Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:46]=3)[CH:41]=2)[N:34]=1.[CH2:59](O)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:37][CH:36]=[C:35]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:46]=3)[CH:41]=2)[N:34]=1
Reactant: CCCCCCCCOc1ccc2cc(-c3ccc(O)c(F)n3)ccc2c1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc2cc(-c3ccc(OCCCCCCCC)c(F)n3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1.06 g (6.11 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 1.60 g (6.11 mmol) of triphenylphosphine in 50 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 0.5 hour. 1.50 g (4.08 mmol) of 2-fluoro-3-hydroxy-6-(6-octyloxynaphth-2-yl)pyridine and 0.80 g (6.11 mmol) of 1-octanol are then added. After a reaction time of 1 hour at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.74 g of 2-fluoro-3-octyloxy-6-(6-octyloxynaphth-2-yl)pyridine. ##STR69##
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=C(Cl)c1ccccc1
Product: O=Cc1cccc2c1ccn2C(=O)c1ccccc1
Yield: 20.9 %

Procedure:
The same procedures used in Example 11 were repeated except for using 725 mg of indole-4-carbaldehyde and 773 mg of benzoyl chloride instead of phenylacetyl chloride to give 260 mg of 1-benzoylindole-4-carbaldehyde as colorless crystals. The yield thereof was found to be 21%.
Reaction SMILES: [F-].[K+].[NH2:3][CH2:4][C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH:6]=1.Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CS(C)=O>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:3][CH2:4][C:5]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:6]=2)=[N:31][CH:30]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(CN)nc(C)n2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CNc3ncc(Cl)cn3)nc(C)n2)cc1
Temperature: 120 °C

Procedure:
Add potassium fluoride (1.82 g, 31.33 mmol) to a solution of 1-[4-[6-(aminomethyl)-2-methyl-pyrimidin-4-yl]oxyphenyl]-N-methyl-methanesulfonamide (11.1 g, 24.10 mmol) and 2,5-dichloropyrimidine (4.31 g, 28.92 mmol) in DMSO (111 mL). Heat the reaction mixture at 120° C. for two hours. Thereafter cool the mixture to room temperature; add water (200 mL), and extract with EtOAc (3×200 mL). Combine the organic extracts; sequentially wash the organic extracts with water (300 mL) then brine (300 mL); dry over sodium sulfate; filter; and concentrate the filtrate under reduced pressure to provide title compound as a crude material. Purify the title compound using silica gel chromatography eluting with a gradient of hexane/EtOAc (1:1) to EtOAc (100%). Collect the relevant fractions containing the title compound and concentrate the fractions. Dissolve the resulting material in THF (200 mL) and EtOAc (300 mL), then add SiliaMetS® Thiol (9.2 g) to remove traces of palladium. Stir the mixture for 2 hr at 55° C. Filter the mixture at 55° C.; collect the filtrate; and evaporate the solvent to provide a solid. Triturate the solid with cold EtOAc (20 mL); collect the solid by filtration; and dry the solid under reduced pressure to provide the title compound as a white solid (8 g, 75%). MS (m/z): 435 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:9](=[CH:8][C:7]=1[O:6][CH3:5])[CH:10]=[C:11]([C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:26])[CH:12]=[CH:13]2
Reactant: COc1cc2ccccc2cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)c3ccccc3)cc2cc1OC
Reaction time: 8 h

Procedure:
Aluminum chloride (16.0 g) was added to a solution of 2,3-dimethoxynaphthalene (18.0 g) and benzoylchloride (12.0 g) in cold methylene chloride (400 ml) and the solution was stirred overnight. After treatment with cold water the phases were separated and the methylene chloride phase washed with 1 M sodium hydroxide. The product was triturated with warm ether. Yield: 7 g, melting point 124-125° C.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:27][CH2:26]1.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[NH:34][C:35]3[C:40]([C:41]=2[CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:27][CH2:26]1
Reactant: CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ccccc2Cl)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
Benzhydryl acetate (2.2 g, 9.71 mmol) and 2-[4-(2-chlorophenyl)piperazinylcarbonyl]indole (3.0 g, 8.83 mmol) were dissolved in a mixed solvent of methylene chloride (50 ml) and chloroform (50 ml), and methanesulfonic acid (1.72 ml, 26.5 mmol) was added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 6.5 g of a crude product. The obtained crude product was washed with ethanol (60 ml) under heating to give 4.0 g (yield: 89%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[NH:7][C:8]([NH2:17])=[C:9]2[C:13]([N:14]=1)=[N:12][C:11]([O:15][CH3:16])=[N:10]2)[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22][CH2:21]1)[CH3:19].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN1CCC(CO)CC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-1H-purin-6-amine (300 mg, 1.264 mmol), (1-ethyl-4-piperidinyl)methanol (362 mg, 2.53 mmol) and tributylphosphine (0.624 ml, 2.53 mmol) were dissolved in THF (12 ml). 1,1′-(Azodicarbonyl)dipiperidine (638 mg, 2.53 mmol) was added and the reaction mixture stirred at rt overnight. The solvent was removed in vacuo and the residue purified by column chromatography, loading in dichloromethane and purified on Flashmaster II silica (Si) 20 g using a 0-100% ethyl acetate in cyclohexane+0-20% methanol (+1% Et3N) gradient over 30 mins. The appropriate fractions were combined and evaporated in vacuo. The material (300 mg) was dissolved in 1:1 MeOH:DMSO 3 ml and re-purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as a clear gum (60 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH2:9][C:8]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48]>O1CCCC1>[C:1]1([N:7]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:10][CH:9]([CH2:46][C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:8]2=[O:34])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)[Si](OCCC1=CCC(=O)N(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1=CC(CC(=O)OCc2ccccc2)C(=O)N(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
Compound (9) (650 mg, 1.38 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -78° C. The resulting reaction mixture was treated with 1.8 mL of a 1M solution of lithium bis (trimethylsilyl)amide in tetrahydrofuran and stirred for 20 min. At this time, benzyl 2-bromoacetate (437 μL, 2.76 mmol) was added, the reaction continued at -78° C. for 10 rain and then warmed to room temperature (removed dry ice/isopropanol bath). After the reaction mixture reached room temperature, 10% NH4Cl (aqueous) was added and the resulting mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous MgSO4, filtered and evaporated at reduced pressure. The residue was purified using flash chromatography (silica gel, 4×20 cm, 20- 40% ethyl acetate/hexane) to yield the title compound (11) (388 mg, 46%). Compound (21): 1H NMR (CDCl3) δ 1.05 (9H, s), 1.98-2.73 (5H, m), 2.90-3.23 (1H, m), 3.37-3.73 (1H, m), 3.77 (2H, t, J=6.8 Hz), 4.07-4.80 (2H, m), 5.03-5.27 (3H, m), 6.97-7.83 (20H, m); MS (DCI/NH4) m/e 618 (M+H)+ ; TLC Rf 0.47 (silica gel, 7:3 hexane:ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]([CH3:21])=[CH2:20])[C:11]1=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:25][OH:26])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]([CH3:21])=[CH2:20])[C:11]1=[O:22]
Reactant: C=C(C)n1c(=O)n(CC(=O)c2ccccc2F)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=C(C)n1c(=O)n(CC(=NO)c2ccccc2F)c2ccccc21
Temperature: 80 °C
Yield: 73.2 %

Procedure:
To a stirred solution of 1-[2-(2-fluoro-phenyl)-2-oxo-ethyl]-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (1.3 g, 4.2 mmol) in ethanol (50 ml) was added hydroxylamine hydrochloride (0.84 g, 12.2 mmol) followed by pyridine (1.7 ml, 21.0 mmol) at ambient temperature. The resulting mixture was warmed to 80° C. for 6 h, cooled to ambient temperature and concentrated. The remaining residue was diluted with water, 1M HCl and ethyl acetate. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 50% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 1.0 g (73%) of the desired product as an oil which solidified on standing.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(Cl)Cl.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C1CCNc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(=O)c2ncccc21

Procedure:
To a solution of 2,3-dihydro-1,5-naphthyridin-4(1H)-one (1 eq.) and DCM (0.2 eq.) is added DIEA (2.2 eq.) and acetyl chloride (1.2 eq.). The reaction is monitored by TLC. The reaction is washed with water, brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)=[C:10]([CH2:29][CH2:30][CH3:31])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:38]1([N:44]=[C:45]=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH:38]1([NH:44][C:45]([NH:26][S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:11]3[CH:27]=[CH:28][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][C:10]=3[CH2:29][CH2:30][CH3:31])[CH:18]=2)(=[O:24])=[O:25])=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(S(N)(=O)=O)c1
Reactant: O=C=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1cccc(S(=O)(=O)NC(=O)NC2CCCCC2)c1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[3-(4-phenoxy-2-propyl phenoxy)propoxy]benzenesulfonamide (0.04 g, 0.0906 mmol) and acetone (3 mL) was added potassium carbonate (0.025 g, 0.181 mmol). To the resulting suspension was added cyclohexyl isocyanate (0.023 mL, 0.181 mmol) dropwise. The reaction suspension was then stirred in a 65° C. oil bath for 5 h. After cooling to room temperature, the reaction was concentrated to a residue. The residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was chromatographed over silica gel with hexanes/ethyl acetate (4:1) and hexanes/ethyl acetate (3:1) to afford the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].S(=O)(=O)(O)O.[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15]>>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]1[O:15][CH:14]([CH2:13][OH:12])[CH2:16][O:1]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Product: OCC1COC(C(Cl)(Cl)Cl)O1
Reaction time: 10 h

Procedure:
A mixture of 16 g of chloral, 5 g of glycerine and 5 ml of concentrated sulphuric acid is,heated on a water-bath for 10 hours, then the reaction mixture is distilled in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1.[CH:15]1([C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[S:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26](/[CH:25]=[CH:24]/[C:21]3[S:22][CH:23]=[C:19]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[N:20]=3)[CH:27]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)cc1
Reaction time: 16 h
Yield: 95.7 %

Procedure:
A solution composed of 1.0 g of 4-carboxymethyl benzoic acid methyl ester, 1.3 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 1.0 g of N-ethyl-N-(dimethylaminopropyl) carbodiimide, 2.4 g of 4-dimethylaminopyridine and 75 ml of methylene chloride at 0° C. After 16 hr. the reaction mixture was washed with 75 ml of water, dried (MgSO4) and the solvents removed by rotary evaporation. The residual materials were recrystallized with ethyl acetate to yield 2.1 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester; m.p. 163°-164° C.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Yield: 53.6 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (19 mg, 0.061 mmol), β-alanine (726 mg, 8.15 mmol) and NaOMe solution (12.3 mL, 6.113 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 12 mg of the title compound as a pale pink solid. MS: (+) m/z 368.33 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:11]#[N:12])[NH:8][C:9]=1[CH3:10])([OH:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:32](O)([CH3:34])[CH3:33]>>[C:11]([C:7]1[NH:8][C:9]([CH3:10])=[C:4]([C:1]([O:3][CH:32]([CH3:34])[CH3:33])=[O:2])[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])#[N:12]
Reactant: CC(C)O
Reactant: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 97.6 %

Procedure:
Methyl (-)-5-carboxy-2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (4.47 g) is reacted with phosphorus pentachloride (3.62 g) and isopropyl alcohol (2.5 g) in the same manner as in Example 7 to provide 5-isopropyl 3-methyl (-)-2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4.9 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH:16]([N:19]=[C:20]=S)([CH3:18])[CH3:17]>>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]2[NH:1][C:20]([NH:19][CH:16]([CH3:18])[CH3:17])=[N:15][S:12](=[O:13])(=[O:14])[C:3]=2[CH:4]=1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)cc([N+](=O)[O-])c2N1

Procedure:
The title compound was prepared from 2-amino-5-chloro-3-nitrobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 266-267° C.; 1H-NMR (DMSO-d6): δ 1.20 (d, 6H, CH(CH3)2), 3.92 (m, 1H, CH(CH3)2), 8.19 (d, 1H, ArH), 8.48 (d, 1H, ArH), 8.72 (br.s, 1H, NH), 10.57 (br.s, 1H, NH); MS: m/e 318/320 (M+); (C10H11N4Cl1O4S1) calc. C, 37.68; H, 3.48; N, 17.58, found C, 37.82; H, 3.54; N, 17.58.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9][C:8]2=[S:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:18](=[O:20])[CH3:19])(=O)C>>[OH:20][C:18](=[C:10]1[S:9][C:8](=[S:13])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:12])[CH2:19][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: O=C1C(=C(O)Cc2ccccc2)SC(=S)N1c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of 25 g. (0.12 m.) of 3-phenylrhodanine, 80 g. (0.34 m.) of triethylorthophenylacetate [prepared as described in J.A.C.S. 68, 1917 (1946)] and 250 ml. of acetic anhydride is heated under reflux for 20 hours and the solution is then concentrated in vacuo. The residue is filtered and the solid is stirred with 160 ml. of dioxane, 160 ml. of water and 40 ml. of 10% sodium hydroxide for 4 hours. The solution is concentrated in vacuo at 35°-40°C. to evaporate the dioxane. The aqueous solution, after washing with ether and decolorizing with charcoal, is made acidic with dilute hydrochloric acid. The solid product is purified by chromatography to give 5-(1'-hydroxy-2'-phenylethylidene)-3-phenyl-rhodanine, m.p. 146-148°C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[F:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[F:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Product: COC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.66 g, 47%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 5.07 mmol) and 4-fluorophthalic anhydride (0.80 g, 5.07 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[O:13][CH2:14][CH3:15])[C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[O:13][CH2:14][CH3:15])[C:6]([OH:8])=[O:7]
Reactant: CCOc1c(OC)cc(C(=O)OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(OC)cc(C(=O)O)cc1OC
Reaction time: 1 h

Procedure:
Combine methyl 3,5-dimethoxy-4-ethoxy-benzoate (2.13 g, 9,421 mmol) and methanol (30 mL). Add a 1M aqueous solution of sodium hydroxide (50 mL, 50 mmol). After 1 hour, acidify the reaction mixture using a 1M aqueous hydrochloric acid solution, extract with ethyl acetate. Dry the organic layer over MgSO4, filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:36][C:2]([CH3:1])([CH3:37])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (2E)-3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidin-4-yl)acrylate (1.13 g) in THF (10 mL) and ethyl acetate (10 mL) was added 10% palladium-activated carbon (113 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.13 g) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:16]=[C:17]=S)[CH:14]=[CH2:15]>>[CH2:13]([NH:16][C:17]1[NH:2][C:3]2[CH:7]=[C:6]([Cl:8])[S:5][C:4]=2[S:9](=[O:10])(=[O:11])[N:12]=1)[CH:14]=[CH2:15]
Reactant: C=CCN=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: C=CCNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and allyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 217°-221° C.; 1H-NMR (DMSO-d6): δ 3.83 (distorted t, 2H), 5.08-5.27 (m, 2H), 5.75-5.99 (m, 1H), 7.07 (s, 1H), 7.49 (br. t, 1H), 11.1 (s, 1H).