Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[NH:15][C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[F:45].N12CCCN=C1CCCCC2>C(#N)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:36][C:37]4[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=4[F:45])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Reactant: COc1ccc(F)c(CBr)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCn1c(=O)n(Cc2cc(OC)ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 20.4 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (100 mg, 0.21 mmol) and 2-bromomethyl-1-fluoro-4-methoxy-benzene (56 mg, 0.25 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.45 mmol). The reaction was stirred at 25° C. The reaction was diluted with ethyl acetate and was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (26 mg, 20%) as a yellow solid. This material was taken on without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]Br)=[N:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A suspension of 7-chloro-2-(bromomethyl)quinoline (50.5 g, 197 mmol, EP 233,763, Example 4, Step 1), 3-hydroxybenzaldehyde (22.9 g, 188 mmol) and K2CO3 (51.7 g, 375 mmol) in 600 mL of acetone was heated to reflux for 2 h. After cooling down, 200 mL of CH2Cl2 was added and the mixture was filtered through celite with acetone:CH2Cl2 3:1. The title product was purified by flash chromatography on silica with EtOAc:toluene 5:95 to yield 46.64 g, 83%. (Alternatively, the product may be purified by a swish in ether:hexane 7:1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br>ClCCl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)sc1C=O
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 3-methylthiophene-2-carbaldehyde (10 g, 0.079 mol) in dichloromethane (10 ml) was added dropwise to a stirred solution of bromine (4.08 ml, 0.079 mol) in dichloromethane (15 ml) at room temperature. The resulting mixture was heated to reflux temperature for 3 hours before cooling to room temperature, washed with water (3×50 ml), saturated NaHCO3 solution (2×25 ml), dried (MgSO4) and the solvent removed at reduced pressure to give the sub-title compound as a brown solid (14.7 g, 66% yield): 1H NMR (400 MHz, CDCl3) δH 2.60 (3H, s), 6.97 (1H, s) 9.20 (1H, s).
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[C:15](C(O)=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.[C:31](=O)(O)[O-:32].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:31](=[O:32])[CH:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=[C:15]=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)C1C=CC=CC1=C=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
N'-t-butyl-N'-benzoylhydrazine (1 g), benzoyl formic acid (0.7 g) and methanesulfonyl chloride (0.7 g) were stirred in toluene (30 ml) and saturated sodium bicarbonate (10 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture and stirred 1 hour at room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (25 ml) and washed with water several times. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white solid. After column chromatography, the product was obtained as a white solid in approximately 70% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)=[CH:5][CH:4]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[C:31]3[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]3=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(OC)cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(OC)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.75 g of ethyl 2-(3-p-methoxyphenylureido)thiazol-4-ylglyoxylate, 0.95 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1OCCOCCOCCOCCOCCOC1>CC#N.O>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CN1CCN(c2ccccc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (1.64 g, 5.5 mmol), K2CO3 (0.92 g, 6.87 mmol), 1-phenylpiperazine (1.05 mL, 5.5 mmol) and a catalytical amount of 18-crown-6 in MeCN (20 mL) was refluxed for 7 hrs, cooled to room temperature, and diluted with water. The resulting solid was filtered, washed with water, and dried to afford 2-(4-phenylpiperazin-1-yl)-N-[3-(quinoxalin-2-yl)phenyl]acetamide (2.1 g, 90% yield). LCMS calculated for C26H25N50 (M+H): 424.52. found 424. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.5 (1H, br. s), 9.52 (1H, s), 8.58 (1H, br. s), 8.20-7.80 (6H, m), 7.55 (1H, m), 7.25-7.15 (2H, m), 6.98-6.90 (2H, m), 6.80-6.72 (1H, m), 3.28-3.25 (6H, m), 2.75-2.65 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH2:30])[CH3:29])[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: C[C@@H](N)c1ccc(F)c(F)c1
Reactant: O=C(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Yield: 90.8 %

Procedure:
Following a similar procedure to that described in Example (1a), 12.91 g of 4-fluorophenyl 3-nitrophenyl ketone and 10.19 g of (R)-1-(3,4-difluorophenyl)ethylamine hydrochloride were reacted, to obtain 18.47 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[H][H]>CO.[Pt](=O)=O>[NH2:24][C:3]1[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][CH2:6][NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
N-(3-Fluoro-2-nitrophenethyl)-1-benzylpiperidin-4-amine (800 mg, 2.238 mmol) was dissolved in methanol (30 mL). Platinum(IV) oxide (18.5 mg, 0.081 mmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 60 psi of hydrogen gas. Reaction shook at room temperature for 1 hour 20 minutes. Reaction was removed from the apparatus. Mixture was filtered through a 0.45 μm PVDF membrane. Filtrate was concentrated to dryness. Title compound was obtained as grey oil in 97% yield. MS (M+H)+=328.5.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])=[CH:31][CH:30]=1>O1CCCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[N:22]1([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)=[O:40])=[CH:27][CH:26]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (67.8 mg) in tetrahydrofuran (2.5 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 2.2 ml) at room temperature, followed by stirring for 2 hours. A solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.5 ml) was further added thereto at room temperature. After 6 hours, a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.85 ml) and diisopropylethylamine (0.322 ml) were added thereto at room temperature, followed by stirring for 2 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (1 ml). The solid was filtered off and dried under aeration to provide the titled compound (17.0 mg, 17%) as white powder.
Reaction SMILES: COC(=O)CC.NC1C=CC(C(N)=O)=CC=1C.C([O:20][C:21](=[O:39])[CH2:22][CH2:23][C:24](=[O:38])[CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH2:36])=[CH:31][CH:30]=1)=[O:28])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.ClCCl>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[CH2:26][CH2:25][C:24](=[O:38])[CH2:23][CH2:22][C:21]([OH:39])=[O:20])=[CH:34][CH:33]=1)(=[O:37])[NH2:36]
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(C(N)=O)cc1
Agent: Cc1cc(C(N)=O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCC(=O)OC
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)c1ccc(C(=O)CCC(=O)CCC(=O)O)cc1

Procedure:
Synthesis of 3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-propanoic acid methyl ester. 4-amino-3-methyl benzamide (20 mg, 0.13 mmol) was added to 7-(4-carbamoyl-phenyl)-4,7-dioxo-heptanoic acid ethyl ester mixture (˜0.11 mmol) in EtOH, followed by the addition of p-toluenesulfonic acid (2 mg, 0.01 mmol). The resultant mixture was heated at 80° C. for 12 hours. The residue of the crude reaction mixture was dissolved in dichloromethane and then purified by silica-gel chromatography using 5% methanol in chloroform as the solvent system (5 mg; product: 3-[1-carbamoyl-2-methyl-phenyl)-5-(4-carbamoyl-phenyl)-1H-pyrrole-2-yl]-propanoic acid methyl ester).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[C:16](OCC)=[O:17]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1c(Cl)ccnc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (234 mg, 6.2 mmol) was stirred in anhydrous THF (30 mL) A solution of ethyl 4-chloro-2-ethylpyridine-3-carboxylate (878 mg, 4.1 mmol) in anhydrous THF (5 mL) was added at 0° C., and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (4-chloro-2-ethylpyridin-3-yl)methanol was obtained as an oil (601 mg, 85% yield) and used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[F:8][C:9]([F:21])([F:20])[CH2:10][CH2:11][S:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:14])=[O:13].[H-].[Na+].Cl>CS(C)=O>[F:21][C:9]([F:8])([F:20])[CH2:10][CH2:11][S:12]([CH:15]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[CH:2])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:14]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 1.0 g of 6-chloro-1-hexyne and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 0.3 g of sodium hydride (60% in oil) was added at room temperature. The mixture was stirred at room temperature for 12 hours, at 60° C. for 2 hours and then at 90° C. for 10 hours. The reaction mixture was allowed to stand near room temperature, and 10% hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.50 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-7-octynoate (hereinafter referred to as the present compound (1)).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: COc1cccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)c1
Yield: 82.2 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 3-methoxyphenylboronic acid (86.13 mg, 0.57 mmol, 2.00 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 85 mg (80%) of 3-(3-methoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:12]=[CH:11][C:9]([OH:10])=[C:8]([CH2:13][CH2:14][CH3:15])[C:7]=2[OH:16])=O)[CH2:3]C1.[NH2:17][OH:18].Cl.C([O-])(=O)C.[Na+]>CO.O>[CH:4]1([CH:6]2[C:12](=[N:17][OH:18])[CH:11]=[C:9]([OH:10])[C:8]([CH2:13][CH2:14][CH3:15])=[C:7]2[OH:16])[CH2:1][CH2:3]1
Reactant: NO
Reactant: CCCc1c(O)ccc(C(=O)C2CC2)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC1=C(O)C(C2CC2)C(=NO)C=C1O

Procedure:
A solution of 4-cyclopropylcarbonyl-2-(n-propyl)resorcinol (1.0 g, 4.54 mmole) in methanol (10 mL) was treated with hydroxylamine.HCl (1.58g, 22.7 mmole) and sodium acetate (1.86g, 22.7 mmole) and the mixture refluxed for 7 hours. The cooled mixture was poured into water and extracted 3× with ethyl acetate. The combined extracts were washed with water (2×), 10% sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude product was chromatographed on silica gel eluting with methylene chloride followed by methanol:methylene chloride (5:95) to afford the title compound. NMR (CDCl3); δ 0.89 (m, 2H); 0.94 (t, 3H); 1.10 (m, 2H); 1.76 (m, 1H); 2.61 (t, 2H); 6.35 (d, 1H); 7.41 (d, 1H).
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[CH2:9]([NH2:16])[CH2:10][S:11]S(O)(=O)=O>>[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH2:1][S:11][CH2:10][CH2:9][NH2:16]
Reactant: C=O
Reactant: NCCSS(=O)(=O)O
Reactant: Cc1c[nH]cn1
Product: Cc1nc[nH]c1CSCCN

Procedure:
Such continuous method is carried out as follows: In an apparatus illustrated in FIG. 1, formaldehyde or oligomer thereof, 4-methylimidazole, and 2-aminoethanethiol sulfuric acid are respectively supplied through conduits 1,2, and 3 into a mixing tank 4 and they are thoroughly mixed. The mixture is supplied from the mixing tank 4 into a reactor 6 via a conduit 5. The reaction solution is continuously withdrawn from the reactor 6 via a conduit 7 and then allowed to cool. The cooled liquid is sent to a separator, e.g. an electrodialytic device 10 via a conduit 9. When water is supplied through a conduit 11 as an outer liquid an aqueous solution of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole is obtained from a conduit 12. As soon as the deposited precipitate is filtered and dried, a crystal of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole can be obtained as a form of salt. The outer liquid obtained in the electrodialysis is withdrawn through a conduit 13 and supplied to a concentrater 14 thereby concentrating it, the liquid is returned to the reactor 6. In the case of using thiazolidine or salt thereof as the raw material, it is supplied to the mixing tank 4 through the conduit 1 or 3 and optionally the mineral acid is supplied thereto through anyone of the remaining conduit. In the case of using the formaldehyde adduct of cysteamine as the raw material, as shown in FIG. 2, cysteamine and formaldehyde are supplied through conduits 1 and 3, respectively to a mixing tank 4 to form the adduct and then supplied to a reactor 6 through a conduit 4, while supplying 4-methylimidazole to the reactor 6 through a conduit 2a.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)(=[O:17])=[O:16])[C:10]2=[O:25])[CH:4]=1)#[N:2].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:15]([C:18]3[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)(=[O:17])=[O:16])[C:10]2=[O:25])[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)cs1
Reactant: BrCc1ccccc1
Product: N#Cc1cc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)cs1

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 4,5-dichlorothiophene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide and benzyl bromide in place of MeI to give the title compound as a white foam.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:39]1([S:45][CH2:46][CH2:47]Br)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:47][CH2:46][S:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: BrCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2ccccc2)CC1
Temperature: 57.5 °C
Reaction time: 4.5 h
Yield: 68.1 %

Procedure:
To 2.5 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 74 mg of potassium carbonate and 64 mg of 1-phenylthio-2-bromoethane were added at room temperature, and stirred at 55-60° C. for 4.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1], to give 93 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(phenylthio)ethyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(F)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2nc(Cl)ccc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
6-fluoro-1,2-dihydroquinolin-2-one (7.8 g, 47.8 mmol) was suspended in phosphorus oxychloride (72.2 g, 470.9 mmol) and stirred for 4 hours at 100° C. in an oil bath. The reaction mixture was concentrated under vacuum to remove the excess phosphorus oxychloride and then ice-water (200 ml) was added. The precipitate that formed was washed with water (2×80 ml) and dried to give 2-chloro-6-fluoroquinoline as a off-white solid (6.8 g, 78%); (ES, m/z): [M+H]+ 182; 1H NMR (300 MHz, DMSO): δ 8.43 (d, J=8.4 Hz, 1H), 8.01 (dd, J=5.4 Hz, 9.3 Hz, 1H), 7.87 (dd, J=3.0 Hz, 9.3 Hz, 1H), 7.72-7.78 (m, 1H), 7.45 (d, J=8.4 Hz, 1H).