Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC#N>[CH2:20]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH:19]=[CH2:18]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of 4-(trifluoromethyl)phenol (50 g, 308 mmol) in CH3CN (600 ml) was added potassium carbonate (64 g, 463 mmol, 1.5 eq) and allyl bromide (48 g, 397 mmol, 1.3 eq) with stirring for overnight at 50° C. in an oil bath. The solids were filtered off and the filtrate was concentrated to a minimum volume, which was diluted by water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (2×200 ml), dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum to afford 1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene as yellow oil (35 g, 56%); 1H NMR (300 MHz, CDCl3): δ 7.52 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 5.98-6.11 (m, 1H), 5.30-5.46 (m, 2H), 4.57-4.58 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH2:5].Br[CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH:5][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: CCOC(CN)OC
Reactant: BrCC1OCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CNCC1OCCO1)OC
Temperature: 25 °C

Procedure:
2-Methoxy-2-ethoxyethylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([C:13]1[S:17][C:16]([CH:18]=[CH2:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:19][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C=Cc1ccc(C(C)(C)C)s1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)s1
Yield: 60.3 %

Procedure:
Sodium hydride (6.05 g-50% suspension in oil, 0.126 mol) was washed with petroleum ether, suspended in dry DMSO (90 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (44.5 g, 0.125 mmol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-t-butyl-2-thiophenecarboxaldehyde (21.01 g, 0.125 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with hexane) to give (5-t-butylthiophen-2-yl)-ethylene (5.25 g, 25%). Ethyl diazoacetate (4.69 g, 0.041 mol) in dry dichloromethane (80 ml) was added dropwise to a solution of (5-t-butylthiophen-2-yl)-ethylene (5.1 g, 0.031 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (20 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 19:1) to give ethyl 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylate (4.72 g, 60%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:10]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=c1cc(CO)cc[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc[nH]c(=O)c1
Reaction time: 16 h

Procedure:
4-Hydroxymethyl-1H-pyridin-2-one from Step 1 (1.3 g, 10.5 mmol) was dissolved in DMF. t-Butyl dimethylsilyl chloride (12.6 mmol, 1.9 g) and imidazole (12.6 mmol, 858 mg) were added and the reaction was stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with H2O (2x) and brine. The organic layer was dried (MgSO4), filtered and concentrated to yield a yellow oil Flash chromatography (EtOAC) yielded 4-(tert-butyldimethylsilyloxy-methyl)-1H-pyridin-2-one as an off white solid.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]([C@@H:38]2[CH2:42][CH2:41][CH2:40][N:39]2[CH3:43])=[O:37])[CH:32]=[CH:33][CH:34]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[CH2:18]([NH:17][C:15]1[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=[C:11]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[CH3:43])=[O:37])[CH:30]=2)[N:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1ccccc1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(benzylamino)pyrimidine-5-carboxamide (50 mg, 0.14 mmol) in NMP (1 mL) was added (S)—N-(3-aminophenyl)-1-methylpyrrolidine-2-carboxamide (33 mg, 0.152 mmol) and pTsOH*H2O (60 mg, 0.28 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give of (S)-4-(benzylamino)-2-(3-(1-methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide (48 mg). MS found for C24H27N7O2 as (M+H)+ 446.5. λ=247.5.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[OH:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl>[Br:1][C:12]1[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([CH:11]=1)[CH2:9][OH:8]
Reactant: BrBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: OCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0°-5° C., 11.5 ml. of bromine in 100 ml. of carbon tetrachloride was added dropwise to a suspension of 24.8 g. of saligenin and 24 g. of calcium carbonate in a solvent mixture of 200 ml. of carbon tetrachloride and 220 ml. of methylene chloride. The reaction mixture was stirred for 24 hours at room temperature, then filtered, and the precipitate was washed with carbon tetrachloride. The CCl4 /CH2Cl2 phase was discarded. The solid substance was taken up in ethyl acetate/water, and the organic phase was separated, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from methylene chloride, thus obtaining colorless crystal flakes (24 g.). Melting point: 107°-109° C. (methylene chloride).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CCOCC1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:20]([C@@H:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:6]([CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[C:2]([NH:1][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:3]=3)[N:7]=2)=[O:31])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared in example 58, 110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Ethanesulfonyl chloride (21 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was warmed to 80° C. for 4 h. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 60% ethyl acetate/methylene chloride) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 50% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-ethanesulfonylamino-benzyl)-1H-pyrazol-3-yl]-propionamide (14 mg, 11%) as a white powder: ESI-LRMS m/e calcd for C27H33ClN4O5S2 [M+] 592.2, found 593.7 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.16 (m, 2H, CH2), 1.14 (t, J=7.3 Hz, 3H, CH3), 1.37-1.83 (m, 8H, 4×CH2), 2.01-2.16 (m, 1H, CH), 3.03 (q, J=7.3 Hz, 2H, SO2CH2), 3.32 (s, 3H, SO2CH3), 3.84-3.92 (m, 1H, CH), 5.15 (s, 2H, NCH2), 6.46 (d, J=2.2 Hz, 1H, Ar), 6.88 (d, Jo=7.7 Hz, 1H, Ar), 7.01 (t, Jm=1.6 Hz, 1H, Ar), 7.06-7.14 (m, 1H, Ar), 7.24 (t, Jo=7.7 Hz, 1H, Ar), 7.56 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.66 (d, Jm=1.6 Hz, 1H, Ar), 7.69 (d, J=2.2 Hz, 1H, Ar), 7.98 (d, Jo=8.2 Hz, 1H, Ar), 9.75 (s, 1H, NH), 10.78 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[O:21].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[O:21])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C(CCCCCCCBr)OCc1ccco1
Solvent: CC#N
Solvent: O
Product: O=C(CCCCCCCOC(=O)c1cc(O)ccc1O)OCc1ccco1

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.8 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (4.7 g), 2-furylmethyl 8-bromooctanoate (7.8 g) and acetonitrile (150 ml) was heated, under reflux for 18 h. The cooled reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×20 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (8.4 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (5:1) as eluent, to give 8-(2-furylmethoxy)-8-oxooctyl 2,5-dihydroxybenzoate as colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
1.0 g of 4-hydroxy-1-indanone, 1.07 g of 2-chloro-5-nitropyridine and 5 g of anhydrous potassium carbonate were dissolved in 10 ml of N,N-dimethylformamide (DMF) and the mixture was stirred at room temperature for 17 hours. After the completion of the reaction, 50 ml of water was added to the reaction solution and the solution was extracted with ethyl acetate. After the organic (ethyl acetate) layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to obtain the titled compound (1.36 g, pale yellow powder).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.O.[C:21](O)(=O)[CH3:22]>>[NH2:1][C:4]1[C:5]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:9]=1[CH2:21][CH3:22]
Reactant: CC(=O)O
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Product: CCc1c(C(F)(F)F)cnc(NS(=O)(=O)CC)c1N
Temperature: 50 °C

Procedure:
3.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was suspended in a solvent mixture comprising 30 ml of water and 30 ml of acetic acid, and 2.2 g of reduced iron was added thereto. Then, the mixture was heated to 50° C. and reacted for one hour. After completion of the reaction, the reaction product was cooled to room temperature, and excess iron was separated by filtration. The filtrate was extracted with ethyl acetate. The extract layer was washed with water and dried. Ethyl acetate was distilled off under reduced pressure to obtain 2.5 g of N-(3-amino-5-trifluoromethylethyl-2-pyridyl)ethanesulfonamide.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[N:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[N:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)nc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)nc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the solution, a solution of 3-chloroperbenzoic acid (0.31 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 2 hours at −78° C. and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 54) (0.70 g) as yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[CH:13]=1)[CH2:2][CH2:3][CH3:4].[Br:14]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:13]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2ccccn2c1Br
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A mixture of 3.5 g of the product of Stage C and 50 ml of chloroform was cooled to 10° C. and 4.55 g of N-bromo succinimide were added. The mixture was stirred at this temperature for 30 minutes and was then poured into a saturated solution of sodium carbonate and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried, filtered and evaporated to dryness to obtain after chromatography on silica (methylene chloride: 95/methanol: 5), 3.8 g of the expected product in the form of a black oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:22])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19]Cl)[CH2:14][CH2:13]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:22])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)CCl)CC1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)COc2ccccc2Cl)CC1
Reaction time: 48 h

Procedure:
To a solution of 9 (0.194g, 0.6mmol) in 4ml acetone was added 2-chlorophenol (0.092g, 0.72mmol) and potassium carbonate (0.3g, 2.2mmol). The solution was heated to reflux and stirred for 48h. The solution was filtered to remove potassium carbonate, concentrated en vacuo, and purified by Prep TLC (10:1 DCM:MeOH) to yield compound 11. Mass spectrum (M+1)=416.32
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:11]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(CN(C)C)c2ncc(C#N)c(Nc3cccc(Br)c3)c2c1

Procedure:
To a stirred mixture of 6-amino-4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and 1.5 ml of acetic acid at 25° C. was added 0.14 ml (1.5 mmol) of acetic anhydride. After 60 m volatile matter was evaporated off under vacuum. The residue was stirred with sodium bicarbonate solution. The resulting solid was filtered off, washed with water, dried, and recrystallized from isopropanol-hexane to give a light yellow solid, mp 162-167° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=O)C>>[CH3:12][O:15][CH2:16][C:17]1[N:10]([CH3:11])[C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1nccnc1N
Product: COCc1nc2nccnc2c(=O)n1C

Procedure:
A mixture of 7.8 g (0.0513 mole) of 3-amino-N-methyl-2-pyrazinecarboxamide [prepared according to W. F. Keir et al., J. Chem. Soc., Perkin Trans 1, 1978, 1002], 39.4 g (0.205 mole) of triethyl orthomethoxyacetate and 45.3 ml of acetic anhydride is refluxed under a nitrogen atmosphere for 3 days. The temperature of this reflux falls with the passage of time from 114° to 90° C. and then remains constant at the latter temperature. After cooling, the reaction mixture is concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a silica column (eluant: chloroform/methanol, 95:5 and then 90:10), and is then recrystallized from ethyl acetate. Yld: 5.0 g (47%), m.p. 130.5°-132.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:27])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([B:18]4[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].O1CCCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([B:18]4[O:19][C:20]([CH3:25])([CH3:26])[C:21]([CH3:23])([CH3:24])[O:22]4)[CH:16]=3)[NH:11][CH:10]=2)=[O:27])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a reaction flask, propane-1-sulfonic acid (2,4-difluoro-3-{hydroxy-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-phenyl)-amide (29, 0.155 g, 0.306 mmol) is combined with 10 mL of tetrahydrofuran and 3 mL of dichloromethane. Dess-Martin periodinane (0.648 g, 1.53 mmol) is added and the reaction is stirred at room temperature for 20 minutes. The reaction is mixed with 1N sodium thiosulfate, extracted with ethyl acetate and the organic layer dried and purified by silica gel column chromatography, eluting with a gradient of 20-100% ethyl acetate in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=506.29.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C:16]2[C:17](=[O:32])[NH:18][N:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.N>>[F:9][C:4]1[CH:3]=[C:2]([N:18]2[C:17](=[O:32])[C:16]([O:15][C:14]3[CH:33]=[CH:34][C:11]([F:10])=[CH:12][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH:20]=[N:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). mp 178-180° C. 1H NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 6.89-7.04 (m, 4H), 7.45-7.52 (m, 1H), 7.45-7.52 (m, 1H), 7.61 (dt, J=6 Hz, 3 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 473 (M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15F3N2O4S.0.5H2O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H, 3.13; N, 5.62.