Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C1COCC1>[N:31]1([CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:42][CH:41]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: Nc1ccc(NCCN2CCOCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(NCCN4CCOCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added N-(2-Morpholin-4-yl-ethyl)-benzene-1,4-diamine (prepared below, 77.1 mg, 0.348 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and then diluted with Hexanes (˜40 mL). The black precipitate that formed was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was dissolved in EtOAc (˜5 mL) and triturated with Hexane (˜50 mL) to give a yellow precipitate. The precipitate was filtered and washed with 0° C. i-prOH (˜5 mL) yielding 45% (0.0677 g, 0.112 mmol) of the title compound.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:6].[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:14]=[N-:15].O>CCO>[CH2:11]([O:10][C:8]([C:7]1[N:15]=[N:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[NH2:6])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC#N
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nnn(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a freshly prepared NaOEt (1.18 mmol) solution in EtOH (0.75 mL) is added ethyl cyanoacetate (100 mg, 0.88 mmol) at 0° C. After stirring at 0° C. for 10 min., azido-benzene (100 mg, 0.84 mmol, prepared according to the method reported by M. Kurumi et al. Heterocycles. 2000, 53, 2809) is added. After the addition, the mixture is allowed to slowly warm up to room temperature and stirred for 14 h. The mixture is then treated with water (3 mL) and extracted with EtOAc (3×3 mL). The combined extracts is concentrated and purified by flash column chromatography (silica gel, 0%-70% EtOAc/hexane) to provide 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as a white solid (100 mg, 51%). HPLC-MS calculated C11H12N4O2 (M+1+): 233.1. Found: 233.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:19]([C:21]#[N:22])=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:13]2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:21][NH2:22])[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)C3(CCN(Cc4ccccc4)C3)c3c(C#N)cccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CN2CC3(CCN(Cc4ccccc4)C3)c3c(CN)cccc32)cc1
Yield: 17.1 %

Procedure:
A solution of 1′-benzyl-1-(4-methoxybenzyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-4-carbonitrile (3.00 g, 7.08 mmol) in LAH (1.0M in THF, 35.4 mL, 35.4 mmol) was heated at reflux for 12 hours. The reaction mixture was quenched with Na2SO4-10 H2O, dried and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by chromatography (hexanes/ethyl acetate gradient) to give (1′-benzyl-1-(4-methoxybenzyl)spiro[indoline-3,3′-pyrrolidine]-4-yl)methanamine (500 mg, 1.21 mmol, 17%). LCMS (APCI+) M+H+ 414 (100%); Rt=3.23 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:14][CH2:13][N:2]1[N:3]=[N:4][CH:5]=[N:1]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:15]([O:14][CH2:13][N:1]1[CH:5]=[N:4][NH:3][NH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1nnn[nH]1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1=NNNN1COCc1ccccc1
Product: c1ccc(COCn2ncnn2)cc1
Reaction time: 4 h
Yield: 44 %
Yield: 47 %

Procedure:
A suspension of 1-H-tetrazole (2.0 g, 28.5 mmol) and potassium carbonate (5.9 g, 42.7 mmol) in DMF (30 mL) was treated with benzyl chloromethyl ether (5.36 g, 34.2 mmol), and the mixture was stirred for 4 hours. Analysis by LC/MS indicated that the reaction was not complete, so the reaction was treated with benzyl chloromethyl ether (0.5 g, 3.19 mmol) and stirred overnight. The mixture was filtered, and the filtrate was concentrated in-vacuo. The residue was diluted with diethyl ether (200 mL), washed 5× with water (50 mL), once with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over a 6×20 mm silica gel column, eluting with 20% then 30% ethyl acetate/hexanes to yield the title compound (2.39 g, 44% yield), and 1-(benzyloxymethyl)-2H-tetrazole (2.56 g, 47% yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:12]3[C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[N:14]=[C:13]3[CH3:21])[CH:9]=2)[CH2:4]1)#N.[OH-:22].[Na+].Cl.C[OH:26]>>[CH3:21][C:13]1[N:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH:3]([C:1]([OH:26])=[O:22])[CH2:11]3)[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:14]=1
Reactant: [OH-]
Reactant: CO
Reactant: Cc1nc2cnccc2n1-c1ccc2c(c1)CC(C#N)C2
Agent: Cl
Agent: [Na+]
Product: Cc1nc2cnccc2n1-c1ccc2c(c1)CC(C(=O)O)C2

Procedure:
A mixture of 2-cyano-5-(2-methylimidazo[4,5-c]pyrid-1-yl)indane (739 mg, 2.70 mmol), 50% aqueous sodium hydroxide (1 ml) and methanol (6 ml) was heated at reflux under nitrogen for 9 hours, cooled, poured onto ice, and the pH of the solution was adjusted to pH 5 by the addition of 2M hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound, (426 mg; 54%) as a colourless solid, m.p. 264°-267° C. Found: C,68.9; H,5.1; N,14.1. C17H15N3O2. 0.2 H2O requires C,68.8; H,5.2; N,14.1%.
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][NH2:9])[C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1=2.[CH2:14]=O>CO>[CH2:14]1[C:6]2[S:2][C:3]3[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=3[C:5]=2[CH2:7][CH2:8][NH:9]1
Reactant: NCCc1csc2ccccc12
Reactant: C=O
Agent: Cl
Solvent: CO
Product: c1ccc2c3c(sc2c1)CNCC3
Yield: 36.1 %

Procedure:
A mixture of 2-(benzo[b]thien-3-yl)ethylamine hydrochloride (0.5 g, 2.34 mmol) and paraformaldehyde (0.125 g, 4.16 mmol) in methanol (15 mL) was refluxed for 24 h. The reaction mixture was concentrated under reduce pressure and the residue was neutralized with saturated NaHCO3 (50 mL), and extracted with ethyl acetate (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to furnish 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine (160 mg, 35%); 1H NMR (200 MHz, CDCl3): δ 2.81 (m, 2H), 3.25 (m, 2H), 4.15 (s,2H), 7.30 (m, 2H), 7.69 (d, J=4.0 Hz, 1H), 7.79 ((d, J=4.0 Hz, 1H).
Reaction SMILES: BrC1[C:7]2[O:8]CC[O:11][C:6]=2C(NC(=O)C)=CC=1.C(C1C2CCCCC=2C(NC(=O)C)=CC=1)#N.[OH:32][C@H:33]1[C@@H:40]2[N:36]([C:37](=[O:54])[N:38]([C:42]3[C:51]4CCCC[C:46]=4[C:45]([C:52]#[N:53])=[CH:44][CH:43]=3)[C:39]2=[O:41])[CH2:35][CH2:34]1.C(O)(C)C>CCCCCC>[OH:32][C@H:33]1[C@@H:40]2[N:36]([C:37](=[O:54])[N:38]([C:42]3[C:51]4[O:8][CH2:7][CH2:6][O:11][C:46]=4[C:45]([C:52]#[N:53])=[CH:44][CH:43]=3)[C:39]2=[O:41])[CH2:35][CH2:34]1
Reactant: CC(=O)Nc1ccc(Br)c2c1OCCO2
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: CC(=O)Nc1ccc(C#N)c2c1CCCC2
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1OCCO2

Procedure:
The title compound (32 mg) was prepared from compound 8D and isolated as a white solid by procedures analogous to those described in Example 2 (2C to 2F). mp196-197° C.; HPLC: 99% at 12.31 min (retention time) (CHIRALPAK® OD column 4.6×250 mm; 25% isopropanol in hexane over 30 min, 1 mL/min, UV detection at 220 nm); MS (ES) m/z 322 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.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>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCC(CN)CC1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc4ncnc(N)c4n3)c2)CC1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with (1-methyl-4-piperidyl)methanamine (CAS 7149-42-0) (77 mg, 0.6 mmol), HATU (129 mg, 0.33 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-((1-methylpiperidin-4-yl)methyl)benzamide 22. LC/MS (ESI+): m/z 377 (M+H). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=8.8 Hz, 2H), 8.42 (s, 2H), 8.23 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 7.96 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.45 (d, J=6.9 Hz, 1H), 2.90 (s, 2H), 2.73 (d, J=52.3 Hz, 4H), 2.19 (s, 1H), 2.04 (s, 3H), 1.83 (s, 2H), 1.64 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+].C(#N)C>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cncs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1

Procedure:
370 mg (1.427 mmol) of 2-amino-6-sulphanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, 383 mg (1.570 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 359 mg of sodium bicarbonate are stirred in 7 ml of DMF for 1 hour. 150 ml of acetonitrile and 100 ml of water are added to the reaction mixture, and the precipitated solid is filtered off and dried under high vacuum. This gives 569 mg (85% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[CH2:20]([S:24][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: Cn1nc(-c2ccccc2)c(Br)c1-c1ccccc1
Reactant: CCCCS
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: CCCCSc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Yield: 97.1 %

Procedure:
A mixture of 4-bromo-1-methyl-3,5-diphenylpyrazole (21 g, 0.0671 mole), copper(1)salt of butanethiol (12.58 g, 0.08 mole), pyridine (10 ml) and quinoline (100 ml) is stirred and heated at 175° C to 180° C for 8 hours. The reaction mixture is cooled, poured into dilute hydrochloric acid (500 ml) and extracted with benzene. The benzene layer is separated and stripped in vacuo to give a brown oil. The oil is slurried with petroleum ether (b.p. 40° C to 60° C), filtered and the filtrate stripped in vacuo to give a brown syrup 21 g (97%), >95% pure by glc.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[ClH:1].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCCCC2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(=O)O)cc2S(=O)(=O)N2CCCCC2)CC1
Product: Cl

Procedure:
The reaction was carried out in a manner analogous to that of Example 37, using 30.4 g of 4-chloro-3-piperidinosulfonyl benzoic acid (0.1 mole) and 50 ml of N-methylpiperazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:40]1[CH:44]=[CH:43][C:42](NC)=[CH:41]1.[CH3:47][N:48](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>O1CCOCC1.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]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:48][CH2:47][C:42]5[CH:43]=[CH:44][S:40][CH:41]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Reactant: CNc1ccsc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1

Procedure:
To a stirred solution of {4-[3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 39 supra) (300 mg, 0.48 mmol), thiophen-3-yl-methylamine (66 mg, 0.583 mmol), DavePhos (38 mg, 20 mol %) and t-BuONa (56 mg, 0.58 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (28 mg, 0.48 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 5 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:EtOAc, 3:1, v/v) to give {4-[3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 120 mg, 38%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:22](=[O:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
The mixture of 2-phenoxyaniline (100 g, 540 mmol), triethylamine (0.090 L, 648 mmol) and 1 L dichloromethane was cooled to 0° C. by ice bath. Acetyl chloride (0.04 L, 567 mmol) was added dropwise. After the addition completed, the reaction was stirred under room temperature for 2 h. The mixture was concentrated and diluted by dichloromethane. The organic phase was washed by water and dried over sodium sulfate. The crude product was purified by silica gel column (20% EtOAc in hexane) to give red brown oily solid N-(2-phenoxyphenyl)acetamide (120 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:27]
Reactant: CI
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 1.0 g (2.985 mmol) of the product of Example 3 in 10 mL of DMF was added 0.149 g (3.731 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature and then 0.28 mL (4.478 mmol) of iodomethane was added. The reaction was then stirred for 18 h, and next diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid. The solid was washed with ether/hexanes (1:1) to give 0.788 g (76%) of the desired product as a white solid. Electrospray Mass Spec: 350.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.C(OCC)C>CN(C=O)C>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Yield: 100 %

Procedure:
A solution of 5-hydroxy-indole (5 g, 38 mmol), tert-butyldimethylsilyl chloride (6.13 g, 39.4 mmol) and imidazole (5.37 g, 68.1 mmol) in DMF (50 ml) was stirred for 20 h at RT. Diethyl ether was added and the mixture was washed wih 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 9.4 g (38 mmol, quant.) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([O:29]CC)=[O:28])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>COCCOC.C(OCC)(=O)C.Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13]1=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(CC)c2cccc(C)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)O)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-ethyl-1-ethoxycarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (1.55 g) and 1N sodium hydroxide (7.0 ml) in 1,2-dimethoxyethane (10 ml) was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo to afford a residue, which was dissolved in a mixture of ethyl acetate and 1N aqueous hydrochloric acid. The separated organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a residue, which was triturated in diisopropyl ether and collected by filtration to give (3RS)-3-benzyloxycarbonylamino-5-ethyl-1-carboxymethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (1.22 g, 84.2% yield) as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54]O)[CH:49]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:54][C:50]2[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(O)cc3)cc12
Reactant: OCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(OCc4cccnc4)cc3)cc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 1-tert-butyl 3-methyl 6-chloro-5-(4-hydroxyphenyl)-1H-indole-1,3-dicarboxylate (30 mg, 0.075 mmol), polymer supported triphenylphosphine (50 mg, 0.15 mmol), anhydrous tetrahydrofuran (1.0 mL), pyridin-3-ylmethanol (0.015 mL, 0.15 mmol), and bis(2-methoxyethyl)-diazene-1,2-dicarboxylate) (35 mg, 0.15 mmol) was sealed in a vial and stirred vigorously at 70° C. for 18 hours. The cooled reaction mixture was filtered through a pad of Celite, and the filter pad was washed with diethyl ether twice. The filtrate was concentrated in vacuo, and the residue partitioned between diethyl ether and water. The organic layer was separated and washed sequentially with water and then brine. The ether layer was concentrated in vacuo and to give the title compound, which was used directly in the next step. MS (ES+) 493 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1([O:7][CH2:6]1)[CH2:4][OH:5])[CH3:2].[C:8](=O)=O.[CH:11]([Mg]Br)=[CH2:12].Cl>O1CCCC1.[Cu](I)I.C(#N)C>[CH2:1]([C:3]([OH:7])([CH2:6][CH2:8][CH:11]=[CH2:12])[CH2:4][OH:5])[CH3:2]
Reactant: CCC1(CO)CO1
Reactant: C=C[Mg]Br
Reactant: O=C=O
Agent: I[Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCCC(O)(CC)CO
Temperature: -27.5 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 2 R 2-ethyl-2,3-epoxypropanol (2.6 g, 25.5 mmol) and copper iodide (475 mg, 2.5 mmol) was stirred in tetrahydrofuran (50 mL) under nitrogen and brought to -30° C. (dry ice, acetonitrile). Vinyl magnesium bromide [32 mL, 2 M in tetrahydrofuran (THF), 2.5 eq] was added from a dropping funnel at such a rate as to maintain the temperature at -25 to -30° C. The reaction mixture was stirred at -30° C. for 2 h then brought to 0° C. and acidified with 10% HCl. The THF layer was separated and the aqueous phase was extracted with ether (3×50 mL). The organic layers were combined, dried over sodium sulfate, oncentrated and distilled to give the title compound as a clear colorless oil (2.2 g, 60%, b.p. 85° C./5 mm). TLC Rf 0.26 (silica gel, 5% MeOH in CH2Cl2, CAS/char:brown).