Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:23]([C:22]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
Four point five grams of 4-hydroxy benzoic acid were dissolved with a mixed solvent of 5 ml of pyridine and 30 ml of carbon tetrachloride. 3.7 g of nonanic acid chloride was dropped into the mixture solution with refluxing for three hours, a small amount of water was added to the residue removed the solvent from the refluxing solution to decompose unreacted nonanic chloride. Then 4-octylcarbonyloxy benzoic acid (C) was obtained after washing methanol. (C) was dispersed in 20 ml of carbon tetrachloride, after adding 5 ml of thionyl chloride, the mixture was refluxed for three hours to obtain 6.5 g of 4-octylcarbonyloxybenzoic acid chloride. 1.5 g of (D) was dissolved with 80 ml of carbon tetrachloride and 10 ml of pyridine and then cooled, 1.7 g of (B) was added to this solution with stirring under ice-cooled condition and the mixture was allowed to stand overnight to precipitate crystals. Following separation of produced crystals and reduction of solvents, the residue was purified by passing through a silica-gel column to obtain crude crystals of (A). Crude (A) was recrystallized with ethyl acetate. Purified (A) was smectic liquid crystal compound having SC* phase. The phase transition points of (A) were shown in table 4. (A) showed a large spontaneous polarization up to 109 nC/cm2 by Sawyer-Tower method described in example 1. When applied a voltage with a square wave to (A), electro-photo-effects of clear contrast and high speed response were observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:28]([C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:18]=1[O:15][C:5]1[CH:6]=[CH:7][C:8]([C:10]([CH3:13])([CH3:14])[CH2:11][CH3:12])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:16])([O-:30])=[O:29]
Reactant: CCC(C)(C)c1ccc(O)c(C(=O)OC)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OC)c1

Procedure:
Methyl-2-hydroxy-5-(1,1-dimethylpropyl)benzoate (3.0 g, 0.0135 mol), 4-chloro-3-nitrobenzotrifluoride (1.94 ml, 0.013 mol) and potassium carbonate (1.1 g, 0.008 mol) were mixed in dimethylformamide (50 mL) for 3 h. The solvents were evaporated and the residue was flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.24 (d, 1H); 7.99 (d, 1H), 7.54-7.68 (m, 2H), 7.15 (d, 1H), 6.82 (d, 1H), 3.70 (s, 3H), 1.61-1.76 (m, 2H), 1.32 (s, 6H), 0.65-0.76 (t, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:6][CH:5]=1.C([O:26][C:27](=[O:47])[CH2:28][CH2:29][CH:30](OS(C)(=O)=O)[CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(C)(C)C.O>CC(N(C)C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]([CH:30]([CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:29][CH:28]([C:7]([CH3:20])([CH3:8])[CH3:6])[C:27]([OH:26])=[O:47])[N:10]=2)=[CH:20][CH:21]=1
Reactant: CN(CCC(CCC(=O)OC(C)(C)C)OS(C)(=O)=O)Cc1ccccc1
Reactant: O=c1[nH]nc(Cc2ccc(Cl)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCC(CC(C(=O)O)C(C)(C)C)n1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3 g sodium hydride (80%, in white oil) are added to 21.6 g 4(4-chlorobenzyl)-1(2H)-phthalazinone in 200 ml dimethylacetamide (DMA) with cooling in an ice bath. 37 g 6-(N-methyl -N-benzylamino )-4-methylsulfonyloxy-caproic acid-t-butyl ester in 80 ml DMA are then added dropwise with cooling and stirring continued for 0.5 hour. The mixture is allowed to warm slowly--overnight--to room temperature and is then heated for 2 hours to 40° C.-50° C. The mixture is hydrolyzed by addition of 200 ml water with ice cooling. The precipitated oil is separated and dissolved in dichloromethane. After extraction twice with water, the organic phase is dried and concentrated. The residue is chromatographed over silica gel (Eluent: dichloromethane/methanol/ammonia 25% 95:4:1). 3.5 g are obtained (yellow oil).
Reaction SMILES: [Cl:1][CH:2]([F:10])[C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O:16][N:17]=O)CC(C)C.C(Cl)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:1][CH:2]([F:10])[C:3](=[O:9])[C:4](=[N:17][OH:16])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)CCON=O
Reactant: COC(=O)CC(=O)C(F)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=NO)C(=O)C(F)Cl

Procedure:
To a solution of methyl 4-chloro-4-fluoro-3-oxobutyrate (31 g) and isopentylnitrite (25.8 ml) in dichloromethane (120 ml) was added dropwise acetylchloride (13 ml) under ice-cooling with stirring and the mixture was stirred for 3 hours at 5° C. to 10° C. The resulting solution was poured into water (300 ml) and adjusted to pH 3.0 with saturated aqueous sodium bicarbonate. The separated organic phase was washed with water (300 ml) and dried with magnesium sulfate and evaporated in vacuo to give methyl 4-chloro-4-fluoro-2-(hydroxyimino)-3-oxobutyrate.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(C(F)(F)F)C(F)(F)C(S(O[CH2:41][C:42]([F:56])([F:55])[O:43][C:44]([F:54])([F:53])[C:45]([O:48][C:49]([F:52])([F:51])[F:50])([F:47])[F:46])(=O)=O)(F)F.O>CS(C)=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:41][C:42]([F:55])([F:56])[O:43][C:44]([F:53])([F:54])[C:45]([O:48][C:49]([F:50])([F:51])[F:52])([F:47])[F:46])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=S(=O)(OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cc(OCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
0.5 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 10 mL of dimethylsulfoxide, and 0.28 g of potassium carbonate and 1.0 g of 2,2-difluoro-2-{2-trifluoromethoxy-(1,1,2,2-tetrafluoroethoxy)}ethyl nonafluorobutylsulfonate were added, followed by stirring at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, and after washing with a saturated salt solution, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:4) to obtain 0.67 g of 5-acetylamino-3-[2,2-difluoro-2-{2-trifluoromethoxy-(1,1,2,2-tetrafluoroethoxy)}ethoxy]-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27](OC)[O:28]C)[CH:8]=[C:9]2[C:17]=1[C:16](=[O:18])[C:15]1([O:20][C:21](=[O:23])[CH3:22])[O:19][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2C(=O)C)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[O:28])[CH:8]=[C:9]2[C:17]=1[C:16](=[O:18])[C:15]1([O:20][C:21](=[O:23])[CH3:22])[O:19][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(C)=O)C(OC(C)=O)(O1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)Oc1cc(C=O)cc2c1C(=O)C1(OC(C)=O)ON2CC2NC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of A-isomer of 11-acetyl-4-dimethoxymethyl-8-oxo-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (6 mg) in acetone (0.5 ml) was added p-toluenesulfonic acid (1 mg). The mixture was stirred for 1 hour at ambient temperature, and then subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and acetone (5:1, v/v) to afford A-isomer of 4-formyl-8-oxo-14-oxa-1,11-diazatetracyclo[7.4.1.02.7.010,12 ]tetradeca-2,4,6-trien-6.9-diyl diacetate (1 mg).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:20][C:11]2=[N:12][C:13]3[NH:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=[C:10]2[CH2:9][CH2:8]1)C.[OH-].[Na+]>C1COCC1.O>[NH:14]1[C:13]2[N:12]=[C:11]3[CH2:20][CH:7]([CH2:6][CH2:5][C:4]([OH:21])=[O:3])[CH2:8][CH2:9][C:10]3=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCC1CCc2cc3c(nc2C1)NCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC1CCc2cc3c(nc2C1)NCCC3

Procedure:
A solution of 14-3 (0.180 g, 0.62 mmol) and NaOH (1.24 mL of a 1N soln, 1.24 mmol) in THF/H2O (5 mL./5 mL) was stirred at room temperature for 12 h. The solution was concentrated. The residue was triturated with Et2O to give 14-4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1ccccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (2-bromophenyl)acetic acid (100 g, 0.46 mmol) in dry THF (2 L) was added NaBH4 (29 g, 0.77 mol) in portions. The contents were cooled to 0° C., and BF3. Et2O (123 mL, 0.77 mol) was added drop wise over 1 h. The mixture was allowed to warm to 25° C. and stirred for 16 h. The reaction was cooled to 0° C. and cautiously quenched with aqueous sodium hydroxide. The contents were stirred for 3 h, and then extracted with EtOAc. The organic layer was dried and concentrated to give 2-(2-bromophenyl)ethanol. 1H-NMR (400 MHz, CDCl3) δ 7.54˜7.56 (in, 1H), 7.23˜7.28 (m, 2H), 7.07˜7.11 (m, 1H), 3.88 (s, J=6.6 Hz, 2H), 3.03 (t, J=6.8 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:19]=[C:18]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH:17]=2)=[CH:8][C:7]=1[CH3:43].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:42][S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]#[C:31][C:18]2[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:44])=[O:2])=[C:7]([CH3:43])[CH:8]=3)[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:19]=2)=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(S(C)(=O)=O)cc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 7.67 h

Procedure:
To a solution of (4-{3-[3-(4-methanesulfonyl-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (50 mg, 0.08 mmol) in THF (1.25 ml) and methanol (0.25 ml) was added a ice-cold solution of LiOH (1 M, 1.25 ml). The reaction mixture was stirred at 0° C. for 460 min., after which water (10 ml) and aqueous HCl (1M, 1.75 ml) were added. The mixture was extracted with ethyl acetate (2×10 ml), and the combined organic phases were dried and evaporated to give the title compound in 15 mg (31%) yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:16]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 0° C. solution of 500 mg of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, 328 mg of 2-methoxyethylamine, 736 mg of HOBt, and 1.82 mL of triethylamine in 9 mL of dichloromethane was treated with 836 mg of EDC.HCl. The mixture was stirred at 25° C. overnight and the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate, and the solution was sequentially washed with water, an aqueous solution of citric acid, an aqueous sodium bicarbonate solution, and brine. The solution was dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in a 4 M solution of HCl in dioxane. After 1 h the mixture was evaporated to give 406 mg of the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18](OCC)=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:18][OH:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2cc(OCc3ccccc3)ccc2[nH]1

Procedure:
The title compound was prepared from ethyl 5-(benzyloxy)-1H-indole-2-carboxylate and lithium aluminum hydride according to the procedure described in step 3 of Example 1. The product was obtained as a white solid, mp: 106–107° C. Mass spectrum (ESI, [M+H]+) m/z 254. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.45 (d, 2H, J=7.33 Hz), 7.37 (t, 2H, J=7.49 Hz), 7.30 (d, 1H, J=7.18 Hz), 7.20 (d, 1H, J=8.71 Hz), 7.04 (s, 1H), 6.74 (dd, 1H, J=8.70 and 1.46 Hz), 6.16 (s, 1H), 5.16 (t, 1H, J=5.49 Hz), 5.01 (s, 2H), 4.55 ppm (d, 2H, J=5.50 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.Cl>CN(C=O)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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCCCC2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A mixture of 3-bromo-1-cyclohexylmethyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.25 mmol), PhSnBu3 (0.1 mL, 0.30 mmol), and PdCl2(PPh3)2 (36 mg, 0.051 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., water and EtOAc were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5% EtOAc/CH2Cl2) to give 71 mg of the title compound. MS: (+) m/z 393.37 (M+1).
Reaction SMILES: [I:1][C:2]1[C:3]2[S:9][CH:8]=[CH:7][C:4]=2[NH:5][N:6]=1.[CH3:10]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:3]2[S:9][CH:8]=[CH:7][C:4]=2[N:5]([CH3:10])[N:6]=1
Reactant: Ic1n[nH]c2ccsc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of 3-iodo-1H-thieno[3,2-c]pyrazole (500 mg, 2.0 mmol) in THF (7 ml) at 0° C. was added KOt-Bu (314 mg, 2.8 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.17 ml, 2.8 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to afford 292 mg (55%) of 3-iodo-1-methyl-1H-thieno[3,2-c]pyrazole as a light brown viscous oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.41 (d, J=5.3 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 4.05 (s, 3H). Also isolated 141 mg (27%) of 3-iodo-2-methyl-2H-thieno[3,2-c]pyrazole as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.36 (d, J=5.3 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 4.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2Br)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-bromobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (41.9 mg) with purity >90%. MS (pos) m/z 405.1, 407.1.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7].[C:14](=[S:16])=[S:15].[W:17](Cl)(Cl)(Cl)(Cl)(Cl)Cl>CO>[CH2:9]([N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:14](=[S:15])[S-:16])[CH2:10][CH2:11][CH2:12][CH3:13].[CH2:9]([N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:14](=[S:15])[S-:16])[CH2:10][CH2:11][CH2:12][CH3:13].[CH2:9]([N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:14](=[S:15])[S-:16])[CH2:10][CH2:11][CH2:12][CH3:13].[CH2:9]([N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:14](=[S:15])[S-:16])[CH2:10][CH2:11][CH2:12][CH3:13].[CH2:9]([N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:14](=[S:15])[S-:16])[CH2:10][CH2:11][CH2:12][CH3:13].[CH2:9]([N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:14](=[S:15])[S-:16])[CH2:10][CH2:11][CH2:12][CH3:13].[W+6:17]
Reactant: S=C=S
Reactant: Cl[W](Cl)(Cl)(Cl)(Cl)Cl
Reactant: CCCCCNCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN(CCCCC)C(=S)[S-]
Product: [W+6]

Procedure:
0.576 kg of granulated caustic soda is added to 8 liters of anhydrous methanol and the mixture is stirred until all solid material has dissolved. 2.26 kg of diamylamine are added to the solution and 0.88 liter of carbon disulfide is introduced over a period of 2 hours. The mixture is stirred for a further 3 hours at 25° C. and a solution of 0.952 kg of tungsten hexachloride in 2.4 liters of anhydrous methanol is then added over a period of one hour and the mixture is stirred for an additional 3 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][NH:22][OH:23])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([N:28]=[C:29]=[O:30])(C)(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][N:22]([OH:23])[C:29]([NH2:28])=[O:30])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: ONC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)N(O)C/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of the product of Step 5, above (17, 0.66 g, 2.1 mmol), in THF (10 ml) was added TMSNCO (0.42 ml, 3.1 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 hour. Methanol (5 ml) was then added and after stirring for 10 minutes, solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate/methanol to afford the title compound (18, 340 mg, 45% yield) as colorless solids.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:25][CH2:26][OH:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:25][CH2:26][OH:27])[CH:11]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2ccc(C#CCO)cc2c1=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCO)c2ccc(CCCO)cc2c1=O
Reaction time: 2 h

Procedure:
To a solution of N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 5 (0.20 g) in a small amount of THF:methanol is added platinuim oxide (0.01 g). The mixture is placed under an atmosphere of hydrogen. After 2 hours, the mixture is filtered through Celite with THF:methanol washes. The filtrate is concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 4% to 16% methanol in dichloromethane. The product-containing fractions are concentrated under reduced pressure to afford 0.14 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:10]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCBr
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN1CCCC1=O
Yield: 31 %

Procedure:
Following example 1, on refluxing 13 g of 50% oil dispersion of sodium hydride (6.5 g NaH, 0.271 M), 20.35 g (0.239 M) of azacyclopentan-2-one and 47.28 g (0.264 M) of 1-bromoheptane in dry toluene for 21 hours was obtained 13.6 g (31%) of colorless oil; boiling point 115°-120°/0.6 mm.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=C[C:3]=1[C:4](O)=[O:5].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]2=[O:22].[NH:23]1C2C(=CC=CC=2)C(=O)C1=O>>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]1[C:16](=[N:1][C:2]3[C:3]([C:4]1=[O:5])=[N:23][CH:8]=[CH:9][N:10]=3)[C:15]2=[O:22]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C1c2cc(F)ccc2-n2c1nc1nccnc1c2=O
Yield: 6 %

Procedure:
Using the procedure in Example 56, and substituting 3-aminopyrazine-2-carboxylic acid for 2-aminonicotinic acid and 5-fluoroisatin for isatin gave 79 mg (6%) of the title compound: mp 336° C. (dec); 1H NMR(DMSO-d6) δ 7.65-8.00 (m, 2H), 8.50 (s, 1H), 9.05-9.20 (m, 2H); MS (M+H)+ 269.