Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]([C:31]([O:33]C)=[O:32])=[C:29]([Cl:35])[N:28]=[C:27]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=1)(=[O:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]([Cl:35])[N:28]=[C:27]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=1)(=[O:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
To a stirred suspension of 1-((2'-((benzoylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-imidazole-5-carboxylic acid, methyl ester (25 mg, 0.044 mmol) in methanol (1.0 ml) was added 2N sodium hydroxide solution (0.50 ml). The pale yellow solution was stirred at room temperature for 3 hours then the methanol was removed in vacuo. Saturated sodium dihydrogen phosphate solution was added followed by ethyl acetate and the organic phase separated. The aqueous phase was re-extracted twice with ethyl acetate, then the combined organic phase washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. Flash chromatography (silica gel, 0.25% acetic acid-2.5% methanolmethylene chloride) afforded 1-((2'-((benzoylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)2-butyl-4-chloro-imidazole-5-carboxylic acid (11.5 mg, 47%) as a white solid; 1H NMR (300 MHz, CD3OD) δ8.27 (d, J=8.5 Hz, 1H), 7.71-7.50 (m, 3H), 7.50-7.36 (m, 4H), 7.35-7.23 (m, 3H), 6.98 (d, J=8.0 Hz, 2H), 5.70 (s, 2H), 2.67 (apparent t, 2H), 1.64 (apparent quin, 2H), 1.35 (apparent sext, 2H), 0.90 (t, J=7.3 Hz, 3H); FAB-MS: 574 (M+Na), 552 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([C@@H:15]1[CH2:17][C@@H:16]1[F:18])[CH:7]=[C:6]([C:19]([O:21]CC)=[O:20])[C:5]2=[O:24].Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([C@@H:15]1[CH2:17][C@@H:16]1[F:18])[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]2=[O:24]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A mixture of ethyl 6,7-difluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (120.8 g; 354.1 mmol), glacial acetic acid (210 ml), and conc. hydrochloric acid (420 ml) was refluxed for 6 hours, followed by cooling. The cooled reaction mixture was poured into ice/water (1500 ml) while being stirred, and the mixture was stirred for an additional 30 minutes at room temperature. Crystals precipitated were collected by filtration, and the crystals were sequentially washed with an excessive amount of purified water, ethanol (300 ml), and diethyl ether (500 ml). The crystals were purified through recrystallization from ethanol-acetone (also through treatment with activated carbon and filtration), followed by drying under reduced pressure at 70° C., to thereby yield 107.0 g of the title compound as white needles (yield: 96.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N12CCCNC1CCCC=C2.O>CN(C)C=O>[N:17]1[CH:16]=[CH:15][N:14]2[C:9]([S:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]3[C:21](=[O:23])[CH2:22][S:18][C:19]3=[O:24])(=[O:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:13]=12
Reactant: O=S(=O)(CCCCCl)c1cccc2nccn12
Reactant: O=C1CSC(=O)N1
Agent: C1=CN2CCCNC2CCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCCS(=O)(=O)c1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 0.27 g (1.0 mmol) of 5-(4-chlorobutylsulfonyl)imidazo[1,2-a]pyridine and 0.177 g (1.0 mmol) of thiazolidine-2,4-dione in 7 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=50/1) to yield 0.22 g (62.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20](OC)[O:21]C)[C:11]3=[O:25])[CH2:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20]=[O:21])[C:11]3=[O:25])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(CN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CCN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21
Temperature: 0 °C

Procedure:
A suspension of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)-1′-(2,2-dimethoxyethyl) spiro[cyclopropane-1,3′-indolin]-2′-one (1 g) in water (1 mL) was cooled to 0° C. and treated with a mixture of DCM and TFA (1:1, 6 mL) for 2 hours. The reaction mixture was poured into saturated aq. NaHCO3 solution and extracted with DCM (3×6 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure. The crude product was used for next step directly without any further purification. LC/MS m/e calcd. for C18H14ClNO2: 311, observed (M+H)+: 312.3.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CC(C)=O>[CH3:1][C:2]1[N:6]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH2:22][CH3:23])=[O:10])[N:5]=[N:4][N:3]=1
Reactant: Cc1nnnn1-c1ncccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccnc1-n1nnnc1C

Procedure:
2-(5-Methyl-1H-tetrazol-1-yl)nicotinic acid (5.6 g, 27 mmole) was suspended in acetone (250 mL), potassium carbonate (5 g) and ethyl iodide (5 mL) were added and the reaction mixture was heated at reflux for 2 hours. The acetone was removed under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, dried, then concentrated under vacuum to provide 6.3 g of ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[CH:16]=[CH:17][NH:18][C:14]=2[CH:13]=[CH:12][N:11]=1>CN(C)C=O>[Cl:9][C:10]1[C:15]2[C:16]([I:1])=[CH:17][NH:18][C:14]=2[CH:13]=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nccc2[nH]ccc12
Solvent: CN(C)C=O
Product: Clc1nccc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Iodosuccinimide (1.3 g, 5.8 mmol) was added to a 0° C. solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (0.60 g, 3.9 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 18 hours, whereupon it was concentrated in vacuo. Purification via silica gel chromatography (0% to 50% ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 900 mg, 3.2 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=5.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.34 (d, J=5.8 Hz, 1H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31])=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: C#CCCCCN
Reactant: CCSc1ncc(C(=O)O)s1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCCNC(=O)c1cnc(SCC)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 moles of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 mole of 1-aminohex-5-yne in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured into 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The mixture is then filtered and the solvent from the resulting filtrate is evaporated under vacuum yielding 2-ethylthio-5-(hex-5-ynylaminocarbonyl)thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13]C(C(F)(F)F)=CC=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.[F:51][C:52]1C=C[C:55](N)=[C:54](C)[CH:53]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:52]([F:51])=[CH:53][C:54]=2[CH3:55])[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1cc(F)ccc1N
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.56 mmol) and 4-fluoro-2-methyl-phenylamine (0.56 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=Cc1c[nH]c2cc(F)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(CO)cc3)cc12
Temperature: 90 °C
Yield: 58.4 %

Procedure:
A mixture of 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (100 mg, 0.413 mmol), [4-(hydroxymethyl)phenyl]boronic acid (69 mg, 0.454 mmol), ethanol (1.04 mL), toluene (1.0 mL) and 2 M aqueous potassium carbonate (0.824 mL, 1.65 mmol) were deoxygenated with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (25 mg, 0.033 mmol) was added and the reaction mixture was deoxygenated with nitrogen for 2 more minutes. The reaction mixture was sealed and heated at 90° C. for 16 hours. After cooling to room temperature, the phases were separated, and the aqueous phase was diluted with water and extracted twice with ethyl acetate. The combined organic layers were concentrated in vacuo and purified using silica gel chromatography (1:3 to 3:1 ethyl acetate/heptanes) to give the title compound (65 mg). MS (ES−) 268.2 (M−H)−.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C)C=O>[CH:30]1([O:3][C:4]2[CH:12]=[C:11]3[C:7]([C:8]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:9][N:10]3[C:13]3[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=3)=[CH:6][CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(O)cc32)n1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(OC4CCCC4)cc32)n1
Reaction time: 0.08 h
Yield: 29.1 %

Procedure:
Sodium hydride (added with 40% mineral oil, 13.5 mg, manufactured by Kanto Chemical Co., Inc.) was added to a solution of ethyl 2-(6-hydroxy-3-phenyl-1H-indazol-1-yl)thiazole-4-carboxylate (20 mg), which had been synthesized from the compound of Reference Example 20 according to the method of Example 3, in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, bromocyclopentane (269 mg, manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether (3×10 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1), to give 6.9 mg of the title compound. LC-MS: HPLC retention time 2.13 minutes, m/z 434 (M+H), condition C-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:8]=1[C:9](O)=[O:10])=[O:6]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]2[C:5](=[O:6])[C:7]3[C:8](=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[C:18]=2[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1
Reactant: COc1ccc(OC)c(C(=O)c2cccc(OC)c2C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COc1cccc2c1C(=O)c1c(OC)ccc(OC)c1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(2',5'-Dimethoxybenzoyl)-6-methoxybenzoic acid (I) (3 g, 0.01 mole) was added in portions to stirred concentrated sulfuric acid (20 ml). After addition the mixture was heated on steam bath with constant stirring for 20 minutes, cooled to room temperature and poured onto crushed ice (400 g) and extracted with chloroform (3 × 100 ml). The organic extract was washed with 2% aqueous sodium hydroxide solution (10 × 100 ml) and water (100 ml), then dried over anhydrous sodium sulfate and the solvent stripped off under reduced pressure to yield 1,4,5-trimethoxyanthraquinone (II), as a brownish yellow solid (2.7 g, 90% yield). Recrystallization from ethanol gave yellow crystals, m.p. 201°-203° C.; IR (CDCl3), 5.92μ; NMR (CDCl3) δ, 7.88-7.20 (m, 5H), 3.94 (s, 3H), 3.92 (d, 6H). Calcd: C, 68.46; H, 4-70. Found: C, 68.33; H, 4.82.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7](I)[N:6]=1)=[O:4].[CH2:25]([OH:28])[C:26]#[CH:27].CN(C=O)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([C:27]#[C:26][CH2:25][OH:28])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(I)c2cccnc2c1OC(=O)c1ccccc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#CCO)c2cccnc2c1OC(=O)c1ccccc1

Procedure:
A mixture of 5-iodo-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (2.00 g, 4.61 mmol), propargyl alcohol (0.563 mL, 9.67 mmol), dichlorobis(triphenylphosphine)palladium(II) (65 mg, 0.092 mmol), and copper iodide (4 mg, 0.023 mmol) were stirred in triethylamine (13 mL) and dry DMF (5 mL) at 30° C. overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography (50-100% EtOAc/Hexane gradient elution switching to 5% MeOH/CH2Cl2) to provide the desired product was a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([CH2:11][OH:12])[CH:3]=1.[H-].[Na+].Br[CH2:16]Cl.[I-].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]2[O:10][CH2:16][O:12][CH2:11][C:4]=2[CH:3]=1
Reactant: COc1cc(Br)cc(CO)c1O
Reactant: ClCBr
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 50 g of 4-bromo-2-hydroxymethyl-6-methoxyphenol in 450 ml of DMF there was added 20 g of sodium hydride (60% oily suspension) while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After adding 15 ml of bromochloromethane and 3.2 g of sodium iodide to the reaction mixture, it was stirred at 80° C. for 6 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (31.2 g) as a white solid.
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1)[CH3:7]>>[CH2:6]([C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH:11]([Li:5])[C:10]=2[N:9]=1)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCc1ccc2c(n1)CCCC2
Product: [Li]C1CCCc2ccc(CC)nc21

Procedure:
By the method described in Example 7 using n-butyl lithium solution (9% w/v, 10 ml, 0.014 mol), and 2-ethyl-5,6,7,8-tetrahydroquinoline (2.3 g, 0.014 mol) and title compound is prepared and converted in situ to methyl 2-ethyl-5,6,7,8-tetrahydroquinoline-8-carboxylate which was converted to the corresponding 8-thioamide by the procedure described in U.S. Ser. No. 460,265.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.00 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and dimethylformamide (15 ml). Triethylamine (0.57 ml) was added, and a solution of benzenesulfonyl chloride (0.35 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.57 g of 4-amino-N-(1-(4-benzenesulfonylaminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:20][C:21]([CH3:26])([CH2:24]O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:23][CH2:22][C:21]([CH3:26])([CH3:24])[CH2:20][O:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)CSCC(=O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CSCC1(c2ccc3c(c2)OCO3)OCC(C)(C)CO1

Procedure:
Ethyl {[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}acetate (Method 11) (15.8 g, 0.056 mol) was dissolved in benzene (500 mL) and 2,2-dimethyl-1,3-propanediol (46.6 g, 0.45 mol) and p-toluene sulfonic acid (cat., 500 mg) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for two hours, given room temperature and concentrated under reduced pressure. The resulting white solid was dissolved in CH2Cl2 (500 mL) and washed twice with water (300 mL) and brine (300 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude oil was purified by flash-chromatography (heptane:EtOAc 4:1) to afford the desired product.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:8][CH:7]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:22]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][CH:11]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3N)cc2)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NCc3ccccc3)cc2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-methylbenzamide hydrochloride (113 mg) in methanol (3 mL) were added benzaldehyde (38 μL) and sodium hydrogen carbonate (47.0 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (21.2 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (85.6 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:28][C:29]([NH2:31])=[NH:30])=[N:11][CH:10]=1.[H-].[Na+].[C:34](OC(=O)CCNS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35]>COCCOC.CCOC(C)=O>[C:34]([O:26][C:25](=[O:27])[CH2:24][CH2:23][NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:17][CH:16]=1)(=[O:20])=[O:21])([CH3:37])([CH3:36])[CH3:35]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NCCC(=O)O)cc12
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CCNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 30 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-β-alanine trifluoroacetate ##STR14## Guanidine hydrochloride (140 mg, 1.46 mmol was added in one portion to a stirred suspension of NaH (35 mg, 80% dispersion by wt in mineral oil, 1.17 mmol) in DME (8.0 mL) and the mixture was heated at 30° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-β-alanine t-butyl ester (150 mg, 0.37 mmol) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3 to 95:5:0.5) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-β-alanine t-butyl ester (75 mg, 0.175 mmol) as a yellow foam