Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([P:3](=[O:14])([CH:12]=[CH2:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[CH2:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([N:22]1[CH2:13][CH2:12][P:3](=[O:14])([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[CH2:1][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CP(=O)(C=C)Cc1ccc(F)cc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=P1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 82 °C
Yield: 77.5 %

Procedure:
Divinyl-(4-Fluorophenylmethyl)-phosphine oxide (0.719 g, 3.42 mmol) and benzylamine (0.45 mL, 4.11 mmol) were dissolved in a mixture of THF (15 mL) and deionized water (15 mL). The reaction mixture was heated at 82° C. for 22 hours. The reaction was not complete and so an additional 0.04 mL of benzylamine was added and the reaction mixture was heated for an additional six hours at 90° C. The reaction mixture was concentrated by rotary evaporation and the product was extracted into dichloromethane and washed with saturated brine. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was taken up in 1:1 ethyl acetate:dichloromethane and passed through a plug of silica. The product was then eluted from the silica with a solution of 10% methanol in ethyl acetate. The solvents were removed by rotary evaporation to yield 0.84 g of 1-benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide (2.65 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 5H); 7.25-7.20 (m, 2H); 7.04-6.98. (m, 2H); 3.6 (s, 2H); 3.17-3.12 (d, 2H); 3.00-2.85 (m, 2H); 2.81-2.66 (m, 2H); 1.98-1.75 (m, 4H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][N:10]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:28]OS([O-])=O.[K+].[OH2:34]>CO>[C:1]1([S:7]([CH2:8][CH2:9][N:10]([CH2:23][C:24]([F:27])([F:25])[F:26])[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:12]=2)(=[O:28])=[O:34])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S([O-])OO
Reactant: N#Cc1ccc(N(CCSc2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: O
Agent: [K+]
Solvent: CO
Product: N#Cc1ccc(N(CCS(=O)(=O)c2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
An ice-cold solution of 4-[[2-(phenylthio)ethyl](2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.056 g, 0.138 mmol) in MeOH (6 mL) was treated with a solution of oxone (0.255 g, 0.415 mmol) in water (3 mL) and stirred at rt. After 1.5 h, the mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes gradient) and the product crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.057 g, 95% yield): MS (ES) m/z 437 (M+1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:21]=[C:20]2[C:14]([C:15]([Cl:26])=[C:16]([O:22][CH2:23][CH2:24][Br:25])[O:17][C:18]2=[O:19])=[CH:13][CH:12]=1.NC(N)=S>>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:21]=[C:20]3[C:14]([C:15]([Cl:26])=[C:16]([O:22][CH2:23][CH2:24][Br:25])[O:17][C:18]3=[O:19])=[CH:13][CH:12]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2c(Cl)c(OCCBr)oc(=O)c2c1
Reactant: S=C=Nc1ccccc1
Agent: NC(N)=S
Product: O=c1oc(OCCBr)c(Cl)c2ccc(NC(=S)Nc3ccccc3)cc12
Yield: 59 %

Procedure:
7-(Phenylthiocarbamoylamino)-4-chloro-3-(2-bromoethoxy) isocoumarin was prepared from the reaction of phenyl isothiocyanate with 7-amino-4-chloro-3-(2-bromoethoxy) isocoumarin, yield 59%, m.p. 157°-158° C.; mass spectrum m/e=361 (M+ -PhNH+ 1). Anal. Calc.: C, 48.36; H, 3.39. Found: C, 48.26; H, 3.40. The bromoethoxy compound was then reacted with thiourea by the same procedure to give the final product, yield 32%; mass spectrum (FAB+) m/e 449 (M+ --Br).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.CCCCCC.ClCC[I:37]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:37])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: ClCCI
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2nc(I)n(C3CCCCO3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.0 g, 3.1 mmol) and N,N,N′,N′-tetramethylenediamine (0.7 mL, 4.6 mmol) in anhydrous THF (23 mL) at −42° C. was added 2.5 M n-butyllithium solution in hexane (4.3 mL, 11.0 mmol) dropwise down the side of the reaction flask. The reaction was stirred at cold temperature and maintained for 1 h before 1-chloro-2-iodoethane (1.4 mL, 15 mmol) was introduced. Stirring was continued for 1.5 h period. LC-MS indicated the reaction had reached complete conversion to the desired product. The reaction mixture was subsequently quenched and worked up with sat. NH4Cl aqueous solution which was extracted with EtOAc (3 times), dried over MgSO4, filtered and concentrated in vacuo to give 4-(2-chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.4 g, 84% yield) determined by LC-MS to be >90% purity. MS (ESI+): m/z 450.1 (M+H+)
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1.[O:11]1CCO[CH2:13][CH2:12]1.[CH2:17]([OH:19])[CH3:18]>>[C:1](=[NH:10])([O:19][CH2:17][CH3:18])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5](=[NH:6])[O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: N#Cc1cccc(C#N)c1
Reactant: CCO
Reactant: C1COCCO1
Product: CCOC(=N)c1cccc(C(=N)OCC)c1
Temperature: 0 °C

Procedure:
A suspension of isophthalonitrile (12.81 g, 100 mmol) in a mixture of dry 1,4-dioxane (100 ml)/absolute ethanol (14.6 ml) cooled to 0° C. is bubbled with HCl gas for 48 hours, during which time the temperature returns to ambient temperature. After 4 additional days of stirring, the white solid obtained (approximately 28 grams of di-chlorohydrate salt) is filtered and washed with diethyl ether. The neutralization of this salt placed in suspension in diethyl ether is carried out by slowly adding potassium an aqueous carbonate solution (30% by weight) up to basic pH. The organic phase is separated, dried on MgSO4, filtered and concentrated under reduced pressure to yield a white solid (yield>90%). δH (300 MHz, CDCl3) 1.44 (t; J 6.9; 6H), 4.32 (q; J 6.9; 4H), 7.47 (t; J 7.5; 1H), 7.86 (d; J 7.5; 2H), 8.16 (s; 1H); SM (Electrospray) m/z 221 (MH+, 100%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[N:20]([O-])=O.[Na+].[Sn]>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [Sn]
Product: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(Quinolin-2-ylmethoxy)-phenylamine (1.73 g) in 30 mL of concentrated HCl at 0° C. was added sodium nitrite (531 mg). After 3 h, tin chlrodie (3.95 g) was dissolved in 20 mL of concentrated HCl and added slowly dropwise and the reaction mixture stirred at ambient temperature for 18 h. The reaction mixture was filtered and the solid dried to provide the title compound as the HCL salt (3.94 g). MS: (M+H m/z=266.3).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][NH:4][NH2:5].[C:8](O)(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Cl:12])/[Cl:10]>C(O)C>[F:1][C:2]([F:7])([F:6])[CH2:3][N:4]1[C:8](=[O:15])[C:9]([Cl:10])=[C:11]([Cl:12])[CH:13]=[N:5]1
Reactant: NNCC(F)(F)F
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Solvent: CCO
Product: O=c1c(Cl)c(Cl)cnn1CC(F)(F)F

Procedure:
2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and refluxed for 5 hours. The solvent was concentrated in vacuo. The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%). 1H NMR (300 MHz, CDCl3) δ 4.8 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS (DCl—NH3) m/z 264 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:13][CH3:12])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Br)cc(F)c1C#N
Reaction time: 16 h
Yield: 53.6 %

Procedure:
To a solution of 4-bromo-2,6-difluoro-benzonitrile (15.0 g, 68.8 mmol) in tetrahydrofuran (150 ml) is added sodium methoxide (4.5 g, 82.6 mmol) at room temperature and the mixture is stirred for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) to obtain 4-bromo-2-fluoro-6-methoxy-benzonitrile (8.5 g, 36.9 mmol, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.NC(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N+:3]=1[O-:14]
Reactant: NC(N)=O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: OO
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
2-chloro-5-methoxycarbonylpyridine (7.0 g) and urea-hydrogen peroxide adduct (6.93 g) were suspended in acetonitrile (100 mL), and trifluoroacetic anhydride (9.92 mL) was dropwise added thereto at 0° C. The reaction mixture was stirred at room temperature for 5 hours, and evaporated in vacuo to remove the solvent. After addition of saturated aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate to the residue, the mixture was extracted 5 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The organic solvent was evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:8) to give the title compound as a pale brown solid (8.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
A mixture of 3-bromobenzenethiol (1.5 g, 7.93 mmol), 2-bromoethanol (1.19 g, 9.52 mmol) and Cs2CO3 (5.16 g, 15.8 mmol) in DMF (10 ml) was heated to 50° C. overnight. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and dried. The crude product was purified by column chromatography to afford the titled compound (1.5 g, 81%). 1HNMR (400 MHz, CDCl3): δ 3.12 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.4 Hz, 2H), 7.14 (t, J=8.0 Hz, 1H), 7.26-7.34 (m, 2H), 7.51 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[I:22][CH2:23][CH2:24][CH2:25][CH2:26]I>CN(C=O)C>[I-:22].[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[N:7]1[CH2:12][CH2:11][N+:10]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:9][CH2:8]1
Reactant: ICCCCI
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [I-]
Product: c1ccc2oc(N3CC[N+]4(CCCC4)CC3)nc2c1
Reaction time: 0.5 h

Procedure:
A 245 mg portion of potassium carbonate was added to 300 mg of 2-(1-piperazinyl)benzoxazole which had been dissolved in 5 ml of DMF, and the reaction was carried out for 30 minutes. Under cooling with ice, 0.23 ml of 1,4-diiodobutane was added to the resulting solution, and the reaction was carried out for 1 hour at the same temperature and then for 2 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in 300 ml of dichloromethane and extracted three times with 100 ml of water. Thereafter, the aqueous layers were combined and lyophilized. By purifying the residue by Diaion HP-20 (Mitsubishi Chemicals), 175 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]2)[CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:4]3[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=3)[CH2:9]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: OC[C@@H]1CN(c2cc(Br)ccn2)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(c3cc(Br)ccn3)CCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A solution of (S)-(4-(4-bromopyridin-2-yl)morpholin-2-yl)methanol (1.0 equiv.), tosyl chloride (1.0 equiv.), triethylamine (1.40 equiv.) and N,N-dimethylpyridin-4-amine (0.1 equiv.) in dichloromethane (0.1 M) at RT. The resulting mixture was stirred at RT for 18 hours. The reaction mixture was then diluted with water and the aqeuous layer was separated and washed sequentially with NaOH (1 M), water, brine dried over sodium sulfate then concentrated in vacuo to yield (S)-(4-(4-bromopyridin-2-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate in 56% yield. LCMS (m/z) (M+H)=427.1/429.0, Rt=0.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([Cl:49])=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:43][C:44]1[S:45][C:46]([Cl:49])=[CH:47][N:48]=1)=[O:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ncc(Cl)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ncc(Cl)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml ) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, a solution of 2-amino-5-chlorothiazole (70 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(Cc1cccc(Cl)c1)CC2

Procedure:
The title compound was synthesized from methyl 6-(3-chlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (140 mg, 0.48 mmol) and lithium hydroxide (188 mg, 4.50 mmol, in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 90 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07-2.20 (m, 1H) 2.52-2.68 (m, 3H) 2.74-2.82 (m, 1H) 2.86-2.93 (m, 1H) 3.33-3.43 (m, 1H) 6.75 (d, J=1.61 Hz, 1H) 7.03-7.09 (m, 1H) 7.20-7.23 (m, 1H) 7.25-7.29 (m, 2H) 8.35 (br. s., 1H). LCMS m/e 276 (M+H). Purity>75% (HPLC).
Reaction SMILES: [C:1]1([N:7]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(Cl)Cl.C(O)C>CO.[Pd]>[C:1]1([N:7]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc(N)cc1)c1ccccc1

Procedure:
22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were hydrogenated in 500 ml of methanol with 2 g of 10% palladium on charcoal at 3 bar hydrogen pressure for 3 hours. After filtration and distillation of the solvent the reaction mixture was washed with 100 ml of ether and the white crystalline product was further reacted directly. Yield: 18.6 g (94% of theory), Rf value: 0.70 (silica gel; methylene chloride/ethanol=19:1)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.O1CCCC1.CO.[OH-].[Li+].Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sc(C2=CCOCC2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
In a round bottom flask equipped with a stir bar, a solution of ethyl 4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylate (109 mg, 0.300 mmol) in tetrahydrofuran (3.33 mL, 41.1 mmol) and methanol (1.67 mL, 41.1 mmol) was treated with lithium hydroxide (1.0M in water, 2.40 mL, 2.40 mmol). The mixture was stirred at room temperature overnight. pH was adjusted to −3 via addition of 1N aqueous HCl solution, and the reaction was then diluted with EtOAc and transferred to separatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (gradient elution, 0 to 10% MeOH in DCM) afforded 4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylic acid (100) (53 mg, yield 53% as a white powder. LCMS: (FA) ES+ 336; 1H NMR (400 MHz, DMSO) δ 13.52 (bs, 1H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 2H), 6.82-6.79 (m, 1H), 4.40 (s, 2H), 4.24-4.22 (m, 2H), 3.77 (t, J=5.4, 2H), 2.50-2.45 (m, 2H).
Reaction SMILES: [H-].[Na+].O[C:4]1[C:13](O)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][C:9]2=[S:15].[CH3:16]I>CCCCCC.C1COCC1.CCOCC>[CH3:16][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][C:9]2=[S:15]
Reactant: Oc1ccc2c(c1O)CCNC2=S
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2c1CCNC2=S
Reaction time: 0.5 h

Procedure:
To 0.15 g of 60% sodium hydride (3.70 mmol) which was washed with n-hexane and suspended in 15 ml of THF was added dropwise at 0 a solution of 0.50 g (2.82 mmol) of 3,4-dihydro-5,6-dihydroxy-1(2H)-isoquinolinethione in 5 ml of THF. The thick white suspension which formed was stirred for 0.5 hours at 0°-5° and then 0.45 g (2.82 mmol) of methyl iodide in 5 ml THF was added and stirring continued for one hour. The resulting yellow solution was diluted with ether, washed with saturated NaCl, dried (Na2SO4), and concentrated. The resulting oil was recrystallized from 1 ml of n-hexane to give pale yellow crystals, 0.55 g (100%); mp 43°-45°.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[CH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=C[C:20]1=[O:29]>>[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([CH:20]=[O:29])[C:8]2=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: O=c1cc(O)c2ccccc2n1-c1ccccc1
Product: O=Cc1c(O)c2ccccc2n(-c2ccccc2)c1=O

Procedure:
Following the procedure set forth in Preparation B, 1- phenyl-4-hydroxy-2(1H)-quinolinone was converted to 1 -phenyl-3-formyl-4-hydroxy-(2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 265 (M·+); NMR (DMSO): δ10.08 (s, 1H, CHO) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH2:14](O)[CH3:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1
Reactant: CCO
Reactant: O=C(O)Cc1n[nH]c2ccccc12
Product: CCOC(=O)Cc1n[nH]c2ccccc12
Yield: 87.8 %

Procedure:
2-(1H-indazol-3-yl)acetic acid (3.9 g, 22.1 mmol) was dissolved in anhydrous ethanol (100 mL) concentrated sulfuric acid (5 mL), and heated under reflux for 16 hours. It was concentrated under reduce pressure to remove most of ethanol, then water (30 mL) was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated to obtain the product 3.96 g, at a yield of 87.8%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:22][CH2:23][CH2:24][OH:25])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:27].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[C:24]([CH2:23][CH2:22][N:17]([C:3]1[C:2]([Cl:1])=[C:11]([CH3:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2)[S:18]([CH3:21])(=[O:20])=[O:19])([OH:27])=[O:25]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1nc2cc(C)c(Cl)c(N(CCCO)S(C)(=O)=O)c2nc1OC
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2cc(C)c(Cl)c(N(CCC(=O)O)S(C)(=O)=O)c2nc1OC

Procedure:
N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-hydroxypropyl)methanesulphonamide (0.94 g, 2.41 mmol) and pyridinium dichromate (2.42 g, 9.63 mmol) in DMF (24 ml) were stirred at room temperature for 18 hours. The reaction mixture was poured into water (25 ml) and extracted twice with dichloromethane. The combined dichloromethane extracts were extracted twice with 10% potassium carbonate solution. The potassium carbonate extracts were acidified to pH1 with 2M HCl and extracted twice with dichloromethane. These combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure to give N-(2-carboxyethyl)-N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide an off-white solid (0.49 g, 51%).