Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]3[CH2:31][S:32][CH2:33][C:29]3=[C:28]([CH:34]=O)[CH:27]=2)[CH:21]=1.CO>COCCOC>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]3[CH2:31][S:32][CH2:33][C:29]3=[C:28]([CH2:34][C:11]#[N:12])[CH:27]=2)[CH:21]=1
Reactant: O=Cc1cc(-c2cccnc2)n2c1CSC2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: N#CCc1cc(-c2cccnc2)n2c1CSC2
Temperature: -30 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of tosylmethyl isocyanide (7.5 g) in 1,2-dimethoxyethane (50 cc) is added over 20 minutes at a temperature of about -30° C. to a solution of potassium tert-butylate (8.7 g) in 1,2-dimethoxyethane (140 cc) cooled to a temperature of about -30° C. The solution obtained is cooled to a temperature of about -60° C., and then a solution of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxaldehyde (8 g) in 1,2-dimethoxyethane (70 cc) is added to it over 30 minutes at a temperature of about -60° C. The solution obtained is brought to a temperature of about 0° C. over 1 hour and then kept at this temperature for 1 hour and 20 minutes. Methanol (105 cc) is then added over 15 minutes, at a temperature of between 3 and 7° C. The solution obtained is heated at a temperature of about 72° C. for 1 hour and 15 minutes and is then stirred at a temperature of about 20° C. for 16 hours. Three-quarters of the solvent are evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 40° C. The residue is taken up with a mixture of distilled water (350 cc) and ethyl acetate (250 cc). The organic phase is separated off and the aqueous phase is extracted 3 times with ethyl acetate (750 cc in total). The organic extracts are combined, washed 3 times with distilled water (450 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 50° C. A crude product (7.6 g) is thus obtained. This product is chromatographed on a 2.7 cm diameter column containing silica (0.063-0.2 mm; 75 g) by eluting with mixtures of cyclohexane and ethyl acetate and collecting 200-cc fractions. The first 2 fractions from the elution with a mixture of cyclohexane and ethyl acetate (50:50 by volume) are rejected. The next 3 fractions from the elution with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and the following fraction from the elution with pure ethyl acetate, are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. 2-[-5-(3-Pyridyl)-1H,3H-pyrrolo[1,2-c]thiazol-7-yl]acetonitrile (6 g) is thus obtained in the form of light yellow crystals melting at 92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and methanesulfonyl chloride (40 mg, 0.35 mL) at ice-bath. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 365.2.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][NH2:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[C:24](OCC)(OCC)(OCC)[CH3:25]>C1(C)C(C)=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:24]([CH3:25])=[N:14][N:13]=[C:8]1[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(C(F)(F)F)ccc3n12

Procedure:
In the manner given in Example 2, 6-(trifluoromethyl)-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-(trifluoromethyl)-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClC=C(Cl)Cl.Cl>O>[CH2:23]([NH:30][C:9]1[C:10]([F:15])=[C:11]([F:14])[CH:12]=[C:13]2[C:8]=1[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClC=C(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
A mixture of 2.57 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 1.8 ml of benzylamine and 180 ml of trichloroethylene was heated under reflux for 3 hours and 40 minutes. Water and 10% hydrochloric acid were added to the reaction mixture to render the aqueous layer acidic. The trichloroethylene layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give 2.78 g of ethyl 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxlate. m.p. 144°-145° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=O)[O:28]CC)[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[N:34]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH3:33])[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Reactant: CNC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1)C1CCCC1
Temperature: 130 °C

Procedure:
To a solution of 0.16 g of ethyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-carbamate obtained in stage a) below in 2 mL of tetrahydrofuran are added successively 0.368 mL of N-methylcyclopentylamine and 0.512 mL of triethylamine. The reaction mixture is heated by microwave at 130° C. for 3 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 0.048 g of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-cyclopentyl-1-methylurea, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid 141 (preparation see below) and amine 5.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C1C=CC=CN=1)C>C(O)C>[C:19]([O:23][C:24]([NH:26][C@H:27]1[CH2:28][CH2:29][C@H:30]([NH:33][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=2)[CH2:31][CH2:32]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: CN(C)c1ccccn1
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate and N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine were reacted in ethanol in the presence of dimethylaminopyridine in the same manner as in Reference Example 3-49 to obtain N-tert-butoxycarbonyl-trans-4-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino)cyclohexylamine.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N(CC)CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-iodo-benzoyl chloride (75 g) in 500 mL CH2Cl2 was added a mixture of Et3N (50 mL) and Et2NH (100 mL) at 0° C. After the addition, the resulting reaction mixture was warmed up to room temperature in 1 hr and was then washed with saturated ammonium chloride. The organic extract was dried (Na2SO4), filtered and concentrated. Residue was recrystallized from hot hexanes to give 80 g of INTERMEDIATE 5.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@:9]([O:36][C:37]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[S:39][CH:38]=2)([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])(=[O:26])=[O:25])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][CH2:6][N:5]1[C:46](=[O:57])[C:47]1[C:52]([C:53]([F:56])([F:55])[F:54])=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:2][CH3:3]>O.C(#N)C>[CH2:1]([C@@H:4]1[C@:9]([O:36][C:37]2[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[S:39][CH:38]=2)([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:25])=[O:26])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][CH2:6][N:5]1[C:46](=[O:57])[C:47]1[C:52]([C:53]([F:54])([F:56])[F:55])=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(c2ccccc2S(=O)(=O)NCCCC(=O)OCC)CC1
Solvent: O
Solvent: CC#N
Product: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(c2ccccc2S(=O)(=O)NCCCC(=O)O)CC1

Procedure:
In an analogous procedure to representative example 65 step 2, ethyl 4-(2-(1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)phenylsulfonamido)butanoate was saponified to provide A58 as a white solid after lyophilization from water/acetonitrile: 1H NMR (300 MHz, CDCl3 8.80 (d, J=4.4 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.98-7.84 (m, 1H), 7.60-7.30 (m, 4H), 6.99 (d, J=7.8 Hz, 1H), 6.72-6.50 (m, 1H), 5.61-5.30 (m, 4H), 3.90-3.67 (m, 1H), 3.43-0.70 (m, 25H).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=O)[O:14][C:15](O)([CH3:23])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=[O:14])[NH:2][N:3]=[C:15]([CH3:23])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2c(F)cccc2F)=C1c1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2c(F)cccc2F)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
0.60 g of hydrazine monohydrate was added dropwise to a mixture of 2.83 g of 3-(2,6-difluorophenyl)-5-hydroxy-5-methyl-4-phenyl-2(5H)-furanone and 15 ml of 1-butanol, followed by stirring at a bath temperature of 110° C. for 2.5 hours. Next, the reaction mixture was cooled to 0° C. The obtained solid was collected by filtration. The collected solid was washed with a mixed solvent (1:1) of hexane and t-butyl methyl ether, and dried under reduced pressure, thereby obtaining 1.70 g of 4-(2,6-difluorophenyl)-6-methyl-5-phenyl-2H-pyridazine-3-one. 1H-NMR (DMSO-d6, TMS) δ (ppm): 2.02 (3H, s), 6.92-6.98 (2H, m), 7.11-7.12 (2H, m), 7.27-7.36 (4H, m), 13.2 (1H, br s)
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:37]1(=[O:43])[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:41]4[C:40](=[O:42])[CH2:39][CH2:38][C:37]4=[O:43])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
In an atmosphere of argon, N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-4-hydroxymethyl-N-(2-methoxyphenyl)benzamide (54 mg, 0.11 mmol), succinimide (13 mg, 0.132 mmol) and triphenylphosphine (34.6 mg, 0.132 mmol) were dissolved in THF (1 ml) to which was subsequently added dropwise diethyl azodicarboxylate (21 μl, 0.132 mmol) while cooling in an ice bath. After 30 minutes of stirring at room temperature, the reaction solution was diluted with water (10 ml) and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a PTLC (chloroform:methanol=20:1) to obtain 42 mg (66.8%) of the title compound in a light yellow amorphous form.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25][CH2:26][O:27][CH3:28])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:38][CH2:39][O:40][CH3:41].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:38][CH2:39][O:40][CH3:41])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25][CH2:26][O:27][CH3:28])[CH3:2]
Reactant: COCCCBr
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCCOC)c2)cc1OCOC
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 4-[4-(2-hydroxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxymethoxy benzoic acid ethyl ester (0.12 g) and potassium carbonate (0.10 g) in N,N-dimethylformamide (1 mL) was added 1-bromo-3-methoxy-propane (0.092 g), and this mixture was stirred at 70° C. for 18 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate (378 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU (195 mg, 1.28 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:1]([S:13][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCSc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 40.5 g (0.2 mole) of 1-dodecanethiol (laurylmercaptan) in 19.2 g (0.4 mole) of sodium hydride (50% in oil) in 1 liter of toluene is refluxed with stirring for 1 hour then cooled to room temperature. To the mixture 32.5 g (0.2 mole) of 5-chloro-2-thiophenecarboxylic acid is added and the mixture is refluxed with stirring for 24 hours after which the mixture is cooled to room temperature and acidified with 5% aqueous hydrochloric acid. Water is added, and the toluene layer is separated, dried over sodium sulfate and evaporated to give 5-(dodecylthio)-2-thiophenecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.[CH:14]([NH:16][NH:17][CH:18]=O)=O>>[N:16]1[N:17]=[CH:18][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]3)[CH:14]=1
Reactant: O=CNNC=O
Reactant: Cc1cc(N)cc2ccc(=O)[nH]c12
Product: Cc1cc(-n2cnnc2)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 6-amino-8-methyl-2-(1H)-quinolone (0.485 g) and 1,2-diformylhydrazine (0.245 g) was stirred and heated in a melt at 200° for 1 hour. The residue was then triturated with hot isopropanol, cooled and filtered and the solid residue was recrystallised from chloroform-isopropanol to afford 6-(1,2,4-triazol-4-yl)-8-methyl-2-(1H)-quinolone 0.25 H2O, m.p. 369°-371° (0.112 g).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[CH2:22]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([Cl:21])=[CH:15][CH:14]=2)[C:19]([Cl:32])=[C:10]([C:8]#[N:7])[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NC1CCCCC1)c1c(O)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Product: N#Cc1c(Cl)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Yield: 51 %

Procedure:
A solution of Compound 65 (2 g, 4.86 mmol) in 20 mL neat phosphorus oxychloride was heated to 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 810 mg (51%) of yellow solids. M.P. 243° C. 1H NMR (DMSO-d6): δ 5.55 (s, 2H), 7.25 (m, 3H), 7.32 (m, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.85 (dd, J=2.1, 9.0 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H). EIMS m/z 352 (M+23).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CN(C)C=O>[C:12]1([C:11]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Anthranilic acid (1.0 g, 7.29 mmol) was dissolved in pyridine (10 mL), benzoyl chloride (1.13 g, 8.02 mmol) was slowly added on an ice bath, and stirred at 50° C. overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in dry methylene chloride (20 mL), oxalyl chloride (925 mg, 7.29 mmol) and a catalytic amount of dimethylformamide were added on an ice bath, and stirred at room temperature for 4 hours. Saturated sodium hydrogen carbonate aqueous solution was added, the mixture was extracted with methylene chloride, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was washed by diethyl ether/heptane, and the target substance (1.13 g, 69%) was obtained as a light yellow solid.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=2[NH:39][C:40](=O)[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=2[NH:39][C:40](=[S:10])[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(N2CCCCC2)c(NC(=S)c2ccncc2)c1
Temperature: 100 °C
Yield: 33.7 %

Procedure:
Lawesson's reagent (328 mg, 0.811 mmol, commercially available product) was added to a toluene (2.5 ml) solution of N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (528 mg, 1.51 mmol), obtained as described in Referential Example 1-3, and the resulting mixture was stirred with refluxing at 100° C. for 12 hours. The mixture was cooled to room temperature, and then an aqueous solution of 2 M sodium hydroxide was added thereto to alkalify the solution. The mixture was reverse extracted three times with an aqueous solution of 12 M sodium hydroxide. 2 M hydrochloric acid was added to the aqueous layer to acidify the solution. Then, the resulting mixture was extracted three times with ether. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=1/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinthioamide (GIF-0616) (186 mg, 33.7%) was yielded as a colorless solid.