Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[N:13]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>ClCCl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH:27]3[CH:26]=[CH:25][N:24]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:23]=[CH:28]3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[N:13]=1
Reactant: Clc1ccc2nc(-c3ccccc3)cn2n1
Reactant: CCOC(=O)Cl
Reactant: c1ccnnc1
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccccc3)nc3ccc(Cl)nn23)C=N1
Temperature: 10 °C
Yield: 260.2 %

Procedure:
26.2 ml (30.3 mmol) of ethyl chloroformate are added, dropwise in 30 minutes, to a solution of 25.2 g (109 mmol) of 6-chloro-2-phenylimidazo[1,2-b]pyridazine and 39.8 ml (548 mmol) of pyridazine in 550 ml of dichloromethane at 8° C. The medium is stirred at 10° C. for a further hour and then left to stir for an additional hour. The medium is cooled to 8° C. and 14.9 ml (273 mmol) of pyridazine and 13.1 ml (137 mmol) of ethyl chloroformate are then added in fifteen minutes. The reaction is allowed to return to ambient temperature with stirring for a further hour. The solvent is evaporated off under reduced pressure and the residue is taken up with 1 l of ethyl acetate. The organic phase is washed with a saturated solution of sodium hydrogen carbonate and then with water. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The product is chromatographed on a neutral alumina column, elution being carried out with a mixture of chloroform and cyclohexane (6/4), to give 35 g of an orangey solid, which is crystallized from 250 ml of diethyl ether, to give 30.1 g of a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:23])([CH3:22])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10]2)=[CH:5][C:4]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:9]1[C:8]([CH3:23])([CH3:22])[CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([OH:24])[CH:5]=2)[CH2:10]1
Reactant: COc1cccc(CN2Cc3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CN2Cc3cc(OC)c(O)cc3CC2(C)C)c1
Yield: 47.5 %

Procedure:
To a solution of 226 (237 mg, 0.45 mmol) in THF (10 ml) at 0° C. (ice-bath) was added TBAF (1.0 M in THF, 0.53 ml, 0.53 mmol). The reaction mixture was stirred at 0° C. for 18 h. water (10 ml) was added and the aqueous layer was extracted with EtOAc (3×). The combined organic layer were washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 100% EtOAc over 25 min) afforded the title compound (70 mg, 43%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.18 (6H, s, 2×CH3), 2.66 (2H, s, CH2), 3.50 (2H, s, CH2), 3.65 (2H, s, CH2), 3.79 (3H, s, OCH3), 3.83 (3H, s, OCH3), 6.47 (1H, s, CH), 6.52 (1H, s, CH), 6.75-6.79 (1H, m, CH), 6.95-6.97 (2H, m, 2×CH), 7.21 (1H, t, J=8.0 Hz, CH). 13C NMR (100 MHz; CDCl3) 23.72 (CH3), 45.54 (CH2), 49.97 (CH2), 52.49 (C), 53.45 (CH2), 55.13 (OCH3), 55.86 (OCH3), 110.69 (CH), 111.73 (CH), 111.90 (CH), 114.09 (CH), 120.88 (CH), 125.60 (C), 126.86 (C), 129.11 (C), 142.41 (C), 143.49 (C), 144.99 (C), 159.59 (C). LC/MS (ES−) tr=1.85 min, m/z 326.27 (M−H)−. HRMS (ES+) calcd. for C20H26NO3 (M++H) 328.1907, found 328.1904.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2](C)(C)C.C(O[O:12][C:13]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=1)(=O)C.Cl.[Cl:31][CH2:32][CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:31][CH2:32][CH2:33][NH:34][C:1](=[O:6])[CH2:2][O:12][C:13]1[C:22]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)OOc1nc2c(nc1Cc1ccccc1)CCCC2
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(COc1nc2c(nc1Cc1ccccc1)CCCC2)NCCCl
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C. to compound 660 (7.45 g, 25 mM) and triethylamine (3.5 ml, 25 mM) dissolved in tetrahydrofuran (45 ml), then the mixture was stirred for 30 minutes. Chloroform (25 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g) and triethylamine (3.5 ml) was added dropwise thereto, then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate to obtain the product. (7.142 g, yield: 79.5%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[ClH:41].COC(C)(C)C>CC(O)C.O1CCOCC1>[ClH:41].[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-[({4-[5-(cyclopropyl methoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}carbonyl)amino]piperidine-1-carboxylate from example D.e1 (2.72 g; 4.95 mmol) is dissolved in dry 2-propanol (50 mL). After addition of 4M HCl in dioxane (5.0 mL) the stirred reaction mixture is heated to 80° C. for two hours. At ambient temperature tert.-butyl methyl ether (100 mL) is added.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=2)[N:9]=1.[C:21]([NH2:26])(=[O:25])[C:22]([CH3:24])=[CH2:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:13][C:11]1[N:10]([C:14]2[CH:15]=[C:16](/[CH:23]=[C:22](\[CH3:24])/[C:21]([NH2:26])=[O:25])[CH:17]=[CH:18][CH:19]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:12]=1
Reactant: Nc1cc(-c2ccccc2F)nn1-c1cccc(I)c1
Reactant: C=C(C)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C/C(=C\c1cccc(-n2nc(-c3ccccc3F)cc2N)c1)C(N)=O
Temperature: 80 °C
Yield: 94.4 %

Procedure:
3-(2-Fluorophenyl)-1-(3-iodophenyl)-1H-pyrazol-5-amine (0.500 g, 1.32 mmol, 1.00 eq), methacrylamide (0.281 g, 3.30 mmol, 2.50 eq), Pd(OAc)2 (0.0118 g, 0.0527 mmol, 0.04 eq), Ph3P (0.0346 g, 0.132 mmol, 0.10 eq) and Et3N (0.919 ml, 6.59 (mmol, 5.00 eq) were combined in DMF (3 ml) and heated at 80° C. overnight. The reaction was cooled to RT, diluted with H2O and extracted with EtOAc (2×). The combined organics were washed with 5% citric acid (2×), brine (1×) and dried (MgSO4). Filtration and evaporation gave crude product which was purified by flash chromatography to afford 0.4192 g (95%) of pure (E)-3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)-2-methylacrylamide. MS (ESI) m/z: 337.2 (M+H+).
Reaction SMILES: Cl.[C:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[C:5]([O:4][C:2](=[O:3])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of N-Boc 1,6-diaminohexane hydrochloride(1.51 g, 6 mmol) and triethyl amine(1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride(1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride(2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil(2.1 g, 87%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:51])[CH2:25][CH2:26][C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:52])#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:51])[CH2:25][CH2:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:52])#[N:2]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4nc[nH]n4)c3)[nH]c(=O)c2c1
Yield: 71 %

Procedure:
A solution of 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide (215 mg, 0.314 mmol), triethylsilane (0.053 mL, 0.330 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from IPE. The resulting powder was recrystallized from ethanol to give is the title compound as a white powder (98.6 mg, 71%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10](Cl)=[N:11][C:12]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)C.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[C:30]=2[CH:29]=[CH:28]1>>[OH:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]3[C:30]=1[CH:29]=[CH:28][NH:27]3)=[N:11][C:12]=2[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(=O)OCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cccc4[nH]ccc34)nc2n1CCO

Procedure:
2-(2-Chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)ethyl acetate (165 mg) was treated with indole-4-boronic acid via General Procedure A and purified via reverse phase HPLC to give 21 mg of 101 as a white solid. MS (Q1) 423.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)CC)(=O)[CH2:19][CH3:20].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH2:19][CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Intermediate 1 (2.0 g, 6.86 mmoles) was taken in a RB flask and to this triethylamine (16 ml) and propionic anhydride (2.80 g, 21.50 mmoles) were added and the mixture was refluxed for 22 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as off-white solid (0.78 g, 31% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10(d, J=2.4 Hz, 1H), 7.97(dd, J=8.9,2.4 Hz, 1H), 7.68(d, J=8.9 Hz, 1H), 7.46(m, 3H),7.27(d, J=6.9 Hz, 2H), 2.55(q, J=7.5 Hz, 2H), 1.19(t, J=7.5 Hz, 3H).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[N:19]1([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[C:33]([C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[CH:53]=4)=[N:34][C:35]4[C:40]([C:41]=3[C:42](O)=[O:43])=[CH:39][C:38]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[C:37]([O:50][CH3:51])[CH:36]=4)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[F:62][C:63]([F:73])([F:72])[C@@H:64]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[NH2:65].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[N:19]1([CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]3[C:33]([C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:59])([F:61])[F:60])[CH:53]=4)=[N:34][C:35]4[C:40]([C:41]=3[C:42]([NH:65][C@H:64]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C:63]([F:72])([F:73])[F:62])=[O:43])=[CH:39][C:38]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[C:37]([O:50][CH3:51])[CH:36]=4)[CH2:29][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1cc2c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide, 0.253 mL of a 50% solution in ethyl acetate, 0.425 mmol) was added to a solution of 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.304 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.395 mmol), N,N-diisopropylethylamine (10.60 μL, 0.061 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The reaction mixture was diluted with saturated NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.160 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.50 (br. s., 1H), 7.97 (br. s., 1H), 7.87 (d, J=7.53 Hz, 2H), 7.80 (s, 1H), 7.71-7.78 (m, 1H), 7.65 (br. s., 2H), 7.42-7.51 (m, 3H), 6.22 (quin, J=8.60 Hz, 1H), 4.10 (s, 3H), 3.40-3.61 (m, 3H), 3.12-3.27 (m, 1H), 2.05-2.44 (m, 6H), 1.58-1.82 (m, 2H), 1.03-1.52 (m, 12H), 0.77-1.00 (m, 2H); MS (m/z) 777.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[C:6]([O:20][CH3:21])[CH:7]=[C:8]([CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[CH:9]=2)[NH:4][N:3]=1.[ClH:22].Cl.OC1C2C(=C(OC)C=CC=2CCN)NN=1>C(O)C.C(OCC)C>[ClH:22].[OH:1][C:2]1[C:10]2[C:5](=[C:6]([O:20][CH3:21])[CH:7]=[C:8]([CH2:11][CH2:12][NH2:13])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cc(CCNC(=O)C(F)(F)F)cc2c(O)n[nH]c12
Agent: COc1ccc(CCN)c2c(O)n[nH]c12
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(CCN)cc2c(O)n[nH]c12

Procedure:
2.7 g of N-[2-(3-hydroxy-7-methoxy-1H-indazol-5-yl)ethyl]trifluoroacetamide is refluxed with hydrochloric acid as disclosed in the preparation of 2-(3-hydroxy-7-methoxy-1H-indazol-4-yl)ethylamine, hydrochloride, thus obtaining by crystallization from ethanol/diethyl ether 1.5 g of 2-(3-hydroxy-7-methoxy-1H-indazol-5-yl)ethylamine, hydrochloride, decomposition point 266°-268° C.
Reaction SMILES: F[C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]SC2C=CC=CC=2)=[CH:6]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:30][C:28]1[CH:29]=[CH:2][C:3]([CH2:4][N:5]2[C:9]3=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]3[C:7]([CH2:18][N:34]3[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]3)=[CH:6]2)=[CH:26][CH:27]=1
Reactant: O=C1CNCCN1
Reactant: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A solution of methyl 3-(chloromethyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (24 mL, 2.0M in CH2Cl2, 48.3 mmol) [prepared as described in step 2 of example 40] was evaporated in vacuo to a residue. To this residue, anhydrous DMF (150 mL) and piperazin-2-one (386.4 mmol, 38.689, 8.0 eq.) were added followed by i-Pr2NEt (18.77 g, 145.2 mmol, 25.29 mL, 3 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 50° C. After stirring for 4 hours (50° C.) the reaction was judged to be complete by HPLC-MS analysis. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a yellow residue. Saturated aqueous sodium bicarbonate (300 mL) was added. White solid precipitated out, and the mixture was sonicated for 30 min and cooled to 10° C. The solid was filtered, washed with cold water (50 mL), and dried in vacuo to afford 18.2 g (95%) of methyl 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—1.41 min, m/e=397.20 (M+H+, base). 1H NMR (300 MHz, DMSO-D6) d ppm 2.55 (t, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.74 (s, 2H) 3.84 (s, 3H) 5.56 (s, 2H) 7.16 (t, J=8.85 Hz, 2H) 7.34 (dd, J=8.19, 5.75 Hz, 2H) 7.71 (s, 1H) 7.81 (s, 1H) 8.41 (s, 1H) 8.93 (s, 1H).
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH:15]=[CH2:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33]OS(C)(=O)=O)[CH2:28]1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C@@:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH:15]=[CH2:16])[C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:28]1)=[O:26]
Reactant: C=Cn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidazole dihydroiodide (0.70 g, 1.40 mmol), 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)-pyrrolidine (0.61 g, 1.3 mmol, example 47.2), triethylamine (4.48 mmol) and acetonitrile (18 mL) under argon for 48 hours. Cool and concentrate in vacuo. Thin layer analysis (silica gel, 10% methanol/0.1% ammonium hydroxide solution in acetonitrile) indicates a mixture with a major component Rf=0.40. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (50 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions to afford a tan solid. Purify the solid (in three separate injections of 110 mg, 250 mg and 250 mg) by reverse phase chromatography (PrepPak 40×100 mm μBondapak C18, 10 μm, 125 A°, Waters 037684, flow rate 35 mL/minute using the following gradients: 5 minutes with 10% acetonitrile/90% water with 0.1% trifluoroacetic acid, increase over 30 minutes to 50/50 water/acetonitrile, hold 5 minutes at 50/50 water/acetonitrile, increase over 5 minutes to 100% acetonitrile, hold 15 minutes at 100% acetonitrile). Combine the desired fractions to afford 0.17 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8]C2C=CC(N)=CC=2)=[CH:6][CH:5]=1)([O-])=O.BrC1C=CC([N+]([O-])=O)=CC=1.Cl[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=1>>[Cl:35][C:34]1[C:29]([O:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:30][CH:31]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:33]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=[N+]([O-])c1ccc(Br)cc1
Product: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
In the above (B), 4-bromonitrobenzene was replaced with 2,3-dichloro-5-trifluoromethylpyridine to obtain 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)aniline.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCC1COc2ccccc2O1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield from 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (br s, 1H), 8.37 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.80-6.90 (m, 4H), 4.37-4.48 (m, 2H), 4.02-4.07 (m, 1H), 3.55-3.75 (m, 2H). [M+H] calc'd for C15H14N2O4, 287. found 287.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].I[CH2:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCn1ccc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 1H-indole-5-carboxylate (6.0 g) in methylsulfoxide (30 mL) was added potassium t-butoxide (3.88 g). The mixture was stirred at room temperature for 10 minutes at which time 1-iodobutane (1.8 mL) was added. The mixture was stirred at room temperature for 5 h then partitioned between water and methylene chloride. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 10% ethyl acetate in hexanes as eluent to give 6.18 g of the title compound: 1H NM (CDCl3) δ 0.923, 1.38, 1.83, 3.9, 4.14, 6.58, 7.15, 7.34, 7.9, 8.39.