnc2N2CCNCC2)cc1
Temperature: 25 °C

Procedure:
Dissolve 2-bromo-3-(4-fluorophenyl)-pyridine (4.4 g, 17.5 mmol) in toluene (185 mL) and add piperazine (4.5 g, 52.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.8 g, 0.873 mmol), sodium-t-butoxide (2.35 g, 24.4 mmol) and racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.63 g, 2.62 mmol). Reflux the mixture for 18 hr.s, then cool to room temperature and filter through Celite®. Dilute the mixture with ethyl acetate and wash with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 15:85 2 M ammonia in methanol:DCM) to give the title preparation as a yellow solid (3.9 g, 87%). MS (APCI): m/z=258 [M+H]+.
Reaction SMILES: CN(CC)C.C([O-])([O-])=O.[K+].[K+].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1>[Cu]I>[OH:27][CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:20][CH:21]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CCN(C)C
Agent: O=C([O-])[O-]
Product: O=C1CCCN1c1ccc(CCO)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of CuI (0.198 mmol), N,N-dimethylethylamine (0.398 mmol), K2CO3 (3.98 mmol) and pyrrolidin-2-one (3.98 mmol) was purged with nitrogen gas. 2-(4-bromophenyl)ethanol (1.99 mmol) was added and the mixture was purged with purged again with nitrogen. The reaction mixture was stirred at 130° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (25 mL), NH4OH (5 mL) and the aqueous layer was extracted with dichloromethane (3×40 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure; the crude was purified by column chromatography to afford the final product. Yield=37%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[SH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>>[CH3:6][O:5][C:3]([CH2:2][S:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:4]
Reactant: COC(=O)CBr
Reactant: O=C(O)c1cccc(S)c1
Product: COC(=O)CSc1cccc(C(=O)O)c1

Procedure:
From methyl bromoacetate and 3-mercaptobenzoic acid (30%): MS (ES-Neg): [M−H]− 225.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([F:22])[CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[F:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Reactant: Cc1cc(B(O)O)ccn1
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: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)ccn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A 25 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2-fluorophenyl)methyl]piperazine-1-carboxylate (1.00 g, 2.68 mmol, 1.00 equiv), (2-methylpyridin-4-yl)boronic acid (0.737 g, 5.38 mmol, 2.01 equiv), Tetrakis(triphenylphosphine)palladium (0.311 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (10 mL) and water (2 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/2) to yield 0.600 g (58% yield) of tert-butyl 4-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 386 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:9]=2[CH:18]=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CO)C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(c1ccc(C(F)(F)F)cc1C=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of (2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)methanol (113.1 mg, 0.37 mmol) in methylene chloride (2 mL) at room temperature was added Dess-Martin periodinane reagent (175 mg, 0.41 mmol). The mixture was stirred at room temperature for 1 hour. 1N NaOH was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with 1N NaOH, brine, dried over sodium sulfate and concentrated in vacuo to yield the title compound (107.2 mg, 95%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.18 (m, 4H) 1.36 (d, J=5.81 Hz, 1H) 1.53-1.69 (m, 4H) 1.71-1.76 (m, J=2.49 Hz, 1H) 1.83-1.90 (m, 1H) 3.22 (s, 3H) 4.73 (d, J=6.22 Hz, 1H) 7.66 (d, J=8.30 Hz, 1H) 7.81 (dd, J=8.30, 1.66 Hz, 1H) 8.14 (s, 1H) 10.41 (s, 1H).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]>C1C=CC=CC=1.CCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:25])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cc(N=C=S)ccc1Cl
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCCCC
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Following a procedure similar to that described in Example 42 but using 2.3 g. sodium in 300 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 21.4 g. 4-chloro-3-nitrophenyl isothiocyanate (m.p. 54°-56°C., prepared from 4-chloro-3-nitroaniline) in 100 ml. dry acetone there was obtained 1-(4-chloro-3-nitrophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 92°-94°C. (from benzene-n-pentane); hydrochloride (22.5 g.), m.p. 138°-140°C. (from acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)=[CH:7][CH:6]=1)=[O:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>C1COCC1>[CH2:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:8]2[O:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(-c2n[nH]c3ccccc23)o1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
A solution of 3-(5-methoxycarbonyl-2-furyl)-1H-indazole (2.0 g, 8.3 mmol) and benzyl bromide (2.5 mL, 21.0 mmol) in THF (100 mL) was added dropwise via dropping funnel to a suspension of sodium hydride (60% dispersion in oil: 0.50 g, 12.5 mmol) in THF (200 mL). The resultant mixture was stirred at room temperature for 20 h. The mixture was poured onto brine and the layers separated. The aqueous layer was extracted three times with ether and then the combined organic material was washed with saturated aqueous NaHCO3 solution, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica (EtOAc:cyclohexane 1:4) and then the product was recrystallised (EtOAc/hexane) to give a yellow solid: mp 137-138° C.; MS (EI) M30 332; 1H-NMR (CDCl3) 3.97 (s, 3H), 5.67 (s, 2H), 7.03 (d, 1H, J=3.7 Hz), 7.22-7.43 (m, 9H), 8.27 (d, 1H, J=8.1 Hz); Anal. (C20H16N2O3) C, calcd 72.28; found 71.92, H, calcd 4.85; found 4.75, N, calcd 8.43; found 8.39.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:14]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:23](=[O:24])[C@@H:22]3[CH2:26][CH2:27][CH2:28][N:21]3[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
5.00 g of 1-Amino-6-aminomethyl-isoquinoline and 6.20 g Boc-L-proline were dissolved in 88 mL DMF. 10.6 g of TBTU was added followed by a dropwise addition of N-methylmorpholine. Stirring was continued for 1 h at ambient temperature and the solvent was removed i.vac. The residue was extracted with 5% aqueous NaHCO3 solution and with ethyl acetate. The organic layer was separated and dried (NaSO4). The solvent was removed to give 10.7 g (quant.) of N-(1-Amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-prolinamide as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:43][CH3:44])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:41][CH2:40][CH2:39][N:38]([CH3:42])[CH2:37][CH2:36]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][N:17](C2CCCCO2)[CH:18]=1)=[O:12])[CH3:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:10]([CH2:8][CH3:9])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:41][CH2:40][CH2:39][N:38]([CH3:42])[CH2:37][CH2:36]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][NH:17][CH:18]=1)=[O:12])[CH3:44]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCN(C)CC3)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCN(C)CC3)cc2[nH]1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 39 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl}urea in solution in 1 mL of dichloromethane. The reaction medium is stirred at 22° C. for 16 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-4 cartridge. The elution is carried out with pure dichloromethane and then with dichloromethane containing 5% of ammoniacal methanol. 12 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea trifluoroacetate salt are obtained in the form of a black resin. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.10 (t, J=7.0 Hz, 6H); 2.20 (broad m, 2H); 2.89 (s, 3H); from 3.07 to 3.68 (m, 8H); 3.34 (q, J=7.0 Hz, 4H); 7.22 (d, J=7.5 Hz, 1H); 7.55 (d, J=12.0 Hz, 1H); 7.96 (s, 1H). EI mass spectrum: m/z=428 M+., m/z=355 (M−C4H11N)+, m/z=69 CF3+ (relative to TFA), m/z=58 C3H8N+ (base peak), m/z=45 CO2H+ (relative to TFA).
Reaction SMILES: [NH2:1][OH:2].Cl.[OH-].[K+].[O:6]1[CH2:12][CH2:11][C:10](=S)[NH:9][CH2:8][CH2:7]1.C(OCC)C>CO>[O:6]1[CH2:12][CH2:11][C:10](=[N:1][OH:2])[NH:9][CH2:8][CH2:7]1
Reactant: S=C1CCOCCN1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: ON=C1CCOCCN1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of NH2OH HCl (2 eq.) in methanol was added to an equimolar methanolic solution of KOH. KCl was filtered off and the filtrate was added to a solution of 1,4-oxazepane-5-thione (1 eq.) in methanol. The mixture was stirred at 55° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was taken in chloroform, washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give, after trituration with ethyl ether, the title compound. 1H NMR (300 MHz, CDCl3) δ 8.9 (bs, 1H), 6.15 (bs, 1H), 3.68-3.51 (m, 4H), 3.21-3.19 (m, 2H), 2.38-2.31 (m, 2H); MS (ES) C5H10N2O2 requires 130. Found: 131 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH3:12])[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:13][NH2:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:12])([CH2:11][NH:14][CH3:13])[OH:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(C)CO2)c1
Reactant: CN
Product: CNCC(C)(O)c1cccc(OC)c1

Procedure:
2-(3-Methoxyphenyl)-2-methyloxiran (34.0 g) was stirred with aqueous methylamine (100 ml, 33%) and alcoholic methylamine (200 ml, 33%) overnight at ambient temperature. The mixture was evaporated to an oil under reduced pressure, dissolved in hydrochloric acid (2 M) and extracted with toluene. After basifying the aqueous acid with sodium hydroxide (5 M) the basic oil was extracted with toluene and dried (MgSO4). The solvent was removed under reduced pressure to leave the title compound as an oil (27.7 g). The hydrochloride was formed in isopropyl alcohol-ethereal hydrogen chloride, m.p. 155°-156° C. (Found: C, 57.55; H, 8.3; N, 5.8% C11H17NO2HCl requires C, 57.0; H, 7.8; N, 6.0%.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:38])[CH2:33][C:34]([OH:37])([CH3:36])[CH3:35]>>[OH:37][C:34]([CH3:36])([CH3:35])[CH2:33][C:32]1[N:38]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: CC(C)(O)CC(N)=NO
Product: CC(C)(O)Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
80 mg (0.188 mmol) of the compound from Example 100A and 52 mg (0.281 mmol) of N′,3-dihydroxy-3-methylbutanimidamide were reacted according to the General Method 2. Yield: 65 mg (67% of theory)
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]>[Pd]>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: [Pd]
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 2.5 °C
Reaction time: 21.5 h
Yield: 85 %

Procedure:
To the solution of 14-hydroxycodeinone produced in Example 5 is added 0.5 g of 5% palladium on carbon, 50% wet. The mixture is hydrogenated at 30 to 40 psi for a period of 18 to 25 hours at ambient temperature. The catalyst is filtered off and is washed with 5 ml of water. The filtrate is cooled to 0-5° C. and with stirring, sufficient concentrated (28-30%) ammonium hydroxide is added to raise the pH to 10-12. The resulting suspension is stirred at 0-5° C. for 1-2 hours. The solid is filtered off and is washed with two 5 ml portions of water. The product is dried in vacuo (e.g., 50 mm Hg) at 30-40° C. to yield 8.1 g of oxodone (85% yield based on thebaine bitartrate). The product purity is better than 98%.