Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][Mg]Br.[OH2:24]>CCOCC>[F:1][C:2]([C:13]1[CH:20]=[CH:19][C:16]([C:17](=[O:24])[CH3:21])=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1
Reactant: C[Mg]Br
Reactant: O
Solvent: CCOCC
Product: CC(=O)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1

Procedure:
A solution of 3.3 g. (0.0118 mole) of 4-(α,α,β,β-tetrafluorophenethyl)-benzonitrile in 25 ml. of dry, peroxide-free tetrahydrofuran is added dropwise to a stirred solution of about 0.03 mole of methylmagnesium bromide in 25 ml. of absolute ether in a nitrogen atmosphere. The mixture is stirred at reflux for about 26 hours. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of about 5 ml. of water and the mixture is diluted with about 50 ml. of ether. The organic phase is decanted and the gelatinous precipitate is washed thoroughly with ether. The combined ethereal extracts are washed once with water, extracted with 15 ml. of ice-cold 6N hydrochloric acid in several portions, and then washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure leaves the product as the oily solid residue. Sublimation at 95°-100° C. and 0.02 mm. gives purified material as white crystals, m.p. 128°-133° C. A sample for analysis, m.p. 134°-135.5° C., is obtained by repeated recrystallization from hexane and resublimation.
Reaction SMILES: C([O:8][C:9](=[O:20])[CH2:10][N:11]1[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:11]1([CH2:10][C:9]([OH:20])=[O:8])[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1
Reactant: O=C(Cn1ccc2ccncc21)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)Cn1ccc2ccncc21
Yield: 89.1 %

Procedure:
To a stirred solution of pyrrolo[2,3-c]pyridin-1-yl-acetic acid benzyl ester (1.0 g, 3.6 mmol) in MeOH (20 mL) in a Parr shaker vessel (250 mL), palladium-charcoal (100 mg) is added under nitrogen atmosphere. Nitrogen is flashed with hydrogen and the solution is hydrogenated at room temperature at 10 psi hydrogen pressure. Reaction is monitored by TLC. After complete consumption of starting material, the reaction mixture is taken out from the Parr shaker and diluted with water. The solution is filtered through a pad of diatomaceous earth and washed successively with hot water. Volatiles are removed under reduced pressure and crude solid obtained is washed with EtOAc (3×50 mL). It is concentrated and dried in vacuum to yield pyrrolo[2,3-c]pyridin-1-yl-acetic acid as a solid (0.565 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[C:7]([C:14]#[N:15])[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22]C(=O)C(C)(C)C)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([C:10]([CH3:11])([CH3:12])[CH3:13])[N:8]=[C:7]2[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:14]2[NH2:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(-c2ccccc2NC(=O)C(C)(C)C)c(C#N)nn1C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1c2c(nn1C(C)(C)C)c(N)nc1ccccc12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a solution of N-[2-(5-butyl-1-tert-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide (1.63 g, 4.28 mmol) in ethanol was added sodium tert-butoxide (0.494 g, 5.14 mmol). The solution was heated at reflux for 1 day, then was allowed to cool to ambient temperature. A precipitate formed that was isolated by filtration and washed with a small amount of water (24 mL) and ethanol (3 mL) to yield 0.4667 g of 1-butyl-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as off-white crystals, mp 222.0-223.0° C.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC>C1COCC1.CCCCCC>[CH2:1]([C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1[B:15]([OH:20])[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(Br)c1Cc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1ncc(B(O)O)c1Cc1ccccc1
Temperature: -78 °C
Yield: 39 %

Procedure:
5-Benzyl-4-bromo-1-methyl-1H-pyrazole (0.27 g; 1.06 mmol) was dissolved in 5.0 ml anhydrous THF and cooled down to −78° C. Afterwards was added Triisopropyl borate (0.46 ml; 2.01 mmol) and n-BuLi; 1.6 mol/1 in Hexane; (0.69 ml; 1.11 mmol). It was stirred for 1 hour within the desired product was formed. It was warmed to 25° C. and quenched with water. It was purified with reverse phase chromatography by using basic conditions.
Reaction SMILES: ClC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6](C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.C1([N:63](C2C=CC(C([O-])=O)=C(C)C=2C)C)CC1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:63])=[O:50])=[C:33]2[S:53]([N:7]([CH:8]1[CH2:9][CH2:10]1)[CH3:6])(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: Cc1c(C(=O)[O-])ccc(N(C)C2CC2)c1C
Agent: CN
Agent: Cl
Product: CN(C1CC1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-cyclopropyl-N-methylamine oxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 372.2 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH2:25][NH3+:26])=[CH:14]2.[Cl-].[C:28]1([N:34]2[C:38]([CH2:39][CH2:40][CH3:41])=[C:37]([C:42](Cl)=[O:43])[CH:36]=[N:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:25][NH:26][C:42]([C:37]3[CH:36]=[N:35][N:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:38]=3[CH2:39][CH2:40][CH3:41])=[O:43])[CH:14]=2)[C:9]=1[Br:8]
Reactant: COC(=O)COc1ccc2cc(C[NH3+])ccc2c1Br
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC(=O)OC)ccc3c2)cnn1-c1ccccc1
Reaction time: 17 h
Yield: 95 %

Procedure:
Triethylamine (0.192 mL, 1.38 mmol) was added under nitrogen to a mixture of 5-bromo-6-methoxycarbonylmethoxy-naphthalen-2-ylmethyl-ammonium; chloride (0.25 g, 0.69 mmol), prepared in the previous step, and 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (0.17 g, 0.69 mmol) in 20 mL of methylene chloride at room temperature. The reaction stirred under nitrogen for 17 h. The reaction was diluted with methylene chloride, extracted two times with water, two times with 5% sodium bicarbonate, dried (MgSO4) and the solvent removed under reduced pressure to give (1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (0.347 g, 95%) as a white solid, mp 144-146° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].O>CO>[NH2:9][C:8]1[C:7]2[C:10]([Cl:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:23]1[N:24]=[C:20]([CH:17]([CH3:19])[CH3:18])[S:21][CH:22]=1
Reactant: CC(C)c1nc(C=O)cs1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Cl
Temperature: 45 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of 7G (6.4 g, 26.7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (4.8 g, 30.92 mmol, 1.16 eq) and NaOH (4.27 g, 106.8 mmol, 4 eq) in MeOH (200 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The yellow precipitates were collected by filtration and dried to give product 10A (9.96 g, 98.9% yield).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]1([CH2:14][CH2:15][CH2:16]CO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC1C=CC(O)=CC=1)C1C=CC=CC=1>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:1]([O:6][CH2:7][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCCCc1ccccc1
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: Oc1ccc(OCc2ccccc2)cc1
Product: C=C(C)C(=O)OCCCCc1ccccc1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A three neck round bottom flask containing a teflon coated magnetic stirring bar was successively charged with 120 mL (1.09 mol) of methyl methacrylate (2), 5.35 g (0.015 mol) of titanium tetrabutoxide (Ti(OC4H9)4), 60 mL (0.39 mol) of 4-phenyl-1-butanol (1), and 14.6 g (0.073 mol) of 4-benzyloxyphenol (4-BOP). An addition funnel, thermometer, and a short path still head with thermometer and receiver flask were placed in the flask necks. The flask was placed in an oil bath and the temperature was increased until distillation began. Methyl methacrylate (2) was placed in the addition funnel and was added dropwise at the same rate as the distillate. The reaction mixture was heated for 4 hours and then cooled to room temperature. The crude product was vacuum distilled to isolate 62.8 g (0.29 mol, 74%) of 4-phenylbutyl methacrylate (3) as a clear, colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][CH:21]([CH:26]([CH3:28])[CH3:27])[C:20]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:30]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][CH:21]([CH:26]([CH3:27])[CH3:28])[C:20]=3[CH:29]=2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OO
Reactant: COc1ccc(SCCCOc2ccc3c(c2)C(C(C)C)OC(=O)N3)cc1OC
Product: COc1ccc(S(=O)CCCOc2ccc3c(c2)C(C(C)C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[3-(3,4-dimethoxy-phenylmercapto)-propoxy]-4-isopropyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[CH:25]=3)=[CH:14][C:8]=2[N:7]=1)[CH3:4].Cl[C:27]1[N:36]=[C:35](Cl)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.[CH2:38]([NH2:40])[CH3:39]>>[CH2:38]([NH:40][C:27]1[N:36]=[C:35]([N:21]2[CH2:20][C:19]3[CH:25]=[C:15]([C:13]4[CH:12]=[CH:11][C:9]5[N:10]=[C:6]([NH:5][CH2:3][CH3:4])[NH:7][C:8]=5[CH:14]=4)[CH:16]=[CH:17][C:18]=3[O:24][CH2:23][CH2:22]2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[CH3:39]
Reactant: CCN
Reactant: CCNc1nc2cc(-c3ccc4c(c3)CNCCO4)ccc2[nH]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: Cl
Product: CCNc1nc(N2CCOc3ccc(-c4ccc5nc(NCC)[nH]c5c4)cc3C2)c2ccccc2n1

Procedure:
Prepared according to the method of example 25 by using N-ethyl-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine dihydrochloride (example 11, step 3) and 2,4-dichloroquinazoline in step 1 and ethylamine in step 2. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 1H), 7.57-7.48 (m, 2H), 7.43 (s, 1H), 7.36-7.28 (m, 2H), 7.19-7.11 (m, 2H), 7.07-6.95 (m, 2H), 6.72-6.58 (m, 1H), 4.95 (s, 2H), 4.43 (s, 2H), 4.11 (s, 2H), 3.32-3.25 (m, 4H), 1.91 (d, 4H), 1.18 (t, 6H); MS (EI) for C28H29N7O: 480 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O-:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[OH:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C([O-])c1cnc2cc(O)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(O)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (414 mg, 2.01 mmol) in a 2:1:1 THF/ethanol/water mixture (36 mL) was treated at ambient temperature with lithium hydroxide monohydrate (2.1 equivalents). The reaction mixture was stirred at ambient temperature overnight. To the reaction were then added another 2.1 equivalents of lithium hydroxide monohydrate and stirring continued for 72 hours. After removal of the volatiles the mixture was diluted with water, cooled in an ice bath, and the pH adjusted to 4 with aqueous 6N hydrochloric acid. The resulting white precipitate was isolated and dried to afford the desired product (358 mg).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([OH:15])[C:9]=1[F:16])[O:6][CH3:7])C.O[Li].O>C1COCC1.CO.O>[F:16][C:9]1[C:10]([OH:15])=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[CH:5]([O:6][CH3:7])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(OC)c1c(F)ccc(O)c1F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(C(=O)O)c1c(F)ccc(O)c1F
Yield: 93.4 %

Procedure:
A solution of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-methoxy-acetic acid ethyl ester (11.6 g) and LiOH.H2O in THF (40 ml), MeOH (40 ml) and H2O was stirred 2 h at 65° C. The organic solvents were evaporated, H2O was added (50 ml) and the pH was lowered with 2 N HCl to pH=2. The product was extracted with AcOEt (3×50 ml). The organic layers were washed with brine (100 ml), combined and dried (Na2SO4). Evaporation of the solvent afforded 9.6 g (94%) of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-methoxy-acetic acid. White solid. MS 217.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]([NH:13][C:14]4C=C[CH:17]=[CH:16][N:15]=4)=[O:12])[C:7](=[O:27])[C:6]=3[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1.NC1[S:35]C=CN=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]([NH:13][C:14]4[S:35][CH:17]=[CH:16][N:15]=4)=[O:12])[C:7](=[O:27])[C:6]=3[O:28][C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccs1
Reactant: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 39.2 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 1, Step 3), commercially available 2-aminothiazole (110 mg, 0.63 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (112 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (79 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silical gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-thiazol-2-yl-propionamide (113 mg, 46.3%) as a white solid. 1H NMR (DMSO-d6) δ: 12.56 (br. s., 1H), 7.50 (d, J=3.4 Hz, 3H), 7.20-7.36 (m, 10H), 7.05-7.15 (m, 3H), 5.06 (d, J=5.9 Hz, 3H), 4.40 (d, J=18.6 Hz, 3H), 4.09 (d, J=18.6 Hz, 3H), 3.76 (s, 6H), 1.52-1.91 (m, 24H), 1.04-1.32 (m, 17H), 0.90-1.03 (m, 7H), 0.79-0.88 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:42])[CH2:38][CH2:39][CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:42][CH:37]([CH2:36][CH3:35])[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 85.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-heptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 72%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To 300 ml (4.53 mol) of chlorosulfonic acid was added 300 g (1.57 mol) of 4-methanesulfonylchlorobenzene at room temperature while stirring. The mixture was heated to 120° C., at which stirring was continued for 16 hours. After cooling, the reaction mixture was poured into ice-water, and the resulting crystals were collected by filtration and air-dried to obtain 293 g (yield: 64%) of HD-39a.
Reaction SMILES: [Cl-:1].[Li+].C1(C)C=CC(S([O:12][CH2:13][CH2:14][CH:15]([CH3:35])[CH:16]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])(=O)=O)=CC=1.O.C(OCC)(=O)C>CN(C=O)C>[Cl:1][CH:13]([OH:12])[CH2:14][CH:15]([CH3:35])[CH:16]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)C(C(=O)NNC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(CC(O)Cl)C(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Lithium chloride (283 mg) was added to a solution of 5-(N′-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3-methyl-5-oxo-1-pentyl toluene-4-sulfonate (330 mg) in DMF (5 mL). The reaction solution was stirred at 80° C. for three hours and then left to cool to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 170 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:10][O:11][CH3:12])[C:8]#N)[N:3]=1.[OH:13]P(O)(O)=O.[OH-:18].[Na+]>>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:10][O:11][CH3:12])[C:8]([OH:13])=[O:18])[N:3]=1
Reactant: [OH-]
Reactant: CON=C(C#N)c1nsc(N)n1
Reactant: O=P(O)(O)O
Agent: [Na+]
Product: CON=C(C(=O)O)c1nsc(N)n1
Reaction time: 3 h

Procedure:
A mixture of 2-(5-amino-1,2,4-thiadiazol-3-yl-2-methoxyiminoacetonitrile (18.3 g, 0.1 mole) in 4N NaOH (250 ml) was heated at 50°-55° C. with stirring for 3 hours. The reaction mixture was adjusted to pH 1 with H3PO4, and washed with ethyl acetate (100 ml), saturated with NaCl, and extracted three times with a mixture of ethyl acetate and tetrahydrofuran (3:1, 300 ml×2, and 200 ml×1). The extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with isopropyl ether to afford pale yellow crystals of the title acid. Yield 16.8 g (83%). M.p. 184°-5° C. (dec.). [Lit.*, m.p. 180°-182° C. (dec.)].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:8])=[O:7].CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH2:20][C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[O:22])[CH:14]=[CH:13][C:12]=2[CH2:11]1)(=[O:7])=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)Cc2ccc3c(c2)CCC(NS(=O)(=O)c2cccs2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccc2c(c1)CCC(NS(=O)(=O)c1cccs1)C2)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A mixture of 1.45 g of methyl 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoate, 10 ml of methanol, 9 ml of a 2N aqueous sodium hydroxide solution and 4 ml of tetrahydrofuran is stirred at room temperature overnight. Methanol and tetrahydrofuran are distilled off, and the residual mixture is washed and acidified. The precipitated crystals are collected by filtration, washed, dried and recrystallized from a mixture of tetrahydrofuran and isopropyl ether to give 1.33 g of 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoic acid as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(Cc1cccs1)C1OC[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(Cc1cccs1)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 81.8 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-(thiophen-2-yl-methyl)-3-(L-arabinopyranosyl)urea and 5.0 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-(thiophen-2-yl-methyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[C:9]([F:15])=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.BrC1C([F:23])=CC=CN=1.FC1C([N+]([O-])=O)=CC=CC=1B(O)O>>[F:15][C:9]1[C:8]([C:3]2[C:2]([F:23])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:14]
Reactant: Fc1cccnc1Br
Reactant: Nc1cccc(-c2ncccc2Cl)c1F
Agent: O=[N+]([O-])c1cccc(B(O)O)c1F
Product: Nc1cccc(-c2ncccc2F)c1F

Procedure:
was prepared by using the same procedures as described for the preparation of 3-(3-chloro-pyridin-2-yl)-2-fluoro-phenylamine in Scheme C6, starting from 2-bromo-3-fluoropyridine [40273-45-8] and 2-fluoro-3-nitrophenylboronic acid [1150114-29-6]. MS (LC-MS): 207 [M+H]+; tR (HPLC conditions k): 2.39 min.