Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: BrCC1CCCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 61.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and bromomethyl cyclohexane (122 mg, 0.690 mmol) gave 2-[5-(4-cyclohexylmethyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (75 mg, 63%). MS (ESI) m/z 531.4 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C=1.[C:23]1(C(Cl)=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C[C:44](N(C)C)=[O:45]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:28]2[C:27]3[C:32](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:31]=[CH:30][CH:29]=2)[CH:44]=[O:45])=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:21]=[CH:22][CH:13]=1
Reactant: COc1ccc(N)cc1OCCc1ccc2ccccc2c1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(N(C=O)c2cccc3ccccc23)cc1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[4-methoxy-3-(naphthylmethoxy)phenyl]naphthylformamide (Exemplary Compound 47) was prepared using the same experimental conditions used to prepare Exemplary Compound 52 (Scheme X, above). From 4-methoxy-3-(2-naphthylethoxy)phenylamine (350 mg, 1.25 mmol) and 1-naphthoyl chloride (240 mg, 1.25 mmol) in 10 mL of dimethyl acetamide containing triethylamine (1 mL, 7.17 mmol) stirred at room temperature for 16 h., was obtained 280 mg of product in (52%) yield as white needles after recrystallization from ethyl acetate/hexane: mp 161-163° C. 1H NMR (400 MHz, Me2SO-d6) δ3.74 (s, 3H); 5.52 (s, 2H); 7.01 (d, 1H, J=8.8); 7.43 (dd, 1H, J=2.3, 8.7); 7.51-7.74 (m, 9H); 7.94-8.21 (m, 6H); 10.43 (s, 1H). Anal. Calcd for C29H23NO3: C, 80.35; H, 5.35; N, 3.23. Found: C, 80.25; H, 5.39; N, 3.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:14])[O:12][CH3:13].[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(N(CC)CC)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.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:14])[O:12][CH3:13]
Reactant: COC(=O)NCc1cc(I)ccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1Cl

Procedure:
A mixture methyl [(2-chloro-5-iodo-phenyl)methyl]carbamate (i.e. the product of Step B) (3.0 g, 9.2 mmol), ethynyltrimethylsilane (1.94 mL, 13.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.032 g, 0.05 mmol), copper(I) iodide (0.018 g, 0.09 mmol), triphenylphosphine (0.024 g, 0.09 mmol) in tetrahydrofuran (18 mL) and triethylamine (18 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated onto silica gel (7 g) and then purified by medium pressure liquid chromatography (0 to 25% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as an oil (1.37 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH2:21][C:20](=[O:22])[CH2:19]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3([OH:22])[CH2:21][O:18][CH2:19]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COC1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Product: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and oxetan-3-one (CAS: 6704-31-0). Brown solid. MS (m/e): 282.4 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@H:8]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN3C[C@H](COc4ccc(F)cc4)CC[C@H]3C2)cc1
Temperature: 95 °C
Yield: 84.3 %

Procedure:
A mixture of 0.500 g (1.89 mmol) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 8), 0.400 g (2.84 mmol) of 4-fluoronitrobenzene and 0.401 g (3.78 mmol) of sodium carbonate in 15 mL of DMSO was heated at 95° C. for 16 h. The mixture was cooled to room temperature, acidified with 1M HCl, washed with ethyl ether (3×), basified with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered and evaporated to give 0.614 g of (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=O)[C:5]2=[CH:4][N:3]=1.CN(C(ON1N=[N:38][C:33]2[CH:34]=CC=N[C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(N)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:38][CH:33]([CH3:34])[CH3:32])=[O:16])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(C(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)NC(C)C)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzoic acid (Example 94) (0.075 g, 0.25 mmol) is dissolved in DMF (5 ml), HATU (0.095 g, 0.25 mmol) is then added followed by N-Methylmorpholine (0.110 ml, 1.0 mmol) and isopropylamine (0.022 ml, 0.25 mmol) and the reaction mixture is stirred at room temperature for 15 hours. The solvent is removed in vacuo and the residue is diluted with water (3 ml) and left to stand for 3 hours. The resulting solid precipitate is collected by filtration, washed with a further 5 ml of water and dried under vacuum to afford the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O1CCOCC1.[Pd]>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:19]=[CH:18][C:17]([N:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)=[CH:30][CH:31]=1
Reactant: COCCCCOc1ccc(C2=CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: COCCCCOc1ccc(C2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
To a mixture of 4-[4-[4-[4-(4-methoxybutoxy)phenyl]-3,6-dihydro-2H-pyridin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (2.20 g) and ammonium formate (1.25 g) in 90% methanol (44 ml) and dioxane was added 10% palladium on carbon at room temperature. The reaction mixture was heated at 100° C. for 2 hours. After cooling, the reaction mixture was filtered and evaporated. Sodium hydrogen carbonate solution was added to the residue. And the resulting precipitate was collected by filtration, washed with water and dried under hi-vacuum to give 1-[4-[4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine (1.36 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1>O1CCOCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=2)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: CSc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSc1cccc(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
A solution of 3-(methylsulfanyl)aniline (658 mg, 4.73 mmol) and pyridine (995 uL, 18.9 mmol) was cooled to 0° C. under N2 before the dropwise addition of bis(trimethylsilyl)trifluorocetamide (1.76 mL, 9.45 mmol) over 5 min. After stirring for 5 min at 0° C., a solution of 4-fluoro-2-nitrobenzenesulfonyl chloride (1.19 g, 4.97 mmol) in 1,4-dioxane (7 mL) was added dropwise over 15 min. The mixture was stirred at rt for 1 h, then at 100° C. for 30 min. After cooling to rt, the mixture was concentrated in vacuo and partitioned between DCM and 1M aqueous HCl (25 mL each). The phases were separated and the aqueous layer extracted with DCM (2×25 mL). The combined organic layers were concentrated in vacuo and purified by gradient flash chromatography, eluting with 5-50% EtOAc in heptane to yield the title compound (865 mg, 2.53 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33](C)(C)[O:34][SiH2]C(C)(C)C)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O>CCO.Cl>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1 h
Yield: 98.5 %

Procedure:
The product from step 4 (367 mg, 0.65 mmol) was dissolved in 4 mL of 1:1 EtOH:THF and 0.5 mL of water was added followed by the addition of 1 drop of concentrated aqueous HCl. The mixture was stirred for 1 hour (ppt formed) and the solid was collected by filtration, washed with THF and air dried overnight to give 286 mg (98%) of the title compound as a white solid. 1H-NMR (DMSO-d6) 9.00 (bs, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 8.02, (s, 1H) 7.96-7.86 (m, 2H) 7.80 (s, 1H), 7.49 (t, 1H), 7.46-7.30 (m, 6H), 7.28 (d, 1H), 7.26 (bs, 1H), 5.72 (s, 2H), 4.60 (s, 2H); LC-MS [M+H]+=447.3, RT=2.72 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH:21][C:22](=[O:41])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]4[CH2:33][CH2:32][CH2:31][N:30]4C(OC(C)(C)C)=O)[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42].O1CCOCC1>C(Cl)Cl>[ClH:42].[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH:21][C:22](=[O:41])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]4[CH2:33][CH2:32][CH2:31][NH:30]4)[CH:24]=3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)Nc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1

Procedure:
To a solution of 7-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (900 mg, 1.62 mmol) in methylene chloride (50 mL) add 4M HCl in dioxane (8.1 mL, (32.4 mmol)) and stir the reaction at room temperature for 24 h. Remove the solvents in vacuo at 40° C., dissolve the residue in EtOAc, and concentrate again concentrate to dryness. Dry the residue in vacuo then triturate in EtOAc and hexane to afford 2.63 g of 7-(3-pyrrolidin-2-yl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl as a solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]3[N:16]([C:18](Br)=[CH:19][CH:20]=3)[CH:17]=1)=[O:11])[CH2:2]2.[C:22]([OH:31])(=[O:30])[C@H:23]([C@@H:25]([C:27]([OH:29])=[O:28])[OH:26])[OH:24].[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([CH:25]([CH:23]([C:22]([OH:31])=[O:30])[OH:24])[OH:26])([OH:29])=[O:28].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]3[N:16]([C:18]([C:32]#[N:33])=[CH:19][CH:20]=3)[CH:17]=1)=[O:11])[CH2:2]2
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CN(C)C=O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cn2c(Br)ccc2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2cnc(C(=O)N[C@H]3CN4CCC3CC4)cn12
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 95 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To an argon sparged solution of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromopyrrolo[1,2-a]pyrazine-3-carboxamide (0.77 g, 2.14 mmol) in DMF (25 mL) is added zinc cyanide (0.26 g, 2.20 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.25 g, 0.21 mmol). The resulting suspension is stirred at 95° C. for 48 h, then filtered through a pad of celite. The residue is purified using preparative chromatography (carried out on a Chiral OD column using a 40% IPA/heptanes each containing 0.1% diethylamine) to give a pale yellow oil that is salted with d-tartaric acid and crystallized from EtOH/Et2O to give a pale yellow solid. Yield 47%. HRMS (FAB) calcd for C16H17N5O+H 296.1511, found 296.1520.
Reaction SMILES: [SiH:1]([Cl:4])([CH3:3])[CH3:2].[SiH:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].[CH2:12]([Cl:15])[CH:13]=[CH2:14]>>[Si:1]([CH2:14][CH2:13][CH2:12][Cl:15])([CH3:3])([CH3:2])[Cl:4].[Si:5]([CH2:14][CH2:13][CH2:12][Cl:15])([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: C[SiH](C)Cl
Reactant: C=CCCl
Reactant: CC[SiH](CC)CC
Product: CC[Si](CC)(CC)CCCCl
Product: C[Si](C)(Cl)CCCCl
Yield: 4.8 %
Yield: 42.5 %

Procedure:
In a 100 ml apparatus, there were combined 7.1 g (0.075 mol) of Me2SiHCl, 8.7 g (0.075 mol) of Et3SiH and 5.7 g (0.075 mol) of allyl chloride. Pt catalyst solution was added (0.05 ml) at 34° C. Gentle heating caused a smooth exothermic reaction to 92° over 36 min. Vacuum distillation yielded 42.5% of Me2SiClCH2CH2CH2Cl and 4.8% of Et3SiCH2CH2CH2Cl. This example shows that Et3SiH at the equimolar level is an effective promoter for the reaction between Me2SiHCl and allyl chloride.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/[OH:6])=O.Cl.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][NH2:17].N1C=CC=C[CH:19]=1>C(OCC)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[N:17]=[C:2]([CH3:1])[C:4]([CH3:19])=[N+:5]1[O-:6]
Reactant: CC(=O)/C=N/O
Reactant: NNc1ccc(F)cc1F
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1nn(-c2ccc(F)cc2F)[n+]([O-])c1C
Temperature: 23 °C
Reaction time: 64 h

Procedure:
To a stirred solution of anti-pyruvic aldehyde 1-oxime (2.2 g, 22.2 mmol) in diethyl ether (50 mL) was added 2,4-difluorophenylhydrazine hydrochloride (4.0 g, 22.2 mmol) and pyridine (2 mL). The reaction mixture was stirred at 23° C. for 64 h. The solid that formed was removed by filtration and washed with diethyl ether. The filtrate was concentrated under reduced pressure. The crude residue was dissolved in pyridine (100 mL). A solution of copper(II) sulfate pentahydrate (11.1 g, 44.4 mmol) in water (60 mL) was added at once and the resulting mixture was stirred at reflux for 20 h. The mixture was diluted with water and extracted with diethyl ether. The combined organic layers were washed with 1.0 M aqueous hydrochloric acid, dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude material was purified by chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to obtain the title compound (1.98 g) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li][CH:22](CC)C.CI>O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:22])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a cold −78° C. solution of 4-chloro-1-[tris(1-methylethyl)silyl]-1H-pyrrolo[2,3-b]pyridine (3.24 mmol, prepared as described in Tetrahedron Lett. 2004, 45, 2317-2319), in dry tetrahydrofuran (22 mL) was added 1.4M sec-BuLi in hexanes (7.12 mmol) dropwise over 5 min. After 30 min, methyliodide (10.5 mmol) was added. After 45 min, the reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and diluted with ethyl acetate (25 mL). The extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% hexanes) to give the title product as a white solid (86%). ESMS [M+H]+: 323.2
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCCC[C@@H]1c1cn[nH]c1
Yield: 73.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (150 mg, 0.22 mmol) prepared in Example 81a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol (1.5 mL), to yield the title compound (70 mg, 72%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)(N=CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:48].N([O-])=O.[Na+].C(OCC)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[C:12](=[CH:17][CH:16]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([OH:48])[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:14]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of the title compound of Example 43 (4.31 g, 6.64 mmol) in THF (30 ml) was added 38 ml of 1N sulfuric acid. After the mixture was cooled to 0° C., a solution of sodium nitrite (NaNO2, 1.45 g, 20.99 mmol) in water (10 ml) was added dropwise. The reaction mixture was stirred at ambient temperature for 7 hours after which time ethyl acetate was added. The organic layer was washed with saturated potassium carbonate, brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (2:98:0.1) as the eluents to afford the title compound of Example 6, 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one as a white solid (3.32 g, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O>CC(O)=O.CC(N(C)C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Reactant: O=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(Nc2nccc(-c3ccc(NCc4ccccn4)s3)n2)c1
Reaction time: 18 h

Procedure:
A solution of [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (prepared according to Method 4) (15 mg, 0.053 mmol) and pyridine-2-carbaldehyde (4.5 uL, 0.048 mmol) were dissolved in a 25% solution of HOAc in DMA (0.5 mL). MP-CNBH3 resin (2.5 eq.) was added after 2 h and the reaction was shaken for 18 h. The reaction was filtered and the resin washed with DMA. The crude mixture was purified by preparative LCMS to afford 11.1 mg, 61.2%). MS: m/z 374 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.26 (s, 3H), 4.42 (d, J=6.5 Hz, 2H), 5.96 (d, J=4.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.986 (d, J=5.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.27 (m, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.56 (d, J=4.0 Hz, 1H), 7.73 (br s, 1H), 7.76 (m, 1H), 7.81 (t, J=5.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.53 (br dd, J=4.5 Hz, 1H), 9.24 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].C(N(CC)CC)C>CC(O)C>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CN(C)CCN
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCN(C)C)ncc23)n1
Yield: 75.3 %

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (400 mg, 1.43 mmol) in 2-propanol (40 mL) was added N, N-dimethylethane-1,2-diamine (139 mg, 1.58 mmol) followed by triethylamine (159 mg, 1.57 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford N,N-dimethyl-N′-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-ethane-1,2-diamine (Yield 356 mg, 75%).