Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:31])=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1[C:32](=O)[CH2:33][CH3:34])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:31])=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1/[C:32](/[CH2:33][CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH3:17]
Reactant: CCOc1cc2c(cc1C(=O)CC)C(C)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OCC)OC(C)(C)C=C2C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (993 mg, 4.11 mmol) and 1-(7-ethoxy-4-methyl-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 60, 225 mg, 0.82 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([O:9][C:10](=[O:37])[NH:11][C@H:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]3[N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=23)[CH2:13]1)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([O:9][C:10](=[O:37])[NH:11][C@H:12]1[CH2:16][CH2:15][C@H:14]([N:17]2[C:18]3[C:23](=[CH:22][N:21]=[C:20]4[C:19]=3[CH:27]=[CH:26][N:25]4[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[N:24]=[N:1]2)[CH2:13]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
Sodium nitrite (612 mg, 8.87 mmol) was added to a stirred solution of racemic trans [3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl amino)-cyclopentyl]-carb amic acid tert-butyl ester (3.80 g, 8.06 mmol) in acetic acid (50 mL). Stirring was continued for 45 minutes at room temperature and then the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed (saturated sodium hydrogen carbonate (3×) and brine) and concentrated to dryness. Purification by column chromatography on silica gel (gradient: DCM to ethyl acetate) gave 3.39 g (87%) of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester as a beige solid. LCMS (Method B, ESI): RT=4.00 min, m+H=483.3; 1H NMR (400 MHz, DMSO) δ: 9.20 (s, 1H), 8.15 (m, 3H), 7.73 (t, 1H), 7.63 (t, 2H), 7.45 (d, 1H), 7.15 (d, 1H), 5.65 (m, 1H), 4.21 (m, 1H), 2.44 (m, 2H, partially obscured by DMSO), 2.16 (m, 3H), 1.65 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>>[C:1]([O:20][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CN(C)CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(C)C
Temperature: 150 °C
Reaction time: 4 h

Procedure:
(a″-1) was synthesized by a dehydrating esterification reaction between oleic acid and N-hydroxyethyl-N,N-dimethylamine. Specifically, a four-neck flask equipped with a stirrer, a temperature gage and a dewatering pipe was charged with 132 g of N-hydroxyethyl-N,N-dimethylamine and 400 g of oleic acid and the mixture was raised to 150° C. The mixture was heated under stirring at this temperature for 4 hours while distilling generated water. The resulting mixture was raised to 180° C. and continuously heated with stirring for 10 hours while 66 g of 2-dimethylaminoethanol was added dropwise. After that, the reaction mixture was cooled to 120° C., unreacted amine was distilled under reduced pressure and the reaction mixture was subjected to distillation to obtain 350 g of the target N-oleoyloxyethyl-N,N-dimethylamine (a″-1).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][CH:12]([CH2:16][C:17]([O:19]C)=[O:18])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:17]([CH2:16][CH:12]([CH3:11])[C:13]([C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([OH:1])[NH:6][C:5]=2[CH:7]=1)=[O:14])([OH:19])=[O:18]
Reactant: Oc1nc2ccccc2[nH]1
Reactant: COC(=O)CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(CC(=O)O)C(=O)c1ccc2nc(O)[nH]c2c1

Procedure:
Carbon disulfide (90 ml), 2-hydroxybenzimidazole (4.1 g) and 2-methyl-3-carbomethoxy propionyl chloride (5 g) are added to aluminum chloride (20.3 g) under nitrogen. The resulting mixture is refluxed for about 45 hours, quenched with ice cold 6N HCl and the acidic mixture filtered. The filtered solid is washed with water and dried in vacuo, affording the desired product as a solid, M.P. 223° C. (dec).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[C:18]1=[O:28])[CH3:15].O>C(OCC)C>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[C:18]1([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:28])[CH3:13]
Reactant: Brc1cccnc1
Reactant: COc1ccc2c(c1)CC(CN(C)C)C2=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)CC(CN(C)C)C2(O)c1cccnc1
Reaction time: 0.67 h

Procedure:
47 ml of n-butyllithium solution (1.6 mol./l in n-hexane) were added dropwise at a temperature of from −30 to −35° C. to a solution of 7.3 ml of 3-bromopyridine in about 125 ml of diethyl ether p.a. After a further 20 minutes at that temperature, 11 g of 2-dimethylaminomethyl-5-methoxy-indan-1-one, dissolved in diethyl ether p.a., were added dropwise, with continued cooling, stirring was continued for 40 minutes at that temperature, and heating was carried out overnight to room temperature. Then 46 ml of water were added at from −10 to 0° C., the phases were separated, the aqueous phase was extracted with diethyl ether (monitoring by thin-layer chromatography), and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The resulting crude product was chromatographed on silica gel with ethyl acetate/25% ammonia solution (v/v=98:2). 7.06 g of 2-dimethylaminomethyl-5-methoxy-1-pyridin-3-yl-indan-1-ol were obtained and were dissolved in about 125 ml of 2-butanone p.a. and converted into the corresponding hydrochloride with about 0.3 ml of water and about 4.2 ml of chlorotrimethylsilane, while cooling with ice; the hydrochloride was filtered off with suction with the exclusion of air and dried in vacuo (about 50 mbar) (yield 6.79 g, mixture of the two diastereoisomers).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[Na+]>[Cl-].C(C(CCCCCCCCCCCCCCCCCC)(CCCCCCCCCCCCCCCCCC)N)CCCCCCCCCCCCCCCCC.O>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: CCCCCCCCCCCCCCCCCCC(N)(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of about 75 g of 4-hydroxyphenylacetic acid, about 273.38 g of 1-tetradecylbromide, about 46.33 g of sodium hydroxide, about 5.0 g of trioctadecyl methylamine chloride and about 500 ml of water was refluxed for about 24 hours with stirring, cooled to room temperature, the aqueous layer decanted and the solid washed with water. The solid was refluxed for about 2 hours with stirring in about 500 ml of ethanol containing about 40 g of sodium hydroxide and about 40 ml of water. The solvents were removed and the residue heated at about 0.1 mm and about 200°-210° C. in a Kugelrohr. The residue was stirred with dilute hydrochloric acid and ethyl acetate on a steam bath until solution was complete. The warm solution was washed with brine, then the solvent was removed and the residue recrystallized sequentially from methanol and hexane, giving about 66 g of the desired title compound as a white solid, mp 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15].C(N(CC)CC)C.CO>O.C(C(C)=O)C(C)C>[C:13]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: CC(=O)CC(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
Into a reaction vessel were charged 598.54 g of methyl isobutyl ketone and 74.82 g(0.45 mol) of 2-methyl-2-adamantanol, and 72.75 g (0.675 mol) of methacryloyl chloride was poured thereto at room temperature under stirring. To the mixture, 82.79 g (0.81 mol) of triethylamine was added dropwise and the resulting mixture was left as it was for 15 minutes. The mixture was heated up to 80° C. and kept at this temperature for 24 hours under stirring. After cooling, 14.42 g (0.45 mol) of methanol added dropwise to deactivate the unreacted methacryloyl chloride while keeping the temperature below 10° C. Then, 223 g of water was added to wash the mixture and thereafter the mixture was separated into layers. To the organic layer, 112 g of a saturated aqueous sodium chloride solution was added, the resulting mixture was neutralized with a 5% aqueous sulfuric acid solution so as to adjust pH to from 7 to 8. Thereafter, the mixture was separated into layers. The organic layer after separation was concentrated at a bath temperature of 40° C. to yield 109.93 g of brown crude 2-methyl-2-adamantyl methacrylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][C:5]2=O>[Pd].C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2
Reactant: Cc1ccc2oc(C(=O)O)cc(=O)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
6-Methyl-4-oxo-4H-chromene-2-carboxylic acid (Aldrich, 3.5 g, 17.1 mmol) was added to a mixture of acetic acid (50 mL) and 10% palladium on carbon (0.35 g) in a Parr shaker. The glass reactor was sealed and flushed with nitrogen, and pressurized with hydrogen (60 psi). The mixture was shaken at 70° C. for 2.5 hours, and filtered and solids were rinsed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.09-2.23 (m, 1H), 2.25 (s, 3H), 2.28-2.40 (m, 1H), 2.72-2.86 (m, 2H), 4.71 (dd, J=8.48, 3.39 Hz, 1H), 6.83 (t, J=8.65 Hz, 2H), 6.90-6.96 (m, 1H). MS (ESI) m/z 210.1 (M+NH4)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C(Cl)Cl>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:4]
Reactant: COc1cccc(N)c1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2ccccc2N)c1
Temperature: 120 °C
Yield: 80 %

Procedure:
Isatoic anhydride (32.63 g, 200 mmol) and 3-methoxyaniline (24.63 g, 200 mmol) were combined neat and heated at 120° C. for 2 hours. The reaction product was taken up in methylene chloride and chromatographed (20% ethyl acetate/hexanes, SiO2), to provide 38.75 g (80%) of 2-amino-N-(3-methoxyphenyl)benzamide. An analytical sample was obtained by recrystallization from ethyl acetate: mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:37])=[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=3)[CH2:19][CH2:20][CH3:21])[C:13]=2[CH3:37])=[CH:4][CH:3]=1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from 4-chlorophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described Example 25.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:36][S:37]([NH:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1)(=[O:39])=[O:38]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][NH:51][CH2:50][CH:47]2[CH2:48][O:49][C:44]3[CH:43]=[CH:42][C:41]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:52][C:45]=3[O:46]2)=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
3-Indolebutyric acid (1.7 g, 8.2 mmole), 1-hydroxybenzotriazole hydrate (1.3 g, 9.8 mmole) and 1,3-diisopropylcarbodiimide (1.5 ml, 9.8 mmole) were combined in 200 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (2.0 g, 8.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Product fractions were concentrated and washed with a minimum amount of THF to remove a by-product and give 3.0 g (82%) of the desired product, (7-methylsulfonylamino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as an oily white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1.[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:16][CH2:15][CH:12]1[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: OCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution containing 38.4 g of 3,4-dichloronitrobenzene in 150 ml of DMSO was added 17.3 g of cyclopropylmethanol. This solution was stirred during the dropwise addition of 9.2 g of sodium hydroxide dissolved in 10 ml of water. This addition was exothermic to 45° C. The mixture was stirred and heated to 75°-80° for 18 hours, than poured over ice water and filtered. The filter cake was recrystallized from methanol to yield 27 g (59%) of light tan solid, melting point, 42°-44° C.
Reaction SMILES: C(C1(C([O-])=O)C(O)=C(C(C)(C)C)C=C(C)C1)(C)(C)C.[K+].[C:21](=[O:23])=[O:22].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([CH2:25][C:21]([OH:23])=[O:22])(=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=O
Reactant: CC(=O)c1ccccc1
Agent: CC1=CC(C(C)(C)C)=C(O)C(C(=O)[O-])(C(C)(C)C)C1
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
6.7 g of potassium 2,6-di-t-butyl-p-cresolate in 30 cc of toluene were introduced into a 4-neck flask, having a capacity of 100 cc, provided with stirrer, thermometer and gas inlet pipe. In a carbon dioxide atmosphere 3.1 g of acetophenone (phenate: substrate molar ratio = 1 : 1) were added; the whole was stirred at 20°C for 4 hours and then acidified with cold sulphuric acid at 10% concentration. The organic phase separated, and was then extracted with a 10% sodium carbonate aqueous solution. 0.9 g of benzoylacetic acid were isolated by acidification and extraction with ether. 2.3 g of acetophenone were recovered from the organic phase.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C@@H:16]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]3=[O:23])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)=[CH:13][CH:12]=2)[C@@H:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:23])(=[O:25])=[O:26])=[CH:28][CH:29]=1
Reactant: COC(=O)C1(c2ccc(CN([C@@H]3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NCCCC[C@H]1N(Cc1ccc(C2(C(=O)O)CC2)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
1-(4-{[(4-Chloro-benzenesulfonyl)-((R)-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-cyclopropanecarboxylic acid methyl ester (0.03 g, 0.06 mmol) was dissolved in MeOH (1 ml) and treated with 1 N NaOH (0.07 ml) for 24 hr at 50° C. The reaction mixture was concentrated under reduced pressure and purified directly using preparative RP(C18) chromatography: lyophilisate 8 mg; MS: m/e=475.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:29]1([CH2:35][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[C:6]([NH:8][S:9]([C:12]3[C:17]4=[N:18][S:19][N:20]=[C:16]4[CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:7]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(NCC2CCCCC2)cc1NS(=O)(=O)c1cccc2nsnc12)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.3 %

Procedure:
To a stirred solution of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-amino-2-(piperidine-1-carbonyl)-phenyl]-amide (EXAMPLE 24; 50 mg, 0.12 mmol) in dichloroethane (4 mL) was added cyclohexanecarboxaldehyde (43 μL, 0.36 mmol), followed by sodium triacetoxyborohydride (50 mg, 0.24 mmol). The reaction mixture was stirred for 12 h at room temperature. 1 M NaOH was added until the solution became basic. The mixture was taken up in 5 mL of DCM and washed with water and aqueous NaHCO3. The organic layer was removed, dried, and purified by preparative reversed-phase HPLC (acetonitrile/water, 0.05% TFA) to afford the title compound (20 mg, 0.04 mmol, 33%). MS (ESI): m/z 514 [M+H]+, 536 [M+Na]+. HPLC (reversed-phase): RT=10.93 min (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 9.36 (s, 1H), 8.20 (dd, J=8.8 Hz, 7.0 Hz, 2H), 7.63 (dd, J=8.8 Hz, 7.0 Hz, 1H), 6.85 (d, J=3.8 Hz, 1H), 6.81 (d, J=2.3 Hz, 1H), 6.15 (dd, J=8.5 Hz, 2.3 Hz, 1H), 3.21 (m, 4H), 2.90 (d, J=6.7 Hz, 2H), 1.74 (m, 6H), 1.57 (m, 2H), 1.46 (m, 4H), 1.22 (m, 3H), 0.96 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COC=Cc1cc2ccccc2cn1
Agent: [Pd]
Solvent: CO
Product: COCCc1cc2ccccc2cn1
Reaction time: 20 h

Procedure:
3-(2-Methoxyvinyl)isoquinoline (a mixture of the cis and trans isomers; 5 g) is dissolved in methanol (50 cc). A catalyst (3% palladium-on-carbon; 0.5 g) is added and the mixture is hydrogenated in an autoclave at 20° C. under a pressure of 15 atmospheres for 20 hours, whilst stirring. The reaction mixture is then filterred and the filtrate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg). The oily residue is dissolved in methylene chloride (10 cc) and the solution is poured into a column (diameter 2 cm) containing silica (100 g) in methylene chloride. Elution is carried out with a 99-1 (by volume) methylene chloridemethanol mixture (2 liters), 100 cc fractions being collected. Fractions 10 to 15 are combined and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg). 3-(2-Methoxyethyl)isoquinoline (2.1 g) is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([C:10]([OH:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].CN(C)C=O.C(Cl)([Cl:20])=O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:4]1[S:5][C:6]([C:10]([Cl:20])=[O:12])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CCCc1nc(C)c(C(=O)O)s1
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(C(=O)Cl)s1

Procedure:
In a 200-ml three-neck flask, 15.0 g (0.08 mole) of 2-propyl-4-methylthiazole-5-carboxylic acid were suspended in 100 ml of xylene, followed by the addition of 0.05 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a flow rate of 1.5 l/hr for 3 hours (0.20 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 16.2 g of 2-propyl-4 -methylthiazole-5-carboxylic acid chloride. Its purity and yield were 97.3% and 98.2%, respectively.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1ccccc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 78.4 %

Procedure:
To a stirred solution of 4-fluoroaniline (2.4 mL, 25 mmol) and pyridine (6.1 mL, 75 mmol) in dichloromethane (30 mL) was added 2-nitrobenzoyl chloride (3.6 mL, 28 mmol). After 12 h, the mixture was diluted with dichloromethane and washed with 1 N aqueous citric acid, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The resulting solid was suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 5.1 g (79%) of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31]([F:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=3[F:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1c(Cl)cccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-chloro-2-fluoro-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 521.