Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:13]1[C:17]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[CH:23]=O)=[CH:16][C:15]2[CH:30]=[CH:31][CH:32]=[CH:33][C:14]1=2.[OH-].[Na+]>CN(C)C=O.O>[S:13]1[C:17]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22](/[CH:23]=[CH:2]/[C:1]([C:4]3[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=3)=[O:3])[CH:25]=2)=[CH:16][C:15]2[CH:30]=[CH:31][CH:32]=[CH:33][C:14]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of 4-acetylbenzoic acid (1.50 g, 9.1 mmol) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (3.27 g, 11.0 mmol) in N,N-dimethylformamide (76 mL) was added a solution of sodium hydroxide (5 M, 7.3 mL, 36.5 mmol). The reaction mixture was allowed to stir at room temperature for 2 h and was then diluted with water to a volume of 150 mL. The solution was washed with dichloromethane and acidified with concentrated sulfuric acid to pH=3. The resulting solution was then extracted with dichloromethane. The dichloromethane extract was washed with brine, dried over sodium sulfate and concentrated. The resulting oily product solidified in ethanol. The solid was further stirred in ethanol for one day and collected by filtration. The solid was washed with ethanol, then dried in vacuo to afford the title compound as a yellow solid (2.2 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H), 7.82 (d, 1H), 7.32 (m, 2H), 6.86 (s, 1H), 4.08 (s, 3H), 4.00 (s, 3H). Anal. Calculated for C26H20O5S·1/6H2O: C, 69.78; H, 4.58; S, 7.17; found: C, 69.95; H, 4.69; S, 7.15. HPLC purity: 97.9% (area percentage).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NC1CCC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with cyclobutylamine following general procedure B to afford 4-cyclobutylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 138.4 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mole) and ethyl 4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved in anhydrous DMF, warmed to 60° C. and treated with anhydrous K2CO3 (17.75 g, 0.128 mole). The solution was maintained at 60° C. for 20 hours, cooled to room temperature, and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 54.32 g of an oil. The oil was dissolved in 250 mL of methanol and 100 mL of water, whereupon a white solid formed that was isolated by filtration, washed with water and dried in vacuo, to afford the ester as a yellow solid (24.31 g, 62%): mp 62–64° C. 1H NMR (CDCl3/90 MHz) 7.64 (s, 1H), 7.30–7.21 (m, 2H), 6.96 (d, 1H, J=Hz), 5.70 (q, 1H, J=Hz), 4.30 (q, 2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: S([O-])(=O)(=O)C.CS(O[CH2:11][C:12]([O:24][CH2:25][CH3:26])([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:13][CH2:14][CH3:15])(=O)=O.[Na].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CO>[N:28]1([CH2:11][C:12]([O:24][CH2:25][CH3:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:13][CH2:14][CH3:15])[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: c1nc[nH]n1
Reactant: CCCC(COS(C)(=O)=O)(OCC)c1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CO
Product: CCCC(Cn1cncn1)(OCC)c1ccc(Cl)cc1Cl
Temperature: 120 °C

Procedure:
The mesylate prepared in accordance with (a) is reacted with the sodium salt of 1,2,4-triazole. This is effected by dissolving 0.83 g of sodium in 30 ml of methanol, adding 2.5 g of 1,2,4-triazole and removing the solvent in vacuo. A solution of 8.55 g of the mesylate in 30 ml of dimethyl sulfoxide is added to the residual sodium salt. After being heated for 5 hours on a bath at 120° C., the mixture is cooled to room temperature and extracted with diethyl ether. The combined extracts are washed with water, dried over sodium sulfate and concentrated in vacuo. Yield of crude product 7.6 g. The crude product is purified by column chromatography (silica gel; 1:4 ethyl acetate/petroleum ether) and affords a colourless oil, which crystallises after a few days. Recrystallisation from 16 ml of petroleum ether gives 3.7 g of the end product. Melting point 67° C. 100 MHz-1H-NMR (CDCl3): δ=7.63 and 7.72 ppm (s, 2H of triazole); 7.0-7.4 ppm (m, 3H, aromatic); 4.8 ppm (m, 2H, --CH2N); 3.2-3.8 ppm (m, 2H, --OCH2 --CH3); 1.7-2.4 ppm (m, 2H, --CH2CH2CH3); 1.3 ppm (t, 3H, --OCH2CH3); 0.7-1.4 ppm (m, 5H, --CH2CH2CH3).
Reaction SMILES: [N:1]([C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:7][CH2:6][CH2:5][C:4]([N:1]=[N+:2]=[N-:3])([CH3:9])[CH3:8])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)N=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutan-1-ol (3.33 g, 25.8 mmol) and DIEA (9.0 mL, 2 equiv, 51.6 mmol) in anhydrous DCM (200 mL) was added methanesulfonyl chloride (2.99 mL, 1.5 equiv, 38.7 mmol) over 5 min. The reaction was stirred and left at 0° C. for 1.5 h. The reaction mixture was extracted with 1 N HCl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give a colorless liquid. The crude oil was purified on an ISCO purification system with gradient elution from 5-40% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless liquid (4.45 g, 83.4). 1H NMR (CDCl3, 400 MHz): δ 1.36 (s, 6H), 1.93-1.98 (t, J=6.8, 2H), 3.32-4.36 (t, J=6.8, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O[CH:15](OC(C)C)[N:16]([CH3:18])[CH3:17])(C)C>>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Product: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-chlorophenyl)ethan-1-one (3.0 g, 19.3 mmol) and N,N, dimethylformamide diisopropylacetal (20 ml) was heated at 150° C. for 16 hours. The reaction mixture was cooled to 0° C. and treated with hexanes (20 ml). The resulting solid was collected via filtration and washed with hexanes to provide the title compound: EI-MS (m/z) 209 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCOCC.Cl.[N:27]([O-])=[O:28].[Na+]>O>[N:27]([N:8]([CH2:7][C:6]1[CH:19]=[CH:20][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:11][CH:10]=1)=[O:28]
Reactant: CC(C)(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 50 g of the hydrochloride salt from Step 1, 500 mL water, 250 mL ether and 170 mL of 1N hydrochloric acid was treated with a solution of 12.3 g sodium nitrite in 50 mL of water. After stirring for 2 h at room temperature the reaction mixture was extracted twice with ether. The combined extracts were washed with water and dried over MgSO4. Filtration and concentration gave N-nitroso-N-(p-chlorobenzyl)-4-t-butylaniline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1CSc1cccc[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1CS(=O)c1cccc[n+]1[O-]

Procedure:
To a vigorously stirred solution of 6.9 gm (0.03 mol) of 2-(2-methylphenylmethylthio)pyridine N-oxide in 50 ml of chloroform maintained at 0° to 10° C. is slowly added a solution of 6 gm (0.03 mol) MCPBA (85%) in 100 ml of chloroform. When addition is complete the temperature is allowed to rise to ambient. After sixteen hours the reaction solution is washed up in the manner described in Example 139.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:35]=[CH:34][C:9]([C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:25]C)=[O:24])[C:17]2=[O:33])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[OH-:36].[Na+]>CO.O>[C:23]([CH:22]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:18][C:17](=[O:33])[N:16]([CH2:20][C:19]([OH:36])=[O:21])[CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:35][CH:34]=1)([OH:25])=[O:24]
Reactant: [OH-]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCNC(=O)c2ccc(NC(=N)N)cc2)C1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(N)Nc1ccc(C(=O)NCCCN(CC(=O)O)C(=O)NC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
380 mg (0.76 mg) of methyl (3-(3-(4-guanidinobenzoylamino)propyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate hydrochloride are dissolved in 10 ml of methanol and 10 ml of water, and 2.28 ml of 1N sodium hydroxide solution are then added. The mixture is stirred at room temperature overnight, concentrated and chromatographed, for purification, on Sephadex LH20 using an homogeneous mixture of butanol/glacial acetic acid/water.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[N+:15]([O-])=O.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.[OH-].[Na+]>O>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[CH2:19][O:18][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH2:12])=[CH:4][C:3]=1[NH2:15]
Reactant: OCC1CCCCO1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(N)c(OCC2CCCCO2)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
27 g of 4-chloro-5-trifluoromethyl-1,3-dinitrobenzene are initially introduced into 36 g of 2-hydroxymethyltetrahydropyran, and 8.8 g of 50 percent strength aqueous sodium hydroxide solution are added at 45° C. in the course of 30 minutes. The mixture is then subsequently stirred at 45° for one hour and 30 ml of water are added. The oil which has separated out is separated off, washed twice with 20 ml of water each time and dried. This gives 18.3 g (53% of the theoretical value) of yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[C:32]([F:35])([F:34])[F:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[C:32]([F:35])([F:33])[F:34])=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
The material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2,-b]pyridine 1e with 6-hydroxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid methylamide 76 h and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ8.51 (1H, d, J=5.5 Hz), 7.89 (1H, s), 7.78 (1H, s), 7.72 (1H, d, J=8.6 Hz), 7.41 (1H, s), 7.18 (1H, d, J=9.8 Hz), 7.03 (1H, s), 6.66 (1H, d, J=5.4 Hz), 3.99 (3H, s), 3.86 (3H, s), 2.81 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 486, found 486.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:33](Br)([CH3:35])[CH3:34]>>[CH:33]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:35])[CH3:34]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Reactant: CC(C)Br
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OC(C)C)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate, using 1.5 equivalents of isopropyl bromide at 150° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[N:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[S:5][CH:6]=1.C(OC(=O)[NH:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[CH:32]2)(C)(C)C>>[CH2:20]([C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[S:5][CH:6]=[C:2]([N:34]4[C:35]5[C:31](=[CH:30][C:29]([NH2:28])=[CH:37][CH:36]=5)[CH:32]=[CH:33]4)[N:3]=3)[CH2:9][CH2:10]2)=[N:15][CH:16]=1)[CH3:21]
Reactant: CCc1cnc(N2CCC(Oc3nc(Br)cs3)CC2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]ccc2c1
Product: CCc1cnc(N2CCC(Oc3nc(-n4ccc5cc(N)ccc54)cs3)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using 4-bromo-2-((1-(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazole and tert-butyl-1H-indol-5-ylcarbamate (0.092 g, 40%); MS: 421.2 (M+1).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:37]([CH2:44][C:45](=O)[CH3:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C>O1CCCC1>[CH3:36][O:35][C:33]1[CH:32]=[C:11]([CH:12]=[C:45]([CH3:46])[CH2:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:10]=[C:9]([O:8][CH3:7])[CH:34]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C=C(C)CCc2ccccc2)cc(OC)c1

Procedure:
A solution of n-butyl lithium (29 ml. of 2.2 M) is added dropwise to 3,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(3,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel (400 g.) and elution with benzene. Yield: 10 g. as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](C)([CH3:25])[C:22](O)=O)[C:17]=3[CH:27]=2)[C:3]1=[O:28].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C>[CH:21]([C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)([CH3:25])[CH3:22]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (2.00 g, 0.00484 mol) and quinoline (20.0 ml) is heated to 140° C. with stirring. After 15 minutes, the mixture is cooled to room temperature, diluted with ethyl acetate, washed sequentially with 2 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to a yellow solid. The solid is recrystallized from hexanes:methylene chloride to give the title compound as an off-white solid (0.640 g, 35.8%, mp 139-140° C.) which is identified by NMR and IR spectral analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Reaction time: 8 h

Procedure:
(2-Chloro-5-nitropyrimidin-4-yl)cyclopentylamine (6.18 mmol, 1.5 g.) and trans-4-aminocyclohexan-1-ol (7.42 mmol, 854 mg mL) were mixed in DMF (18 mL) and N,N-diisopropylethylamine (7.42 mmol, 1.29 mL) was added. The reaction mixture was stirred overnight. Solvent was removed in vacuo and the residue purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→7:3 n-hexanes/ethyl acetate→ethyl acetate) to give the desired product (1.75 g, 88% yield). ES-MS: 322 (M+1). When the hydrochloride salt of an amine is used in place of the trans-4-aminocyclohexan-1-ol described above, 2 to 3 equivalents of N,N-diisopropylethylamine or sodium bicarbonate and tetrahydrofuran or acetonitrile were used as solvent.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Cl:18])=[CH:12][C:11]=1[F:19])[C:8]#[N:9].[OH2:20].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Cl:18])=[CH:12][C:11]=1[F:19])[C:8]([NH2:9])=[O:20]
Reactant: COc1cc(C(N)C#N)c(F)cc1Cl
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc(C(N)C(N)=O)c(F)cc1Cl
Reaction time: 3 h
Yield: 68 %

Procedure:
Then, 3.6 g of concentrated sulfuric acid was added to 0.33 g of water, to which 3.6 g of 2-amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 15 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 2.45 g (yield, 68%) of 2-amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)acetamide, m.p. 161.7° C.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([C:10](=[O:24])[NH:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:20][C:19](=[O:21])[C@H:18]([CH3:22])[NH:17][C:16]=2[N:23]=1)[CH3:9])(C)(C)C.[ClH:27]>>[ClH:27].[CH3:6][NH:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:20][C:19](=[O:21])[C@H:18]([CH3:22])[NH:17][C:16]=2[N:23]=1)=[O:24]
Reactant: C[C@@H]1Nc2nc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)ccc2NC1=O
Agent: Cl
Product: CN[C@@H](C)C(=O)Nc1ccc2c(n1)N[C@@H](C)C(=O)N2

Procedure:
Methyl-[(S)-1-((S)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (30 mg, 0.08 mmol) was treated with HCl according to the General procedure 3 (HCl deprotection) to afford the title compound (15 mg). 1H NMR (400 MHz, Me-d3-OD): 7.25 (1H, d), 6.91 (1H, d), 4.43-4.32 (1H, m), 4.12 (1H, d), 2.79 (3H, s), 1.67 (3H, d), 1.53 (3H, d). MS: [M+H]+=264.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 2.00 g of the compound obtained in Step 86-2 in CHCl3 (30 ml) was added TFA (6 ml) under ice cooling, then, the reaction solution was stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure to obtain 3.47 g of the title compound (yellow oil form, crude form).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].Cl>C(=O)(O)[O-].[Na+]>[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 14 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 200 ml of 1N aqueous sodium bicarbonate and 15.9 g of 4-acetamidophenol is heated to about 95°-100°C for 21 hours while stirring under nitrogen. It is cooled to room temperature and made strongly acidic with concentrated hydrochloric acid. The precipitate formed is filtered off, to yield the 4-(4-acetamidophenoxy)-3-nitro-5-sulfamoylbenzoic acid, which after trituration with aqueous ethanol melts at 293° with decomposition.