Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=5)[CH3:27])[CH2:22][CH2:21]4)[CH:17]=[CH:16][C:12]=3[C:13](O)=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:41]([C:44]1[CH:45]=[C:46]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:47]=[CH:48][C:49]=1[NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)([O-:43])=[O:42].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:26]([N:23]2[CH2:22][CH2:21][N:20]([C:18]3[CH:17]=[CH:16][C:12]([C:13]([NH:61][S:58]([C:46]4[CH:47]=[CH:48][C:49]([NH:50][CH2:51][CH:52]5[CH2:53][CH2:54][O:55][CH2:56][CH2:57]5)=[C:44]([N+:41]([O-:43])=[O:42])[CH:45]=4)(=[O:59])=[O:60])=[O:14])=[C:11]([O:10][C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)[CH:19]=3)[CH2:25][CH2:24]2)[CH3:27])=[CH:39][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(c2ccc(C(=O)O)c(Oc3cccc4[nH]ccc34)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCC4CCOCC4)c([N+](=O)[O-])c3)c(Oc3cccc4[nH]ccc34)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 175E (66 mg), 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide (75 mg) and 4-dimethylaminopyridine (58.4 mg) in dichloromethane (5 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (45.8 mg). The mixture was stirred at ambient temperature overnight and concentrated. The concentrate was purified by RP HPLC (10-70% acetonitrile in 0.1% trifluoroacetic acid water/70 minutes). The desired fractions were concentrated to remove acetonitrile and the concentrate was diluted with dichloromethane and neutralized with aqueous NaHCO3. The dichloromethane layer was dried over Na2SO4 and concentrated to provide the title compound. 1H NMR (500 MHz, dimethysulfoxide-d6) δ ppm 11.31 (1H, s), 11.25 (1H, s), 8.62 (1H, t), 8.50 (1H, d), 7.68 (1H, dd), 7.53 (2H, d), 7.46 (2H, d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17 (1H, d), 7.12 (1H, dd), 7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42 (1H, d), 6.26 (2H, s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s), 2.29-2.39 (2H, m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H, m), 1.22-1.31 (2H, m), 1.17 (3H, d).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][CH2:9][C:10]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][C:10]1([C:14]([Cl:3])=[O:16])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OCC1(C(=O)O)CCC1
Reactant: O=S(Cl)Cl
Product: CC(=O)OCC1(C(=O)Cl)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.65 ml, 22.7 mmol) was added to neat 1-acetoxymethylcyclobutanecarboxylic acid (3.3 g, 18.9 mmol). The resulting mixture was stirred at room temperature for 1 hour, then heated on a steam bath for 5 minutes. After cooling, the excess thionyl chloride, HCl and SO2 were removed under reduced pressure (water aspirator). The remained residue was purified by distillation to provide the desired product as a colorless oil: bp 51°-3° C. (0.02 mm); NMR (CDCl3) δ=1.8~2.7 (9H, m containing a singlet at 2.04 δ), 4.40 (2H, s).
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.[CH3:17][O:18][C:19](=[O:41])[CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][C@H:26]1[C@H:30]([Cl:31])[CH2:29][C@@H:28]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C@@H:27]1[CH2:39][OH:40].C(=O)(O)[O-].[Na+].S(=O)(=O)(O)O>ClCCl.C(OCC)C.O>[CH3:17][O:18][C:19](=[O:41])[CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][C@H:26]1[C@H:30]([Cl:31])[CH2:29][C@@H:28]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C@@H:27]1[CH:39]=[O:40]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
9 g of Collins reagent is dissolved in 85 ml of dichloromethane, and a solution of 2 g of VI in 25 ml of dichloromethane is instilled with stirring in 5 minutes, stirred 15 minutes, diluted with 200 ml of diethyl ether, shaken with sodium bicarbonate solution, diluted sulfuric acid and salt water, dried over magnesium sulfate and concentrated by evaporation in a vacuum. 1.72 g of aldehyde VII is obtained as oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1.CCN(C(C)C)C(C)C.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(CO)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CO)c23)C1
Temperature: 140 °C
Yield: 67.7 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-acetamide (0.200 g, 0.694 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.417 g, 2.08 mmol), and DIEA (0.363 mL, 2.08 mmol) were placed in n-BuOH (2 mL) and heated to 140° C. for 18 hours. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-75 CH3CN/water) to give (R)-tert-butyl 1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.220 g, 68% yield).
Reaction SMILES: C(OC([N:8]([C@@H:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:25])[C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH2:10]1)=O)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[C:26]1([C@H:24]([NH:8][C@H:9]2[CH2:13][CH2:12][C@@H:11]([C:14]3[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH3:25])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](c2cccc(CC(=O)O)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N[C@H]1CC[C@@H](c2cccc(CC(=O)O)c2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
{3-[(1R,3S)-3-{(tert-Butoxycarbonyl)[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenyl}acetic acid (417 mg, 0.88 mmol) was dissolved in 1,4-dioxane (6 mL), followed by addition of a 1,4-dioxane solution of 4N hydrochloric acid (2 mL), and the mixture was stirred for 2 days at room temperature. The reaction solvent was distilled off under reduced pressure, followed by addition of water and methylene chloride. Then, the mixture was neutralized with a 1N aqueous sodium hydroxide solution, and was then extracted with methylene chloride. After the extracted solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (6 mL), followed by addition of an ethyl acetate solution of 1N hydrochloric acid (2 mL), and then the solvent was distilled off under reduced pressure. Hexane was added to the residue, followed by ultrasonic wave treatment, and then the solid matter generated was collected by filtration to give the title compound (324 mg, 90%).
Reaction SMILES: COC1C=C2C([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N+]([O-])=C2)=CC=1.P(Cl)(Cl)(Cl)=O>>[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])#[CH:7]
Reactant: COc1ccc2cc(-c3ccccc3OC)[n+]([O-])cc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: C#Cc1ccccc1OC
Yield: 198.7 %

Procedure:
7-Methoxy-3-(2-methoxyphenyl)isoquinoline-2-oxide (0.60 g) and phosphorous oxychloride (5 ml) were reacted at 110° C. for 2 hr. The reaction solution was concentrated, and to the resulting residue were added ethyl acetate and an aqueous saturated sodium bicarbonate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.56 g of the title compound as a white solid. (232-5) 1-(4-Ethylpiperazin-1-yl)-7-methoxy-3-(2-methoxyphenyl)isoquinoline dihydrochloride
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][NH:37][CH2:38][CH2:39][OH:40])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:14]=[CH:15][C:16]=4[O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11](=[O:34])[C:10]=1[C:9]=23.[CH2:41]([NH2:45])[CH2:42][CH2:43][NH2:44].CO.ClCCl>C(N(CC)CC)C>[NH2:44][CH2:43][CH2:42][CH2:41][NH:45][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36][NH:37][CH2:38][CH2:39][OH:40])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:14]=[CH:15][C:16]=4[O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11](=[O:34])[C:10]=1[C:9]=23
Reactant: O=C1c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2-c2nn(CCNCCO)c3ccc(Cl)c1c23
Reactant: NCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: NCCCNc1ccc2c3c(nn2CCNCCO)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 46.8 %

Procedure:
Under a slow stream of argon gas, a mixture of 19.4 g (0.035 mol) of crude 5-chloro-2-[2-[(2-hydroxyethyl)amino]ethyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd]-pyrazol-6(2H)-one (2) and 29 ml (25.8 g, 0.35 mol) of 1,3-propanediamine was stirred at 130° C. for 3.5 hours, allowed to cool and triturated with water and 2-propanol. The solid was collected, washed successively with water, 2-propanol and ethanol, and dried under vacuum at 40° C. to give 16.9 g of crude product. Chromatography over 1 kg of silica gel (230-400 mesh) with a mixture of methanol:dichloromethane:triethylamine in the following ratios: 20:79:1, then 30:69:1, and finally 40:59:1 provided 11 g. This material was recrystallized from pyridine, washed with 2-propanol, and dried under vacuum overnight at 60° C. to afford 9.7 g (46.8%) of 3, mp 204°-206° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([CH3:32])[C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCOC(OC(OCC)=O)=O>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[C:28]([CH3:32])[C:29]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=2)=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)C(=O)O
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)C(C)=Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 55.9 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (0.15 mmol, 54.21 mg), 3-(4-tert-butyl-phenyl)-2-methylacrylic acid (0.14 mmol, 30 mg), DEPC (1.2 eq, 0.17 mmol, 25.49 μl), and TEA (2 eq, 0.28 mmol, 39.03 μl) were added in DMF. The reaction mixture was stirred for 12 hrs. The reaction mixture was purified according to similar procedure of Example 21 to yield title product (34.8 mg, 55.96%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1.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>[N:6]1[CH:7]=[CH:2][CH:3]=[C:4]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C
Yield: 171.5 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (from Example 23a, 500 mg, 1.28 mmol) in toluene (10.0 mL) was added 3-pyridinyltributyltin (564 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (428 mg, 86%). MS (CI/NH3) m/z 390 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.24-1.67 (m, 2H), 1.44 (s, 9H), 1.86-2.10 (m, 2H), 3.32-3.45 (m, 2H), 3.95-4.27 (m, 3H), 7.28-7.44 (m, 2H), 7.81-7.86 (m, 1H), 8.14-8.17 (m, 1H), 8.65-8.73 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:32]1[C:40]([CH3:41])=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[C:35]([CH3:42])[CH2:36]2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:42][C:35]1[CH2:36][C:37]2[C:33]([CH:34]=1)=[C:32]([C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:40]([CH3:41])=[CH:39][CH:38]=2
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CC1=Cc2c(ccc(C)c2Br)C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1=Cc2c(ccc(C)c2-c2cc(C)cc(C)c2)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3,5-Dimethylphenylboronic acid (2.3 g, 15 mmol), prepared as described under (e) above, cesium carbonate (4.9 g, 15 mmol), and Pd2(dba)3 (87 mg, 94 μmol) (dba=dibenzylidene acetone) were dissolved in 30 ml of 1,4-dioxane. To the resultant solution were added P(t-Bu)3 (57 μL, 280 μmol) and 4-bromo-2,5-dimethylindene (3.1 g, 15 mmol) and the reaction was stirred at 80° C. for five hours. After this time, the solvent was removed in vacuo and the residue was taken up in 100 ml of diethyl ether and filtered through a celite-packed frit to remove cesium salts. Thereafter the solvent was removed in vacuo and the residue was loaded onto a silica gel column and eluted with hexane. Yield: 2.1 g (56%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[N:33]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)(=[O:40])=[O:39])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)N1CCCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)N1CCCC1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}pyrrolidine-1-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and pyrrolidine-1-sulfonyl chloride following
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:16]=[CH2:17])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)(=O)C>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][CH3:17])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=Cc1cccc2cccc(C(=O)OCC)c12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2cccc(CC)c12
Yield: 94.6 %

Procedure:
A solution of 8-vinyl-naphthalene-1-carboxylic acid ethyl ester (1.1 g) in EtOH (25 ml) was treated with acetic acid (1 ml) and Pd/C (270 mg; 10%) and hydrogenated at normal pressure overnight. The catalyst was filtered off. The filtrate was concentrated. The crude product was isolated by chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 3:2) to give 8-ethyl-naphthalene-1-carboxylic acid ethyl ester (1.05 g) as colorless liquid. MS (ISP): 229.3 ((M+H)+.).
Reaction SMILES: C(OP(OCC)(OCC)=O)C.[CH3:12][O:13][C:14]1[CH:23]=[C:22]([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[C:20]=2[Cl:25])[N:15]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[N+:42]([O-])([O-:44])=[O:43].[K+]>CO>[N+:42]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([Cl:25])=[C:21]2[C:16]=1[N:15]=[C:14]([O:13][CH3:12])[CH:23]=[C:22]2[CH3:24])([O-:44])=[O:43]
Reactant: COc1cc(C)c2c(Cl)c(OC)ccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: CCOP(=O)(OCC)OCC
Solvent: CO
Product: COc1cc(C)c2c(Cl)c(OC)cc([N+](=O)[O-])c2n1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 20-liter reactor equipped with a mechanical stirrer, thermowatch, and condenser was charged with triethylphosphate (6.3 liters) and 2,6-dimethoxy-5-chloro-4-methylquinoline (5) (500 g, 2.11 moles). Phosphorous pentoxide (1.052 kg, 7.11 moles) was added in one portion and the resulting slurry stirred for 60 minutes. Reaction temperature was adjusted to 35° C. and solid potassium nitrate (0.423 kg, 4.21 moles) added in one portion. N-hexane is added and the reaction temperature was maintained at 35-40° C. for 2 hours. Methanol (4.2 liters) was added and the mixture heated to reflux and held for 1 hour. The yellow slurry was cooled to 0-5° C. and held for 2 hours. The product was collected by suction filtration, washed with water to neutral pH, then methanol, air dried and oven dried at 60-70° C. to yield the title compound 350 g (68%); mp 199-200° C.;
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C@@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1.C(N(CC)CC)C.[C:25]1(=[O:35])[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>O1CCCC1.CN(C)C1C=CN=CC=1>[C:28]([C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[C:25]([NH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C@@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:35])([OH:30])=[O:29]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1C(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 68.7 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.5 g, 1.6 mmol) in anhydrous tetrahydrofuran (50 ml) under an atmosphere of nitrogen was added dry triethylamine (0.49 ml, 3.5 mmol) and the mixture stirred until dissolution was complete. To this solution was added phthalic anhydride (0.28 g, 1.9 mmol) and 4-dimethylaminopyridine (5 mg) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (200 ml). The organic layer was separated and washed successively with dilute hydrochloric acid (2×50 ml, 1M), water (1×50 ml) and brine (1×50 ml), then dried (MgSO4) and evaporated to give a solid which was recrystallised from ethyl acetate/hexane to give the title compound as colourless crystals (0.45 g), m.p. 241°-243° C.; δ (360 MHz, DMSO) 1.71 (1H, ddd, J=13.0, 12.5 and 4.1 Hz, CHACHBHCCHD), 2.45 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 3.74 (3H, dd, J=12.6 and 4.1 Hz, CHACHBHCCHD), 5.19 (1H, m, CHACHBHCCHD), 6.68 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.82 (1H, s, ArNH), 6.84 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.54 (4H, m, ArH), 8.64 (1H, d, J=7.0 Hz, CHDNHCOCH2), 12.86 (1H, bs, CO2H); m/e (FAB+) 423 (M+1).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[NH:30][CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:30]([CH:1]=[O:3])[CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:9]
Reactant: CC(=O)O
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.22 ml) was added dropwise formic acid (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g) in THF (15 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(3-ethoxypropoxy) phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.36 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:12]1[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(Cl)c2ccc(OC)c(C)c2n1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Ethoxy-7-methoxy-8-methyl-quinolin-4-ol (1.0 g, 4.3 mmol) was dissolved in POCl3 (21 mL) under a nitrogen atmosphere. The reaction was heated to 85° C. for 1 h. The reaction was cooled to 0° C. and ice was added slowly. After 30 min, pH was adjusted to 6 with 1N NaOH(aq). The solution was extracted with ethyl acetate (2×50 mL). The organic layers were dried with sodium sulfate, filtered and were concentrated. 4-Chloro-2-ethoxy-7-methoxy-8-methyl-quinoline (875 mg, 81%) was purified by silica gel chromatography to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 2-aminophenol (1.09 g, 10.0 mmol) and triethylamine (2.09 mL, 15.0 mmol) in THF (20 mL) was added benzoyl chloride (1.16 mL, 10.0 mmol) in THF (4 mL) dropwise over a period of 5 min at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature for overnight. The reaction mixture was concentrated at reduced pressure. The residue was taken up in methanol, aqueous sodium hydroxide (NaOH) (8M, 5 mL) was added. After 5 min the pH of the reaction mixture was adjusted to 7.0 by addition of glacial acetic acid and concentrated in vacuo. The reaction mixture was dissolved in dichloromethane (CH2Cl2), washed successively with 1M aqueous hydrochloric acid (HCl), saturated aqueous sodium hydrogen carbonate (NaHCO3). The organic layer was dried over sodium sulphate (Na2SO4), filtered and concentrated to give desired product (1.69 g).