Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[C:15]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH2:30])[CH3:29])=[CH:23][CH:22]=1)([O:17][CH3:18])=[O:16]>>[C:15]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:14])([F:13])[F:1])[S:4][C:5]=2[CH3:12])[CH3:29])=[CH:23][CH:22]=1)([O:17][CH3:18])=[O:16]
Reactant: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2nc(C(F)(F)F)sc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed by reduction. The compound is purified on a silica gel column using ethyl acetate/methanol=9/1 as eluant.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9]
Reactant: NCc1ccccc1Cl
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: O=C1OCCC1=CNCc1ccccc1Cl
Yield: 64.8 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (10 mmol) and 2-chlorobenzylamine (11 mmol) and proceeding according to the abovementioned method A2, 3-(2-chlorobenzylamino)methylenedihydrofuran-2-one (1.54 g, efficiency: 75%) is produced in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:11]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=O.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH2:11][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: COc1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(CNCc2ccc(OC)cc2)c1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 4-methoxybenzylamine (5.6 g, 41.2 mmol) in methanol (100 mL) was added methyl 3-formylbenzoate (5.2 g, 31.7 mmol) at ambient temperature. The solution was stirred for 30 minutes and sodium cyanoborohydride (3.0 g) was added. The mixture was stirred at ambient temperature overnight and concentrated to about 20 mL. Water (100 mL) was added and the mixture acidified with 2N hydrochloric acid to a pH of 3. The mixture was partitioned between ethyl acetate and brine and the organic phase separated and concentrated. The residue was purified by flash chromatography on silica gel using 10% methanol in ethyl acetate to give 6.0 g (67%) of the title compound. MS (DCI): m/z 286 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[C:15]([CH3:22])=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C>[NH2:19][C:16]1[C:15]([CH3:22])=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:10][C:11]=2[C:17]=1[CH3:18]
Reactant: Cc1cc2nc(NC(=O)OC(C)(C)C)[nH]c2c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCO
Product: Cc1cc2nc(NC(=O)OC(C)(C)C)[nH]c2c(C)c1N
Yield: 88.7 %

Procedure:
A suspension of 2-(t-butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole (0.625 g, 2.04 mmol) in ethanol (70 mL) is treated with hydrogen at 45 psi for 15 hours. The mixture is filtered on Celite and the filtrate is rotary evaporated to afford 5-amino-2-(t-butoxycarbonyl)amino-4,6-dimethylbenzimidazole (0.5 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:28][C:27]([C:29]([O:31]C)=[O:30])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>O1CCOCC1>[CH:1]1([C:7]2[C:8]3[S:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CCN(CCN(C)C)c2ccccc2-1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3sc(C(=O)O)cc32)-c2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution (0.05 M) of methyl 12-cyclohexyl-5-[2-(dimethylamino)ethyl]-6,7-dihydro-5H-thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]benzodiazepine-10-carboxylate (from Step 1) in dioxane was treated with 1 N KOH solution (5 eq.). The mixture was stirred at 60° C. for 2 h then treated with 1 N hydrochloric acid. The solvents were removed in vacuo and the residue purified by RP-HPLC (column: Waters XTERRA PREP MS C18, 5 μm; solvents: A: water+0.1% trifluoroacetic acid; B: MeCN+0.1% trifluoroacetic acid; 10% B in A isocratic for 1 min, linear to 50% A in B in 4 min, linear to 40% A in B in 1 min, 40% A in B isocratic for 1 min, linear to 30% A in B in 1 min) to afford the title compound (59% over two steps) after lyophilisation as a solid. 1H-NMR (400 MHz DMSO-d6, 300K δ) 9.12 (bs, 1H), 7.93 (s, 1H), 7.48-7.23 (m, 4H), 4.18 (m, 2H), 3.46 (m, 4H), 3.13 (m, 2H), 2.67 (m, 1H), 1.78-1.27 (m, 10H). MS (ES+) m/z: 438 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[CH2:13][CH2:12]2)=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([CH:11]2[CH2:12][CH2:13]2)=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C#N
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinamide (180 mg, 0.6 mmol) in acetonitrile (20 mL) was added POCl3 (276 mg, 1.8 mmol) and pyridine (285 mg, 3.6 mmol). After stirred at r.t for 2 hrs, the mixture was poured into aq. NaHCO3, extracted with EtOAc. The separated organics was dried and concentrated in vacuo to afford crude 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinonitrile (150 mg).
Reaction SMILES: [CH:1]12B[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3]C2.[OH-].[Na+].[CH2:12]([OH:14])C.OO>O1CCCC1>[CH:7]1([CH:6]([CH:5]2[CH2:4][CH2:3]2)[CH2:12][OH:14])[CH2:8][CH2:1]1
Reactant: CCO
Reactant: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCC(C1CC1)C1CC1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a solution of the compound of Preparation 155 (1 g, 9.24 mmol) in tetrahydrofuran (15 ml) under nitrogen was added 9-borabicyclo[3.3.1]nonane (18.5 ml of a 0.5M solution in tetrahydrofuran, 1 mol. equiv.) and the solution stirred for 18 hours. Sodium hydroxide (3.08 ml of a 3M aqueous solution, 1 mol. equiv.) was added followed by ethanol (5 ml). The reaction was cooled to 5° C. and hydrogen peroxide (3.14 ml of a 30% w/w aqueous solution, 3 mol. equiv.) added. The reaction was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH3:6][O:5][C:1]([CH2:2][CH2:3][N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:4]
Reactant: C=CC(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)Cc1ccccc1
Yield: 98 %

Procedure:
At room temperature, to a 500 mL three-necked bottle, 18.9 g (0.22 mol) of methyl acrylate and 100 mL of methanol were added, and a mixture solution of 10.7 g (0.1 mol) of benzylamine and 50 mL of methanol was slowly added dropwise to the three-necked bottle under stirring. The temperature was naturally elevated, and the addition rate was controlled so that the temperature of reaction system was not greater than 50° C. After the addition, the reaction was stirred at room temperature for 0.5 h, and reacted for 8 h under reflux. After completion of the reaction, the unreacted methanol and methyl acrylate were removed by vacuum distillation to obtain light yellow oily product N,N-bis(β-methoxy carbonylethyl)benzylamine, 27.3 g, yield 98%, by 174-176° C./533 Pa.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][CH2:5][CH3:6].[C:7]([CH:10]1[CH2:13][N:12]([C:14](=[O:34])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:30](=[N:31][CH:32]=2)[NH:29][C:28](=[O:33])[C:21]2([CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:20]3)[CH2:11]1)(=O)[CH3:8]>CO.ClCCl>[CH3:27][N:24]1[CH2:25][CH2:26][C:21]2([CH2:20][C:19]3[C:30](=[N:31][CH:32]=[C:17](/[CH:16]=[CH:15]/[C:14](=[O:34])[N:12]4[CH2:11][CH:10](/[C:7](=[N:2]/[O:3][CH2:4][CH2:5][CH3:6])/[CH3:8])[CH2:13]4)[CH:18]=3)[NH:29][C:28]2=[O:33])[CH2:22][CH2:23]1
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reactant: CCCON
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCO/N=C(\C)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
1-(Aminooxy)propane hydrochloride (10.5 mg, 0.093 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (20.0 mg, 0.052 mmol) in methanol/dichloromethane (1.5 mL, 9:1) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using chloroforme/methanol (9:1) as eluent. Triturations in acetone allowed isolation of the title product as a white solid (9 mg, 39%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CN([CH:21]=[C:22]([C:30](=O)C)[C:23](OC(C)(C)C)=O)C.CCN(CC)CC>C(#N)C>[F:1][C:2]1[C:3]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17][C:22]([CH3:30])([CH3:23])[CH3:21])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(-n2ncc(C(=O)O)c2C)c1F
Reactant: CC(=O)C(=CN(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccnc(-n2ncc(C(=O)OC(C)(C)C)c2C)c1F
Temperature: 85 °C

Procedure:
1-(3-Fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.123 g, 0.575 mmol) in acetonitrile (2 mL) was added TEA (0.080 mL, 0.575 mmol) and Intermediate 43A (0.073 g, 0.517 mmol). The orange solution was heated to 85° C. for 1 h. Additional tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.160 mL) and Et3N (0.080 mL) were added into the solution and the reaction was heated at 85° C. for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography to give tert-butyl 1-(3-fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as yellow oil. MS(ESI) m/z: 292.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.29 (t, J=4.8 Hz, 1H), 2.54 (s, 3H), 2.43 (d, J=1.5 Hz, 3H), 1.58 (s, 9H). To the oil was added 4 N HCl in dioxane (2 mL) and the reaction was stirred at rt for 4 h. The clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (15 mg, 11%) as sticky pink solid. MS(ESI) m/z: 236.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.Cl[C:13]1[C:14]([N+:25]([O-:27])=[O:26])=[CH:15][C:16]2[N:20]=[C:19]([CH3:21])[N:18]([CH2:22][CH3:23])[C:17]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:22]([N:18]1[C:17]2[CH:24]=[C:13]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[C:14]([N+:25]([O-:27])=[O:26])=[CH:15][C:16]=2[N:20]=[C:19]1[CH3:21])[CH3:23]
Reactant: Sc1cccc2cnccc12
Reactant: CCn1c(C)nc2cc([N+](=O)[O-])c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc2cc([N+](=O)[O-])c(Sc3cccc4cnccc34)cc21
Temperature: 130 °C
Reaction time: 6 h
Yield: 36.3 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 20 ml, 6-chloro-1-ethyl-2-methyl-5-nitro-1H-benzo[d]imidazole 910 mg (3.1 mmol) and potassium carbonate 1.29 g (9.3 mmol) were added, and the mixture was stirred for 6 hours at 130° C. The reaction mixture was concentrated under reduced pressure, the residue was crystallized with ethyl acetate, and 1-ethyl-6-(5-isoquinolylsulfanyl)-2-methyl-5-nitro-1H-benzo[d]imidazole 410 mg (35.8%) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:38])[CH2:9]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:39][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 1.5 h

Procedure:
A solution of acryloyl chloride (53.4 mg, 0.59 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 103, 270 mg, 0.59 mmol) and DIPEA (0.112 mL, 0.65 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and was then diluted with CH2Cl2 (25 mL) and washed with sat. NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 provided the title compound mixed together with diacylated material. This material was dissolved in CH2Cl2 and triturated with diethyl ether. The resulting precipitate was collected by filtration, washed with diethyl ether (10 mL) and air dried to give impure product (120 mg) as a yellow solid. This solid was purified by crystallisation from CH3CN to give the title compound (47 mg, 0.092 mmol, 16%) as a yellow solid. All the residues were combined, concentrated in vacuo and crystallised from CH3CN to give a second crop of the title compound (26 mg, 0.051 mmol, 9%) as a yellow solid. Total yield of title compound=73 mg, 24%; 1H NMR: (CDCl3) 1.87-1.99 (1H, m), 2.11-2.24 (1H, m), 2.30 (6H, s), 2.83-2.95 (1H, m), 3-3.19 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 5.75 (1H, dd), 6.34 (1H, dd), 6.44 (1H, dd), 6.79 (1H, s), 7.20 (1H, d), 7.23-7.32 (2H, m) partially obscured by CDCl3 peak, 7.37-7.42 (1H, m), 7.67 (1H, s), 8.08 (1H, d), 8.38 (1H, d), 8.46 (1H, s), 9.00 (1H, s), 9.71 (1H, s); m/z: ES+ MH+ 512.26.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 25.2 mmol, Ark Pharm) in DMF (150 mL) was cooled in an ice bath to about 0° C. and then NaH (60% dispersion in mineral oil, 1.21 g, 30.3 mmol) was added. After about 15 min, 4-tert-butylbenzene-1-sulfonyl chloride (6.46 g, 27.8 mmol) was added. The reaction was maintained between about 0-10° C. for about 2 h. Then, the reaction was diluted with water (200 mL) to give a yellow suspension. The solid was collected by vacuum filtration, while washing with additional water (100 mL), and dried in a vacuum oven at about 70° C. to give 2-bromo-5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (9.05 g, 91%): LC/MS (Table 2, Method a) Rt=3.05 min; MS m/z: 394/396 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:27]([C:29]4([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]4)=[O:28])=[CH:22][C:21]=3[F:42])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[F:42][C:21]1[CH:22]=[C:23]([N:26]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:27]([C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[O:28])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)c(F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of N-(4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (5.5 g, 9.73 mmol) in MeOH (500 mL) was added a catalytic amount of Pd/C (10%). The reaction mixture was stirred at rt under H2 atmosphere overnight. The mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid (4.6 g, 93%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[N:27][C:28]=3[NH2:30])[N:23]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)[CH2:33][CH2:32]3)[N:22]=2)=[CH:17][C:16]=1[O:44][CH3:45]>N1C=CC=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)[CH2:33][CH2:32]3)[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[C:16]([O:44][CH3:45])[CH:17]=3)[C:29]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethyl)-1-benzenecarbonyl chloride (262 mg, 1.256 mmol) in dichloromathane (1 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.145 mmol) in pyridine (8 mL) at 0° C. After 30 minutes, the ice bath was removed the the reaction mixture was stirred at room temperature for 1.5 hour. Solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethyl)benzamide (516 mg, 74%). 1H NMR (CDCl3-d) δ 1.55 (m, 2H), 1.74 (m, 2H), 2.10-2.27 (m, 6H), 2.30 (s, 3H), 2.51 (m, 4H), 2.66 (m, 3H), 3.96 (s, 3H), 4.04 (s, 3H), 4.78 (m, 1H), 5.57 (bs, 2H), 7.30 (m, 2H), 7.79 (d, J=8.25 Hz, 2H), 8.04 (d, J=8.05 Hz, 2H), 8.38 (s, 1H), 8.64 (s, 1H), 8.68 (d, J=8.20 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][N:12]=[N+]=[N-])[O:10][C:6]=2[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][C:3]=1[F:22]>[Pt]>[F:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][NH2:12])[O:10][C:6]=2[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][C:3]=1[F:22]
Reactant: Cc1ccccc1-c1cc(F)c(F)c2c1OC(CN=[N+]=[N-])C2
Agent: [Pt]
Product: Cc1ccccc1-c1cc(F)c(F)c2c1OC(CN)C2
Yield: 100.5 %

Procedure:
Treatment of (±)-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide (0.85 g, 2.82 mmol) with sulfided platinum on carbon (0.30 g, 5 wt. %) generally according to the procedure described for Example 1 gave 0.78 g (67%) of (±)-1-[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a grey solid, hydrochloride salt. mp >224-227° C.; Anal. calcd. for C16H15F2NOHCl 0.4H2O: C, 60.25; H, 5.31; N, 4.39. Found: C, 59.98; H, 5.33; N, 4.39.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[CH:18]=[CH2:19].C1(C(N)C2CCCCC2)CCCCC1>C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.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]>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([NH:10][C:3]1[C:2](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1)=[O:16]
Reactant: COc1ccc(Br)c(NC(=O)C(C)(C)C)n1
Reactant: C=CC(=O)OCCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CCCCOC(=O)/C=C/c1ccc(OC)nc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A mixture of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-2,2-dimethylpropanamide (78.783 g, 274 mmol), bis(tri-t-butylphosphine)palladium(0) (1 g, 1.957 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.892 g, 0.974 mmol) in dry, degassed 1,4-dioxane (600 ml) was treated with n-butyl acrylate (47.1 ml, 329 mmol) and dicyclohexylmethylamine (64.5 ml, 302 mmol). The reaction mixture was then heated at 80° C. for 4 h and then at 120° C. for 3 h. The reaction was then evaporated and water (1000 ml) was added and the mixture was extracted with diethyl ether (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product. This was then dissolved in DCM (300 ml) and chromatographed (10-30% ethyl acetate:40-60 petroleum ether) and then dried in vacuo to give product as a white solid (87.412 g, 95%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=O.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>C(O)(=O)C.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[N:17]/[CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[C:13]([F:12])([F:22])[F:23]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: O=Cc1nc2ccccc2[nH]1
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccccc1C/N=C/c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1.1 g (7.5 mmol) 1H-benzimidazole-2-carbaldehyde (Fluorochem), 1.3 g (7.5 mmol) 2-trifluoromethylbenzylamine and 1 drop glacial acetic acid in 10 ml methanol was stirred at room temperature for 72 hours. The resulted yellow solution was evaporated to c.a. 2–3 ml, cooled to −40° C. and the formed solid filtered. It was washed with methanol/water mixture (1/2) and dried under reduced pressure. Yield—1.96 g (86.4%). 1H NMR (250 MHz, D2-DCM), δ: 5.03 (s, 2H), 7.28–7.69 (m, 8H), 8.46 (s, 1H).