Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:25]=1)[N:7]=[C:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11]2.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].[F-].[Cs+].O>C1COCC1.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>[C:21]([O:20][C:18]([NH:17][C:8]1[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=3)=[CH:25][C:6]=2[N:7]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=Cc2ccc(-c3cccc(C#N)c3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of (1E,4E)-ethyl 8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate (2.05 g, 5 mmol), 3-cyanophenylboronic acid (1.47 g, 10 mmol), CsF (2.28 g, 15 mmol), and Pd(PPh3)4 (0.345 g, 0.3 mmol) in anhydrous THF (100 mL) was refluxed for 12 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography to afford 1.12 g (52%) of (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:13][OH:14])[N:8]2[CH2:11][CH3:12])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH2:11]([N:8]1[C:7]([CH2:13][OH:14])=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:23]1[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=[C:22]1[CH3:21])=[N:3][C:4]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH3:12]
Reactant: CCn1c(CO)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: CCn1c(CO)nc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc21

Procedure:
(2-chloro-9-ethyl-6-morpholino-9H-purin-8-yl)methanol (2.3 g) was reacted with 2-methylbenzimidazole via General Procedure I for Buchwald coupling. The crude product (9-ethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol (3g) was obtained after concentration of the reaction mixture and filtration after addition of water.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3c(Cl)cnn3C)c2)cc1F
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a solution of 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.040 g, 0.12 mmol) in CH2Cl2 (1.8 mL) was added 3-fluoro-4-methylbenzoyl chloride (0.025 mL, 0.14 mmol) and trietylamine (0.022 mL, 0.15 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.0096 g, 14%). LCMS m/z (%) 473 (M+H35Cl, 100), 475 (M+H 37Cl, 27). 1H NMR (400 MHz, DMSO-d6) δ: 10.31 (s, 1H), 7.96 (dd, J=2.6, 11.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.67 (s, 1H), 7.49-7.44 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.48-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.66 (s, 3H), 4.00-2.90 (m, 10H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[C:29]2[CH:37]([F:39])[F:38])[N:17]=1>C1COCC1.C(O)(=O)C.O>[F:39][CH:37]([F:38])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:21]=[C:16]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[O:8][CH3:9])[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1
Reactant: COc1ccncc1N
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccncc1Nc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a solution of 0.134 g (1.08 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.5 mL of butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 15 min. A solution of 0.133 g (0.36 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (2:3) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.078 g (48% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 161-163° C.; 1H NMR (DMSO-d6) δ9.43 (br s, 1H), 8.61-8.37 (m, 3H), 7.83-7.81 (m, 2H), 7.41 (br s, 2H), 7.20 (d, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.5%.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:23][O:22][C:20]([CH2:19][O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: COC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1.O>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:14])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCOC(C)CCCCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 82.5 %

Procedure:
In a solution of 3 g of 6-pentyloxyheptanol in 10 ml of pyridine, 3.4 g of p-toluenesulfonyl chloride was added in 30 min. at 0°-5° C. After the addition, the mixture was stirred for 5 hours at an increased temperature of 20°-25° C. After the reaction, the mixture was poured in cold water, acidified with 6N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried with anhydrous MgSO4, followed by distilling-off of the ethyl acetate to obtain 4.36 g of 6-pentyloxyheptyl p-toluenesulfonate.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([C:21](=[O:30])[N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=1[F:31])[C:10](=[O:32])[NH:9]2)=[O:4].O.[OH-].[Li+].CO.Cl>O1CCCC1.O>[C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([C:21](=[O:30])[N:22]([CH3:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=1[F:31])[C:10](=[O:32])[NH:9]2)([OH:4])=[O:2]
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cc(C(=O)N(C)c4ccccc4)ccc3F)c(=O)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)c1ccc(F)c(-n2c(=O)[nH]c3csc(C(=O)O)c3c2=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 5-methoxycarbonyl-3-[2-fluoro-5-(N -methyl-N-phenylcarbamoyl) phenyl]thieno[3,4-d]pyrimidine -2,4(1H,3H)-dione (0.18 g) and lithium hydroxide-monohydrate (0.17 g) in tetrahydrofuran (6 mL)-methanol (3 mL)-water (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=8/1) to give the title compound (0.12 g).
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][CH3:13]>C(Cl)Cl>[CH2:9]([CH:10]1[CH:11]([CH2:12][CH3:13])[C:6](=[O:7])[N:5]1[S:2]([Cl:1])(=[O:4])=[O:3])[CH3:8]
Reactant: CC/C=C/CC
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC1C(=O)N(S(=O)(=O)Cl)C1CC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Chlorosulfonylisocyanate (5.17 ml, 59.4 mmol) in DCM (12 ml) was stirred at 25° C. and treated dropwise with (E)-hex-3-ene (7.39 ml, 59.4 mmol) in DCM (6 ml). The mixture was stirred at RT for 72 hrs. The reaction mixture was heated over 6 hrs at 40° C., before being poured onto ice. The mixture was extracted with DCM (3×100 ml) and the combined organics were washed with water (×1), dried MgSO4 and evaporated to dryness to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([C:20]#[N:21])=[C:6]([NH:8][C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH:7]=1.C1N(P(N2CC2)(N2CC2)=S)C1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:21][C:20]1[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[C:3]([N+:22]([O-:24])=[O:23])[CH:4]=2)[NH:8][C:9](=[O:19])[C:10]=1[C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cc(C)cc(CC(=O)Nc2cc(Cl)c([N+](=O)[O-])cc2C#N)c1
Agent: S=P(N1CC1)(N1CC1)N1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2c(N)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-chloro-2-cyano-4-nitrophenyl)-2-(3,5-dimethylphenyl)acetamide (prepared essentially as described in EXAMPLE 10, StepA, 250 mg in 7 mL N,N-dimethylformamide) was added 46 mg of 95% sodium hydride and the mixture stirred at room temperature. After 1.5 hours, the reaction mixture was diluted with ethyl acetate and quenched by the careful addition of 10% aqueous sodium bisulfate. The organics were then washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was suspended in methylene chloride and the solids collected by filtration and dried in vacuo to give the title compound (188 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8](=O)[NH:7][C:6]=2[CH:13]=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:13]=1
Reactant: O=C1CCSc2ccc(F)cc2N1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)NCCCS2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (76 mg, 0.38 mmol) dissolved in toluene (1 mL) and cooled to 0° C. in an ice bath. Red-Al (275 mL, 0.91 mmol) was added and then the reaction allowed to warm to room temperature. The reaction was heated at reflux for 1.5 hours. 1 N sodium hydoxide was added slowly until pH>10, this was stirred for 10 minutes, extracted with dichloromethane (3×25 mL), washed with water, and dried (sodium sulfate). The concentrated organics were purified by preparative thin layer chromatography on silica gel and eluted with 50% ethyl acetate in hexanes to give 7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (30.8 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.32 (t, 1H, J=7.5 Hz), 6.53–6.42 (m, 2H), 4.09 (s-broad, 1H), 3.31–3.27 (m, 2H), 2.83–2.79 (m, 2H), 2.11–2.04 (m, 2H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[C:12]([OH:14])=[O:13].N(C(OCC)=O)=NC(OCC)=O.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[C:12]([O:14][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:13]
Reactant: CC(Sc1cc2ccccc2[nH]1)(C(=O)O)c1ccccc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Sc1cc2ccccc2[nH]1)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution (5 ml) of 2-(1H-indol-2-yl)thio-2-phenylpropionic acid (1.5 g) and diethyl azodicarboxylate (0.96 g) in anhydrous tetrahydrofuran, a solution (5 ml) of benzyl alcohol (0.81 g) and triphenylphoshine (1.44 g) in anhydrous tetrahydrofuran was added dropwise under an argon atmosphere, and the mixture was stirred at room temperature overnight. The solvent was evaporated off under reduced pressure. Benzene was added to the residue, and deposited crystalline matter was filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (diluting solvent: n-hexane/ethyl acetate=9:1), and was further recrystallized from ethyl acetate/n-hexane to give 1.37 g (yield 71 %) of the product compound as a colorless scale-like crystal. The melting point was 102°-103° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:17]
Reactant: O=C(Br)CBr
Reactant: Nc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)Nc1cnccn1
Reaction time: 8 h

Procedure:
To a stirred suspension of pyrazin-2-ylamine (1.87 g) and potassium carbonate (8.19 g) in dichloromethane (25 mL) was added by dropwise addition 2-bromoacetyl bromide (1.72 mL). The reaction mixture was stirred overnight and then washed with water (2×50 mL). The organic phase was separated, dried with magnesium sulfate and evaporated to yield the sub-titled compound (0.70 g).
Reaction SMILES: [O:1]1CCOCC1.[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][N:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[C:32]([CH3:41])=[CH:31][C:30]4=[O:42])([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.[OH-].[K+].C(O)C>C(OCC)C>[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][N:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[C:32]([CH3:41])=[CH:31][C:30]4=[O:42])([C:25]([NH2:26])=[O:1])[CH2:21][CH2:20]3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: C1COCCO1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2c(C)cc(=O)n(CCC3(C(N)=O)CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C

Procedure:
To 1 mL of a 1,4-dioxane solution containing 30 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexanecarbonitrile, 1 mL of 20% aqueous potassium hydroxide solution and 1 mL of ethanol were added at room temperature and refluxed with heating for 4 hours. Further, 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 4 hours, thereafter 1.5 mL of 20% aqueous potassium hydroxide solution was further added and refluxed with heating for 9.5 hours. After 1 mL of 20% aqueous potassium hydroxide solution and 0.5 mL of ethanol were added and refluxed with heating for 1 hour, further 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 8 hours. After 1 mL of 20% aqueous potassium hydroxide solution was added and refluxed with heating for 6 hours, the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure. The residue was adjusted to pH 11 with 2.0 mol/L hydrochloric acid and chloroform was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, diethyl ether was added, and the resulting solid was filtered to give 21 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexanecarboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(Cl)cc(Cl)c1
Yield: 83 %

Procedure:
The procedure used in Example 84 was used to prepare this compound from a mixture of 16.3 g (0.10 mole) of 3,5-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene. The compound was obtained in 83% yield as a white, fluffy solid, mp 146°-147° C. (benzene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:15])[N:6]=[CH:5]2
Reactant: Oc1ncc2cc(Br)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 6-bromoquinazolin-2-ol (9.72 g, 40 mmol) in phosphorus oxychloride (100 mL) was refluxed for 5 hours. The reaction was cooled to room temperature, and most of phosphorus oxychloride was removed under reduced pressure. The residue was dropwise added to ice water (500 mL), and the resulting precipitate was collected by the filtration to give the title compound (9 g, 87%) as a yellow solid. MS (ES+) C8H3BrClFN2 requires: 260, 262, found: 261, 263 [M+H]+.
Reaction SMILES: O1CCCCC1[O:7][C@H:8]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:9][O:10][C:11](=[O:41])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C.COC1C=CC(O)=CC=1>[OH:7][C@H:8]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:9][O:10][C:11](=[O:41])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OC[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OC[C@H](O)c3ccccc3)cc2)cc1
Temperature: 55 °C
Yield: 54.8 %

Procedure:
6.4 g of (R)-4-(4-(6-Acryloyloxyhexyloxy)benzoyloxy)cinnamic acid 2-(tetrahydropyran-2-yloxy)-2-phenyl-ethyl ester (20) (9.8 mmole) were dissolved in 35 ml of absolute ethanol and 0.5 g (2 mmole) of pyridinium 4-toluensulfonate and 40 mg of 4-methoxyphenol (to avoid polymerization) were added. The mixture was heated at 55° C. for 20 h. After cooling to room temperature, a white powder precipitated. It was filtered and washed with ethanol. It was dried in a dessicator with silica. 3 g of a white solid (55%) were obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:30][C:31]([NH2:33])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(NCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][S:23]3(=[O:25])=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:30][C:31]([NH2:33])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(NS(=O)(=O)CCCCl)cc2)cc1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCNCC
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCCS3(=O)=O)cc2)cc1NCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
12 mg of 4-(benzylamino)-6-({4-[(3-chloropropylsulfonyl)amino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 306) was dissolved in 1 mL of acetonitrile, to which 0.2 mL of diethylamine and 7 mg of potassium carbonate were added, and stirred at 80° C. for 1 hour. After cooling, water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 12 mg (100%) of the title compound as a brown crystalline powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29].Cl.[NH2:31][OH:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[ClH:28].[OH:32][NH:31][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2cccc(C(=N)NO)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in step (a) of the Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was removed in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and then treated with hydroxylamine hydrochloride (140 mg, 2.0 mmol) and Na2CO3 (106 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 days. Methylene chloride (150 mL) was added to the mixture, washed with 10% K2CO3 (2×50 mL), and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) added and the solvent removed in vacuo. The residue was purified by flash chromatography (1:1 ethyl acetate/methylene chloride) to give the title compound as a white foam (95 mg, 39%). 1H-NMR (300 MHz, CDCl3) δ 2.25 (s, 3 H), 4.89 (br s, 1 H), 4.98 (d, 2 H, J=10.7 Hz), 5.58 (br s, 1 H), 6.15 (br s , 1 H), 7.33-7.64 (m, 6 H), 7.76-7.83 (m, 1 H), and 7.92 (d, 1 H, J=4.0 Hz). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O5SCl: 447.1 (M+H), 469.1 (M+Na). Found: 447.1, 469.2.