Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:7]=1)(=[O:3])[CH3:2].[CH3:39][I:40]>>[I-:40].[C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N+:34]=1[CH3:39])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1C(C)(C)C
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1C(C)(C)C
Product: [I-]

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.256 g of product from Example 34 and 1.52 ml of methyl iodide. The residue is recrystallized from methyl alcohol to give 0.315 g of the desired product as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][Cl:10])[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[ClH:10].[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][NH:16][C:14](=[NH:13])[SH:15])[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(C)c(O)c1CCl
Reactant: NC(N)=S
Solvent: CCO
Product: C=Cc1cnc(C)c(O)c1CNC(=N)S
Product: Cl

Procedure:
A mixture of 21.0 g of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine, 6.74 g. of thiourea, and 200 ml. of ethanol was refluxed 3 hours. The cooled mixture was filtered and the solids were washed with ether to give 2-methyl-3-hydroxy-4-isothioureidomethyl-5-vinylpyridine hydrochloride.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCCOC>[NH:15]1[CH2:16][CH2:17][CH:12]([O:11][C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=2)[CH2:13][CH2:14]1
Reactant: OC1CCNCC1
Reactant: Clc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(OC2CCNCC2)nc1
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
NaH (2.88 g, 66 mmol, 55% dispersion in mineral oil) was stirred in dry DME (200 ml), under Argon. A mixture of 2,5-dichloropyridine (8.87 g, 60 mmol) and 4-hydroxypiperidine (6.67 g, 66 mmol) dissolved in dry DME (200 ml) was added to the NaH suspension dropwise, over a period of 30 minutes. After complete addition the reaction is heated to 82° C. for 48 hrs, maintaining the Argon blanket. The reaction was slowly quenched with water before removing most of the THF. Extracted the aqueous with DCM (×3). The organic layers were dried with Na2SO4 and evaporated in vacuo to afford 2-(4-piperidinyloxy)-5-chloropyridine as a yellow oil (12.7 g, quantitative).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C(F)(F)F)cccc12
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C(F)(F)F)cccc23)n[nH]1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 20.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethyl)quinazolin-4-ol (121 mg, 0.34 mmol) were added phosphoryl tribromide (890 mg) and toluene (1 mL) followed by DIEA (0.117 mL, 0.67 mmol). The mixture was heated at 105° C. for 1 h. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (150 mg, 1.5 mmol) in DMF (4 mL) and the mixture was stirred at rt for 1.5 h. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethyl)quinazolin-4-amine (30 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.03 (s, 1H) 7.77 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.27 (d, J=7.53 Hz, 1H) 8.67 (s, 1H) 8.97 (d, J=8.29 Hz, 1H) 11.00 (br s, 1H) 12.18 (br s, 1 H); LC-MS (ESI) m/z 439 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][O:12][CH3:13].C(N(C(C)C)CC)(C)C>>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C=O)c1
Temperature: 0 °C

Procedure:
A solution of 3-hydroxybenzaldehyde (20 g), chloromethylmethyl ether (25 ml) and diisopropylethylamine (114 ml) intetrahydrofuran (300 ml) was stirred at room temperature overnight. To the reaction mixture was added ice water and was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=25:1) to give the title compound (23 g) having the following physical data.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2
Reactant: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(C(CO)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)-3-(4-methyl-1-oxo-1,3-dihydro isobenzofuran-5-yl)propan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.18 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. After stirring at room temperature for 24 h, solvent was removed under reduced pressure and the residue was purified by preparative-HPLC to give the title compound, which was separated by SFC chiral chromatography into two single enantiomers Isomer A (faster eluting) and Isomer B (slower eluting. Column: CHIRALPAK AD 250×30 mm I.D., 20 μm; Mobile phase: Supercritical CO2EtOH (0.2% NH3H2O)=45/55; Flow rate: 80 ml/min. For both isomers: LC-MS (ESI, m/z): 455 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: IC1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C2CCCC2)C1

Procedure:
Pyrrolidin-3-yl-carbamic acid tert-butyl ester (8) (0.20 g, 1.07 mmol, 1 equiv), iodo-cyclopentane (0.253 g, 1.29 mmol, 1.20 equiv) and triethylamine (0.28 g, 2.15 mmol, 2.00 equiv) were dissolved in acetonitrile (25 mL). The solution was heated to reflux until TLC indicated completion of the reaction. The solvent was evaporated under reduced pressure to yield the title compound. (0.25 g, 1.00 mmol, quantitative).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][O:13][C:14]([C:16]1([NH2:29])[CH2:27][C:26]2[C:28]3[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17]1)=[O:15].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>CN(C=O)C>[CH3:12][O:13][C:14]([C:16]1([NH:29][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH2:27][C:26]2[C:28]3[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17]1)=[O:15]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: COC(=O)C1(N)Cc2cccc3cccc(c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (1.12 g, 7.4 mmol), 2-amino-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (2.05 g, 7.4 mmol), HATU (3.38 g, 8.9 mmol) in anhydrous DMF (28 mL) is added DIPEA (4.89 mL, 29.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (300 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give the pure product (22) as white solid (353 mg, 13%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](=[O:5])[CH3:4].OC1C([O:21][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=C(I)C=CC=1>C(#N)C>[CH3:6][C:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:1])[C:3](=[O:5])[CH2:4][O:24][S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:21])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: CC(=O)C(C)(C)c1ccccc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)C(C)(C)c2ccccc2)cc1

Procedure:
To a solution of 3-methyl-3-phenyl-butan-2-one (example 207D) (8.7 g, 53.6 mmoles) in ACN (150 mL) is added hydroxy(tosyloxy)iodobenzene (22.1 g, 56.3 mmoles). The reaction mixture is heated at reflux for 5 hours. Solvent and volatiles are removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (heptane:AcOEt) (90:1) to give toluene-4-sulfonic acid 3-methyl-2-oxo-3-phenyl-butyl ester.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[Cl:34])[N:21]=1>O>[NH2:19][C:20]1[N:25]=[C:24]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[N:23]=[C:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[Cl:34])[N:21]=1
Reactant: Nc1nc(Cl)nc(-c2cc(Cl)ccc2Cl)n1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N(CCO)CCO)n1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of diethanolamine (9.2 g), N,N-dimethylformamide (200 ml), and anhydrous potassium carbonate (15 g) was added 20 g of 2-amino-4-chloro-6-(2,5-dichlorophenyl)-1,3,5-triazine with stirring at room temperature and the mixture was stirred at room temperature for 7 hours. This reaction mixture was diluted with 2L (litters) of water and stirred for 1 hour. The resulting crystals were collected by filtration, rinsed with water, and dried to give 24 g of white crystals. This crystal crop was recrystallized from methanol, collected by filtration, and dried to provide 21 g of the title compound as white crystals. m.p. 199-200° C.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[C:22](O)(C(F)(F)F)=O>CO.C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:18][CH3:22])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: ClCCl
Solvent: CO
Product: COC(C)(C)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Yield: 179.2 %

Procedure:
A solution of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 120 mg, 0.346 mmol) and TFA (0.013 mL, 0.173 mmol) in methanol (2 mL) was stirred at rt over a weekend. The mixture was diluted with DCM, washed with 1 M aqueous sodium hydroxide and water, dried and concentrated. The residue was combined with that from another reaction done with 20 mg of Intermediate 73-2, and purified by column chromatography (eluting with hexane-EtOAc) to provide 4-bromo-7-(2-methoxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (112 mg, 77%). 1H NMR (400 MHz, chloroform-d) δ 10.53 (1H, br. s.), 8.68 (1H, d, J=8.36 Hz), 7.59 (1H, d, J=1.10 Hz), 7.36-7.44 (3H, m), 3.13 (3H, s), 1.64 (6H, s). Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[C:21]([NH:32][CH:33]4[CH2:38][CH2:37][N:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:35][CH2:34]4)[N:22](COCC[Si](C)(C)C)[N:23]=3)[N:9]=[C:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:11]=2[CH:12]=1)#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[NH:23][N:22]=[C:21]([NH:32][CH:33]4[CH2:34][CH2:35][N:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:37][CH2:38]4)[C:8]=3[N:9]=[C:10]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[C:11]=2[CH:12]=1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(C#N)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(N)(=O)=O)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
306 mg of 4-{[7-cyano-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide are introduced into 20 ml of DCM. After cooling to 0° C. using an ice bath, 1.5 ml of TFA are added and the mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of water, neutralized with 2 ml of 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/NH4OH mixture (92.5/7.5/0.75 by volume). This gives 8 mg of 4-{[7-cyano-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide. 1H NMR: 1.61-1.73 (m, 2 H) 2.09 (m, 2 H) 2.63-2.72 (m, 2 H) 3.47 (m, 2 H) 3.67-3.76 (m, 1 H) 6.13 (d, J=7.0 Hz, 1 H) 6.70 (s, 2 H) 7.34 (t, J=7.8 Hz, 2 H) 7.65-7.74 (m, 1 H) 8.18 (broad s, 1 H) 8.28 (broad d, J=8.6 Hz, 1 H) 8.56 (d, J=8.6 Hz, 1 H) 13.05 (s, 1 H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[C:11]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[CH3:47][N:44]1[CH2:43][CH2:42][N:41]([C@@H:38]2[CH2:39][CH2:40][C@H:35]([N:16]3[C:12]4=[N:13][CH:14]=[N:15][C:10]([NH2:9])=[C:11]4[C:18]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][CH2:26][CH2:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:23][CH:24]=4)=[N:17]3)[CH2:36][CH2:37]2)[CH2:46][CH2:45]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)Cc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-2-phenylacetamide diacetate (0.200 g, 0.00031 mol) was suspended in anhydrous tetrahydrofuran (15 mL), the suspension was cooled to 0° C. and lithium aluminum hydride (0.177 g, 0.00416 mol) was added at once. The resulting mixture was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for 18 hours. It was quenched by dropwise addition of water, the solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(phenethylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.039 g, 0.0000619 mol) as a white solid.
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a stirring solution of 2 (0.77 g, 2.24 mmol) in CH2Cl2 (25 mL) at 0° C., was added, drop wise, TFA over 15 min. The pale yellow, reaction was stirred at 0° C. for 1 h then allowed to stand at RT for 15 min. The reaction was concentrated to a viscous oil, redissolved in CH2Cl2 (20 mL) and reconcentrated to a gummy solid. The crude product was crystallized from ether/hexanes to afford the title compound (3) as a white solid (0.30 g, 41%). 1H NMR (300 MHz, DMSO-d6): δ 1.59 (s, 8H), 2.29 (br s, 4H), 6.52 (d, J=16 Hz, 1H), 7.15-7.39 (m, 7H), 7.59 (d, J=16 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 12.41 (s, 1H). LRMS (APCI): m/z 433 (M+H)+. Anal. Calcd for C23H24O2: C, 83.07; H, 7.30. Found: C, 82.73; H, 7.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10](I)[N:11]=1)[CH2:7][CH2:6][O:5]2.N([Si](C)(C)C)[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:29]([NH2:27])=[O:30])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 12-bromo-4-iodo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca 1(14),2,4,10,12-pentaene (11.0 g, 28.7 mmol) in dried DMF (300 mL) was added Pd(PPh3)2Cl2 (1.0 g, 1.4 mmol) and (Me3Si)2NH (14 g, 86 mmol). The mixture was stirred at 70° C. for 4 h under carbon monoxide atmosphere. After removal of the solvent, the residue was treated with ice-water, filtered, extracted with ethyl acetate (400 ml), dried over anhydrous Na2SO4, and concentrated to give 12-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (7.2 g, 97% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 308.1 [M+H+].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CN(C)C=O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccccc2=O)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
4.4 g of 60% sodium hydride was suspended into 150 ml of N,N-dimethylformamide, to which 10.78 g of 2-hydroxypyridine was added little by little at a room temperature. 30 min after, 12.4 g of 4-fluorobenzaldehyde was added and stirred at 120° C. for 3 hours. The reaction solution was concentrated under a reduced pressure and iced water was added, which was extracted with chloroform. After drying with anhydrous magnesium sulfate, the solvent was distilled off. Resultant crystals were washed with ethyl acetate to obtain 10.3 g of the above-captioned compound as fine gray powder (yield: 52%).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2cc(Cl)cc(Cl)c2n1
Product: CC(C#N)(Cn1cc2cc(Cl)cc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 109) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (80 mg, 76%). MS (ES): M/Z [M+H]=473. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.11 (d, 1H), 5.25 (d, 1H), 7.48 (s, 1H), 7.84-7.91 (m, 3H), 7.95 (d, 2H), 8.54 (s, 1H) and 9.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1C)[CH3:3].N1CC(OC2C=CC(CN(C)C)=C(C)C=2)C1.CNC.[Cl:43]C1C=C(O)C=CC=1C=O>>[NH:12]1[CH2:13][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:6]([Cl:43])[CH:7]=2)[CH2:11]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CNC
Agent: Cc1cc(OC2CNC2)ccc1CN(C)C
Product: CN(C)Cc1ccc(OC2CNC2)cc1Cl
Yield: 10 %

Procedure:
Using similar protocols as described in Examples 20A, 20B and 20C employing dimethylamine and 2-chloro-4-hydroxybenzaldehyde as starting material afforded 0.13 g (10%) of 47A as an oil. 1H NMR (500 MHz, CDCl3): δ 2.26 (s, 6H), 3.45 (s, 2H), 3.78 (m, 2H), 3.92 (m, 2H), 4.96 (m, 1H), 6.65 (d, 1H), 6.76 (d, 1H), 7.27 (m, 1H).
Reaction SMILES: CC([O-])=O.CC([O-])=O.[Pd+2:9].[CH:10]1([P:16]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][C:26]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:24]=2[CH:35]([CH3:37])[CH3:36])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH:10]1([P:16]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([CH:29]([CH3:30])[CH3:31])=[CH:27][C:26]([CH:32]([CH3:33])[CH3:34])=[CH:25][C:24]=2[CH:35]([CH3:36])[CH3:37])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Pd:9]
Reactant: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: [Pd]
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of the catalyst was prepared as follows: An oven-dried Wheaton vial equipped with a magnetic stir bar was charged with Pd(OAc)2 (5.60 mg, 0.025 mmol, 1.0 eq.) and 2-dicyclohexylphosphino-2′.4′,6′-tri-iso-propyl-1,1′-biphenyl (4c) (24.5 mg, 0.050 mmol, 2.0 eq.). Toluene (3.0 mL) was added and the vial was sealed with a PTFE-lined plastic cap. The resulting mixture was stirred at 23° C. for 1 h to yield a reddish Pd/4c catalyst solution (0.00833 N Pd in toluene).