Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[NH:28][N:27]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][NH:17]C(OC(C)(C)C)=O)(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]3[CH2:33][CH2:32]3)[NH:28][N:27]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][NH2:17])(=[O:14])=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: O=C(O)C(F)(F)F
Product: NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 38.8 %

Procedure:
Tert-butyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (23 mg, 0.05 mmol, 1.0 equiv.) was stirred in TFA at r.t. for 30 min. The reaction was concentrated and to the residue was added aqueous NaHCO3 and extracted with EA (3×). The combined EA layers were dried (Na2SO4), filtered, concentrated and washed with ether to afford the 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonohydrazide (Compound 251) (8 mg, 44%). LC-MS (m/z)=412 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.75-0.76 (m, 2H), 0.98-0.99 (m, 2H), 1.91-1.95 (m, 1H), 4.23 (d, J=7.2 Hz, 2H), 6.41 (s, 1H), 7.94 (s, 1H), 8.30 (d, J=1.2 Hz, 1H), 8.46 (s, 2H), 9.47 (d, J=7.6 Hz, 1H), 12.37 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:36]1[C:32](=[O:42])[C:33]3[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:35]1=[O:37])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 93.4 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.59 g, 6 mmol) and potassium phthalimide (1.67 g, 9 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (3.04 g, 93.5%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:25])=[CH:9][C:10]([O:23][CH3:24])=[CH:11][C:12]=3[C:13]2([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])O)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].C([O+]([B-](F)(F)F)CC)C>C1(C)C=CC=CC=1>[N:26]([C:13]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]2[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=[C:8]([F:25])[C:7]=2[O:6][C:5]2[C:14]1=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=2)=[N+:27]=[N-:28]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Agent: CC[O+](CC)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(N=[N+]=[N-])c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2-(7-bromo-4-fluoro-9-hydroxy-2-methoxy-9H-xanthen-9-yl)acetate (1.0 g, 2.432 mmol) in toluene (25 ml) was added azidotrimethylsilane (0.560 g, 4.86 mmol). The solution was cooled to 0° C. and (diethyloxonio)trifluoroborate (0.308 ml, 2.432 mmol) was added drop wise. The mixture was stirred overnight at RT. The solution was quenched with MeOH (10 ml) and diluted with EtOAc. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution and brine, and then concentrated to afford crude ethyl 2-(9-azido-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)acetate (1 g, 2.292 mmol, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([NH2:21])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][C:19]#[N:21])=[CH:24][CH:25]=1
Reactant: CC(C)(CC(N)=O)Cc1nc2ccccc2n1Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(CC#N)Cc1nc2ccccc2n1Cc1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
2.7 g of 4-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,3-dimethylbutanamide are dissolved in 50 ml of chloroform. 2.3 ml of phosphorus oxychloride are added and the mixture is refluxed for 5 hours. After cooling, the solvents are evaporated off under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum to give an oil which crystallizes from ether. The crystals are filtered off, washed with ether and then dried to give 2.5 g of 4-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,3-dimethylbutyronitrile in the form of crystals melting at 110° C.
Reaction SMILES: C(O[C:6]([C:8]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1>>[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH:34][C:6]([C:8]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]3[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:30]1
Reactant: Cn1ccc(N)n1
Reactant: COCC1Cc2c(OCc3ccccc3)cc(C(=O)OC(C)(C)C)cc2O1
Product: COCC1Cc2c(OCc3ccccc3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-benzyloxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204b) and 1-methyl-3-aminopyrazole (268 mg, 2.95 mmol) to give a white solid (645 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1 H) 7.34-7.44 (m, 5 H) 7.29 (d, J=2.27 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.89 (s, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.12 (s, 2 H) 5.01-5.09 (m, 1 H) 3.79 (s, 3 H) 3.56-3.66 (m, 2 H) 3.45 (s, 3 H) 3.29 (dd, J=16.42, 9.60 Hz, 1 H) 3.01 (dd, J=16.42, 7.33 Hz, 1 H); LCMS for C22H23N3O4 m/z 394.00 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:12])=[N:6][C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C1(C)C=CC=CC=1.[C:20](OCC)(=[O:22])[CH3:21]>C(O)(=O)C>[CH3:12][C:5]1[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[C:4]=1[C:1]([CH2:2][C:20](=[O:22])[CH3:21])=[O:3]
Reactant: CC(=O)c1c(C)cc(C)nc1C
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)c1c(C)cc(C)nc1C
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of 172.0 g of 3-acetyl-collidine, 4.5 l of anhydrous toluene, 195 g of ethyl acetate and 282.5 g of potassium tert.-butylate is heated at 100° for 4 hours under nitrogen. The reaction mixture is cooled and poured into 1/2 l of ice water and 140 ml of acetic acid, and the phases are separated and worked up in the customary manner to give 186.1 g of 2,4,6-trimethyl-nicotinoyl-acetone ##SPC8##
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>O1CCOCC1>[CH2:34]([NH:41][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: NCc1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(NCc3ccccc3)cc2n(C)c1=O
Reaction time: 14 h

Procedure:
N-[3-(7-Chloro-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (100 mg, 0.21 mmol) is mixed with benzylamine (35 mg, 0.32 mmol), Pd2(dba)2 (4.8 mg, 2.5%), 1,3-Bis(2,6-di-i-propylphenyl)imidazolium chloride (4.6 mg, 5%) and potassium tert-butanoxide (35.6 mg, 0.32 mmol) under an argon environment. 6 mL of anhydrous 1,4-dioxane is added and the reaction is continued at 100° C. for 14 hours. After cooling and removal of solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the product N-[3-(7-Benzylamino-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide as pale solid. This product is dissolved into 10 mL of ethanol and 8 mg of 10% palladium carbon powder is added. The reaction is stirred at room temperature under a 50 psi hydrogen environment for 16 hours. After passing through a celite plug to remove the palladium carbon and removing the solvent, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product as a white solid: 1H NMR 400 MHz (DMSO-d6) δ 10.42 (s, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 8.26 (d, 1H, J=7.8 Hz), 7.96 (d, 1H, J=7.7 Hz), 7.78 (t, 1H, J=7.8 Hz), 7.69 (m, 2H), 7.61 (s, 1H), 7.24 (d, 1H, J=8.1 Hz), 6.53 (s, 2H), 6.29 (s, 1H), 3.49 (s, 3H), 2.12 (s, 3H); MS m/z 453.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([CH:16]=1)[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:19]([O:23][C:24](=[O:27])[CH2:25][Zn+])([CH3:22])([CH3:21])[CH3:20].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[C:13]([C:14]#[N:15])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(OCc2ccccc2)cc1C#N
Temperature: 60 °C

Procedure:
To a solution of 5-(benzyloxy)-2-bromobenzonitrile (0.73 g, 2.53 mmol) in THF (10 ml) was added 2-tert-butoxy-2-oxoethylzinc chloride (10.13 ml, 5.07 mmol). Nitrogen gas bubbled through the mixture for 10 min. then Pd2(dba)3 (0.116 g, 0.127 mmol) and X-PHOS (0.121 g, 0.253 mmol) were added and the resulting mixture heated at 60° C. for 50 min. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1×15 mL), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 50M, using a gradient eluant of EtOAc/Hexane (0-15%) to afford the title compound. LC/MS (m/z): 346 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH:44]3[CH2:46][CH2:45]3)=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH:44]3[CH2:45][CH2:46]3)=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K29) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (210 mg, 48%).
Reaction SMILES: [I-:1].[Na+].C1(C)C=CC(S(O[CH2:13][CH:14]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=O)=O)=CC=1>CC(C)=O>[CH2:26]([O:25][CH:14]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][I:1])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCOCC(COS(=O)(=O)c1ccc(C)cc1)OCCCCCCCC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCOCC(CI)OCCCCCCCC
Yield: 79.6 %

Procedure:
Sodium iodide (4.07 g) was added to a stirred solution of 2,3-di-n-octyloxy-1-propyl p-toluenesulfonate (860 mg) in acetone (14 ml) at room temperature and heated under reflux for 11 hours. The resultant mixture was evaporated under reduced pressure, and the residue was dissolved in a mixture of water (20 ml) and diethyl ether (10 ml). The aqueous solution was separated and extracted with diethyl ether, and then the organic layer and the extract were combined. The organic solution was washed with a saturated aqueous solution of sodium chloride twice, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give oil (620 mg) of 2,3-di-n-octyloxy-1-propyl iodide.
Reaction SMILES: [CH2:1]([Si:5]([CH3:8])([CH3:7])[CH3:6])[CH2:2][CH:3]=[CH2:4].C[Si](C)(C)Cl.[Br:14]CCC=C.Br>>[Br:14][CH2:4][CH2:3][CH2:2][CH2:1][Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: C=CCC[Si](C)(C)C
Reactant: C=CCCBr
Agent: Br
Agent: C[Si](C)(C)Cl
Product: C[Si](C)(C)CCCCBr

Procedure:
Thus, 3-butenyltrimethylsilane, prepared from trimethylchlorosilane and the Grignard reagent of 4-bromo-1-butene, undergoes the free radical catalyzed addition of hydrogen bromide to give 4-bromobutyltrimethylsilane. The reaction of an alkyl bromide with sodium nitrite in dimethylsulfoxide gives a nitroalkane with alkyl nitrites as byproducts. This reaction proceeds smoothly with 4-bromobutyltrimethylsilane to give 4-nitrobutyltrimethylsilane. The oxidative nitration reaction of this compound gave 4,4-dinitrobutyltrimethylsilane, which, under standard aqueous fluorination conditions, gave 4-fluoro-4,4-dinitrobutyltrimethylsilane. The reaction sequence may be summarized by the following equations: ##STR2##
Reaction SMILES: O.O.Cl.[CH:4]1([C:10]([N:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:37])=[O:36])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][CH3:47]>CN(C=O)C>[CH:4]1([C:10]([N:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37][CH2:45][CH2:46][CH3:47])=[O:36])[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:19][CH2:20]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCBr
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1ccccc1N(CCN1CCN(c2ccccc2OC)CC1)C(=O)C1CCCCC1
Yield: 62 %

Procedure:
A mixture of 0.17 g of the compound 49A of example 49, 0.14 g of anhydrous potassium carbonate, 0.2 mL of 1-bromopropane and 3 ml, of DMF was stirred at 60° C. under nitrogen atmosphere for 6 h. The cooled mixture was filtered, poured into 50 mL of H2O and extracted with EtOAc. The organic layer, dried on anhydrous Na2SO4, was evaporated to dryness to give 0.10 g (62%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[H][H]>[Pd].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OC)c2oc3ccnc(Cl)c3c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2oc3ccncc3c12

Procedure:
A mixture of Methyl-1-chloro-6-Methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 11) (330 mg), 10% Pd on carbon (50 mg), triethyl amine (2.0 mL) and DMF (10.0 mL) was hydrogenated in a Parr apparatus at 50-55 psi of Hydrogen gas. Catalyst was removed by filtration and filtrate was concentrated under vacuo. The residue obtained was purified by silica gel column using chloroform:acetone (8:2) as an eluent to afford intermediate-13 (200 mg) as light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
A mixture of 2-chloro-pyrimidine-4-carboxylic acid (2.0 g, 13 mmol), 4-trifluoromethyl phenyl boronic acid (2.4 g, 13 mmol), tetrakis(triphenylphosphine)palladium(0) (0.7 g, 0.6 mmol), potassium phosphate (5.3 g, 25 mmol), 1,2-dimethoxyethane (40 mL) and water (8 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were discarded, and the aqueous layer was acidified with concentrated HCl to pH 2. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a white solid (1.4 g, 42%). MS (ESI): mass calcd. for C12H7F3N2O2, 268.0 m/z found, 269.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([C:25](OCC1C=CC=CC=1)=[O:26])[C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[CH:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[CH2:1]([O:8][C:9]([CH:11]1[C:12]2[C:17](=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[CH:14][N:13]=2)[NH:18][C:25]1=[O:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cc(C(F)(F)F)cnc2C1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A mechanically stirred mixture of 2-bis(benzyloxycarbonyl)methyl-3-nitro-5-trifluoromethylpyridine (1.2 g, 2.5 mmol), iron dust (495 mg, 8.9 mmol), and glacial acetic acid (50 mL) was heated at reflux for 2 hr. After cooling, the mixture was poured into ice/water. The precipitated white solid was collected by filtration, air-dried and then dried in vacuo overnight. Yield: 780 mg (93%); mp>250° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](O)=[O:18])=[CH:11][CH:12]=2)[N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:6]=1)=[O:4].[CH2:30]([NH2:33])[C:31]#[CH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:18])[NH:33][CH2:30][C:31]#[CH:32])=[CH:11][CH:12]=2)[N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:6]=1)=[O:4]
Reactant: CNC(=O)c1nn(C2CCCCO2)c2cc(Nc3ccccc3C(=O)O)ccc12
Reactant: C#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(C(=O)NC)nn(C3CCCCO3)c2c1
Reaction time: 4 h

Procedure:
To a solution of 2-[3-Methylcarbamoyl-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid (150 mg, 0.381 mmol) in DMF (3.6 mL) was added propargylamine (0.052 mL, 0.761 mmol), triethylamine(TEA) (0.264 mL, 1.90 mmol), and HATU (217 mg, 0.571 mmol). The reaction was stirred for 4 hours, and then diluted with EtOAc (30 mL) and water (30 mL). The layers were separated, and the aqueous was extracted with EtOAc (2×20 mL). The combined organics were washed with saturated NaCl (15 mL) and then dried over Na2SO4. The solids were removed by filtration, and the liquid was concentrated by rotary evaporation to a yellow oil (164 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C(N(CC)CC)C>>[N+:19]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]=2)([O-:21])=[O:20]
Reactant: CS(=O)(=O)NCCCCN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Yield: 82.5 %

Procedure:
A modification of the method described in Part E of Example 1 was used to treat 7-benzyloxy-4-chloro-3-nitroquinoline (14.4 g, 45.8 mmol) with N-(4-aminobutyl)methanesulfonamide hydrochloride (10.2 g, 50.4 mmol) and triethylamine (19.2 mL, 137 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was triturated with water while heating at reflux. The resulting solid was isolated by filtration, washed with water and diethyl ether (2×100 mL), and dried under high vacuum to provide 16.8 g of N-[4-(3-nitro-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide as a yellow powder.
Reaction SMILES: C(O[C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([Br:13])=[C:8]([O:14][C:15]2[CH:20]=[C:19]([CH:21]([F:23])[F:22])[CH:18]=[C:17]([C:24]#[N:25])[CH:16]=2)[C:7]=1[F:26])C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[CH3:39].NC1C=CC(S(N)(=O)=O)=CC=1>>[Br:13][C:9]1[C:10]([Br:12])=[CH:11][C:6]([CH2:5][C:4]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](=[O:37])(=[O:36])[NH2:38])=[CH:31][C:30]=2[CH3:39])=[O:27])=[C:7]([F:26])[C:8]=1[O:14][C:15]1[CH:20]=[C:19]([CH:21]([F:22])[F:23])[CH:18]=[C:17]([C:24]#[N:25])[CH:16]=1
Reactant: CCOC(=O)Cc1cc(Br)c(Br)c(Oc2cc(C#N)cc(C(F)F)c2)c1F
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Agent: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)Cc1cc(Br)c(Br)c(Oc2cc(C#N)cc(C(F)F)c2)c1F

Procedure:
[4,5-Dibromo-3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (200) was isolated as a byproduct in the Sandmeyer reaction used in the preparation of 186 described in step 1 of example 40. The dibromo compound was converted to I-104 by the procedure described in steps 7 to 9 of example 1 except in the present example, 4-amino-3-methyl-benzenesulfonamide replaced 4-amino-benzenesulfonamide.