Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:13])[CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]([S:24](Cl)(=[O:26])=[O:25])([CH3:23])[CH3:22]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:13])[CH2:11][NH:12][S:24]([CH:21]([CH3:23])[CH3:22])(=[O:26])=[O:25])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@@H](CN)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and an addition funnel is charged with (2R)-2-(4-nitrophenyl)propylamine (11.75 g, 65.21 mmol), methylene chloride (150.0 mL) and triethylamine (18.2 mL, 130.4 mmol). To this solution at 0° C. was added isopropylsulfonyl chloride (8.92 mL, 63.9 mmol) over a period of 20 minutes. Reaction was then stirred to room temperature overnight, then quenched with 1N HCl (150.0 mL). The lower organic layer is separated and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (14.11 g, 97%) as an oil; 1H nmr (CDCl3, 300 MHz) δ 1.26 (d, 3H, J=6.7 Hz), 1.31 (d, 6H), 3.06 (m, 1H), 3.30 (m, 1H), 4.25 (broad triplet, 1H), 7.38 (d, 2H), 8.10 (2H); 13C nmr (CDCl3, 300 MHz) δ 16.75, 18.95, 41.29, 50.15, 53.85, 124.22, 128.52, 151.26.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:17]2[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CNCC(C)C1
Reactant: CC#CCOc1ncnc(Cl)c1F
Solvent: CCO
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.51 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 8 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.40 g of 4-(2-butynyloxy)-5-fluoro-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (4)). Compound (4) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.3/1.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1([CH3:17])[O:16][CH2:15][CH2:14][O:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([N:8]([CH2:9][CH:10]([C:12]1([CH3:17])[O:13][CH2:14][CH2:15][O:16]1)[OH:11])[C:20](=[O:21])[CH2:19][Cl:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C(O)CNCc2ccccc2)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(O)CN(Cc2ccccc2)C(=O)CCl)OCCO1

Procedure:
To a solution of 2-(2-benzylamino-1-hydroxyethyl)-2-methyl-1,3-dioxolane (5.55 g) in a mixture of tetrahydrofuran (50 ml) and water (50 ml) was added a solution of chloroacetyl chloride (1.9 ml) in tetrahydrofuran (4 ml) under ice-cooling with stirring, while keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for one hour, the mixture was extracted with ethyl acetate (150 ml), washed with brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (60 g) and eluted with a mixture of hexane and ethyl acetate (5:5, V/V) to give 2-[2-(N-benzyl-N-chloroacetylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (5.39 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:27]=1[CH2:28][S:29](Cl)(=[O:31])=[O:30]>>[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:27]=1[CH2:28][S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Reactant: O=S(=O)(Cl)Cc1c(Cl)cccc1Cl
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3c(Cl)cccc3Cl)cc2)c2ccc3c(c2N1)CCCC3
Yield: 29.4 %

Procedure:
By using 5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (50 mg, 0.156 mmol) obtained in Example 55, and 2,6-dichlorobenzylsulfonyl chloride (81 mg, 0.312 mmol), the title compound (25 mg, yield 29%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:18]=[C:17]([NH:19]C(=O)C)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1cc(/C=C/c2ccccc2)nc2ccccc12
Agent: Cl
Product: Nc1cc(/C=C/c2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A suspension of N-{2-[(E)-2-phenylethenyl]-4-quinolinyl}acetamide (1.00 g, 3.5 mmol) in 6 N hydrochloric acid (10 mL) was stirred at reflux for 4 h. After cooling to ambient temperature and stirring for 18 h, the solid was collected by filtration. The solid was treated with 10% ammonium hydroxide solution (60 mL) by stirring at ambient temperature overnight, then extracted with ethyl acetate (30 mL). The ethyl acetate layer was separated, washed with water (50 mL), brine (20 mL), dried over Na2SO4, filtered, and the solvent remove in vacuo to provide the title compound as a yellow-orange solid (0.72 g, 84%). MS (API+): M+1: 247 (100%); 1H NMR (300 MHz, DMSO-d6) d 6.79 (br s, 2H, exchangeable), 6.81 (s, 1H), 7.26 (d, J=16.2 Hz, 1H), 7.30-7.46 (m, 4H), 7.55-7.61 (m, 1H), 7.62 (d,J=16.2 Hz, 1H), 7.67-7.73 (m, 2H), 7.77 (d, J=8.4 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13](C3C4C(=CC=C(C(F)(F)F)C=4)NN=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:31]=1[C:32](Cl)=[O:33].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:32](=[O:33])[C:31]3[C:30]([F:29])=[CH:38][CH:37]=[CH:36][C:35]=3[F:39])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc(C(F)(F)F)cc23)[nH]1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2c(F)cccc2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (1 g, 4.9 mmol) (Example 55) and 2,6-difluro-benzoyl chloride 1.5 g, 8.8 mmol) (Aldrich, Milwaukee, Wis.) in benzene (10 mL) at room temperature was added a solution of tin (IV) chloride (1 mL, 2.26 g, 8.6 mmol). After stirring at room temperature for overnight, the reaction was diluted with water and ethyl acetate. The organic layer was washed with 2N NaOH, dried and purified on a silica gel column to give 205 mg of 5-(2,6-difluro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[C:27](Cl)=[O:28].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([C:17]1[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][O:20][C:16]=1[CH3:15])=[O:28]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 23.5 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0421 g, 0.179 mmol), 5-methyl-3-phenylisoxazole-4-carbonyl chloride (0.044 g; 0.179 mmol), and triethylamine (0.063 mL; 0.447 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.016 g (24%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-3-phenylisoxazole-4-carboxamide as a solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[Cl:16][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][NH:8]2)=[CH:13][C:12]=1[CH3:15]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1cc2c(CCN)c[nH]c2cc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.654 g; 1.87 mmol) and triphenylphosphine (0.737 g; 2.81 mmol) in methanol (10 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a solution of tetrabutylamonium fluoride (5.62 mL 1M) in THF and stirred at room temperature for 36 hours and concentrated under reduced pressure to yield 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine which was used without any further purification.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:11]1[CH:12]=[C:13]([CH:17]2[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[NH2:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:1][S:2]([NH:5][C:29]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:8]([NH2:9])=[O:10])[CH2:26][C:25]2([CH3:28])[CH3:27])=[O:30])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a suspension of methanesulfonamide (160 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A32. A solution of 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B32. Solution B32 was added to Solution A32 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzamide (13 mg, 10%) as a white solid: MS (ESI) M+1=402.3.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:41]1[C:45]([CH3:46])=[N:44][N:43]=[N:42]1)[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.O1CCCC1>[CH2:1]([S:17][CH2:18][CH:19]([N:41]1[C:45]([CH3:46])=[N:44][N:43]=[N:42]1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)n1nnnc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCSCC(CO)n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of 2.90 g (4.5 mM) of 1-hexadecylthio-2-(5-methyl-1H-tetrazol-1-yl)-3-triphenylmethoxypropane and 170 mg (0.9 mM) of p-toluenesulfonic acid monohydrate in 60 ml of methanol-tetrahydrofuran (1:1) mixture is stirred at room temperature for overnight. The mixture was poured into ice-water containing 151 mg (1.8 mM) of sodium bicarbonate and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by column silica gel chromatography using toluene:ethyl acetate (4:1-1:1) mixture as an eluent and 1.46 g (81% yield) of the title compound Vi1 is obtained. mp. 77°-78° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([C:9](OCC)=[O:10])[C:3]=1[F:14].CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]=[O:10])[C:3]=1[F:14]
Reactant: CCOC(=O)c1ncc(F)c(Cl)c1F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: O=Cc1ncc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a solution of ethyl 4-chloro-3,5-difluoropicolinate (1.5 g, 6.77 mmol) in toluene (25 mL) at −78° C. was added DIBAL (6.77 mL, 6.77 mmol) and the mixture was stirred for 4 hours. Then 3N HCl solution (20 mL) was added slowly and the mixture was allowed to warm to room temperature. After 1 hour, a saturated solution of NaHCO3 was added and the mixture was extracted with Et2O (2×150 mL). The combined organics were dried over Na2SO4 and evaporated to give 4-chloro-3,5-difluoropicolinaldehyde (1.15 g, 6.48 mmol, 96% yield) as a yellow liquid which was used in next step without further purification. MS [M+H] found 178.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:32])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[C:10]([Br:32])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1

Procedure:
Prepared in analogy to that of Example 103(a) from 1-benzyl-2,3-dibromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 531 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[C:10]([NH:14][C:15]([C:17]1[S:39][C:20]2[N:21]=[C:22]([S:37][CH3:38])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH:35]=[CH2:36])(=[O:34])=[O:33])[CH:26]=3)[C:19]=2[C:18]=1[NH2:40])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][C:15]([C:17]1[S:39][C:20]2[N:21]=[C:22]([S:37][CH3:38])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH2:35][CH2:36][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])(=[O:34])=[O:33])[CH:26]=3)[C:19]=2[C:18]=1[NH2:40])=[O:16])([CH3:12])([CH3:11])[CH3:13]
Reactant: COCCNCCOC
Reactant: C=CS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Product: COCCN(CCOC)CCS(=O)(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
Reaction of bis-(2-methoxyethyl) amine (244 mg) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and 0.1% aq TFA.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2cc(F)ccc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A solution of 2,5-difluorobenzoyl chloride (2.0 mL, 16.14 mmol) and dichloromethane (14.25 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (2.0 g, 16.14 mmol), pyridine (3.9 mL, 48.42 mmol) and dichloromethane (57.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The solid was slurried in hexanes (150 mL) and was filtered to give 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.61 g, 61%) as a tan solid. ESI-MS m/z calc. 264.07. found 265.3 (M+1)+; Retention time: 1.22 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.12-8.05 (m, 1H), 7.58 (ddd, J=8.3, 5.4, 2.9 Hz, 1H), 7.52-7.41 (m, 2H), 7.25-7.19 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:26]([F:37])[CH:25]=2)=[CH:20][CH:19]=1.O>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:26]([F:37])[CH:25]=3)=[CH:38][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Reactant: CC(C)(C)c1cc(C(C)(C)C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3C(C)(C)C)cc2)cc1F
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
To a solution of 3,5-di-tert-butyl-1H-pyrazole (0.50 g, 2.8 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.13 g, 3.3 mmol) under ice-cooling and the mixture was stirred for 20 min. Then ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (0.98 g, 2.8 mmol) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to give the title compound (0.73 g, yield 57%) as colorless crystals. melting point 73-74° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N+:28]=2[O-:37])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N+:28]=3[O-:37])[CH:22]=2)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1c(-c2cccc(Br)c2)cccc1C(F)(F)F
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)[n+]3[O-])c2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2-(3-bromo-phenyl)-6-trifluoromethyl-pyridine 1-oxide (1.12 g, 3.52 mmol) in toluene (10 mL) and ethanol (1 mL) at room temperature under argon was added 2 N aqueous sodium carbonate solution (5.41 mL, 10.82 mmol) followed by tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The resulting mixture was stirred at 90° C. for two hours and then allowed to cool to room temperature. The phases were separated and the aqueous phase was extracted with toluene (5 mL). The combined organic phases were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 9:1) to give 2-(4′-benzyloxy-3′-methoxybiphenyl-3-yl)-6-trifluoromethyl-pyridine 1-oxide as a clear oil, 1.11 g (70%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C:11](=[O:24])[CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][C:7]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:6]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]=1)([O-:3])=[O:2].O.NN>ClCCl.CO>[NH2:13][CH2:12][C:11]([NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:7]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:8]=1)=[O:24]
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CN2C(=O)c3ccccc3C2=O)c([N+](=O)[O-])cc1Oc1ccccc1
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(NC(=O)CN)c([N+](=O)[O-])cc1Oc1ccccc1
Reaction time: 19 h
Yield: 73.5 %

Procedure:
To 350 ml of a dichloromethane-methanol (5:2) solution containing 9.5 g of N-(4-nitro-2-phenoxy-5-phthalimidoacetylaminophenyl)methanesulfonamide was added 0.64 ml of 99% hydrazine monohydrate at room temperature, followed by stirring for 19 hours. The precipitate was removed by filtration, followed by washing with hot acetonitrile. The filtrate was washed with water, and concentrated under reduced pressere. The resulting precipitate was washed with ethanol and dried to give 5.2 g of N-(5-aminoacetylamino-4-nitro-2 -phenoxyphenyl)methanesulfonamide as yellow crystals.