Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH:39](O)[CH3:40])=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH:39](/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)[CH3:40])=[O:9]
Reactant: CC(O)/C=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-4-{4-(1-imidazolylmethyl)phenyl)-3-buten-2-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column. Two kinds of diastereomers were eluted by silica gel column chromatography with a eluate consisting of a mixture of hexane, ethyl acetate and methanol in a ratio of 5:5:1. The first eluted moiety is referred to as "Compound a", and the later eluted moiety is referred to as "Compound b".
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[N:3]=1.CN.[CH2:25]([N:27](CC)CC)C>C1(C)C=CC=CC=1>[CH3:25][NH:27][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[N:3]=1
Reactant: CCN(CC)CC
Reactant: Clc1nc2ncnn2c(NC2CCCC2)c1-c1ccccc1
Agent: CN
Solvent: Cc1ccccc1
Product: CNc1nc2ncnn2c(NC2CCCC2)c1-c1ccccc1
Yield: 75 %

Procedure:
A mixture of 5-chloro-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine (3.1 g, 10 mmol) prepared by a method analogous to Example 2, methylamine (5 ml), triethylamine (5 ml) and toluene (50 ml) was refluxed for 10 hours. After cooling, the reaction mixture was washed with water (50 ml) and the organic layer separated, dried over sodium sulphate and evaporated. Recrystallization of the solid residue from diisopropyl ether gave 2.3 g 5-methylamino-6-phenyl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as colourless crystals, m.pt. 158°-160° C. Yield: 75% of theoretical 1H-NMR: δ=1.25-1.7 (mm, 8H); 2.95 (d,3H); 3.42 (m,1H); 4.48 (m,1H); 5.55 (d,1H); 7.3-7.5 (m,5H); 8.03 (s,1H)
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH:26]=C)[CH:4]=1)[CH3:2].I([O-])(=O)(=O)=[O:29].[Na+].C(#N)C.O>[Os]=O.CC(C)=O>[CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH:26]=[O:29])[CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(CC)c(Cc2ccc(-c3ccn(C)n3)cc2)cc1C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CCc1cc(C=O)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of methyl 4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate (0.21 g), osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.64 g) in acetone (4.00 mL)-acetonitrile (4.00 mL)-water (4.00 mL) was stirred overnight at room temperature. The insoluble substance was removed by filtration, the filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.21 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[CH2:13])[C:8]([C@@H:14]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH3:15])=[CH:7]2.C[N+]1([O-])CC[O:31]CC1.[OH2:35]>C1COCC1.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.O.[O-][Os]([O-])(=O)=O.[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:31])[CH2:13][OH:35])[C:8]([C@@H:14]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH3:15])=[CH:7]2
Reactant: C=Cc1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1C(O)CO)N1C(=O)c2ccccc2C1=O
Reaction time: 0.08 h

Procedure:
To a stirred solution of (S)-2-(1-(8-chloro-2-vinylquinolin-3-yl)ethyl)isoindoline-1,3-dione (200 mg, 0.55 mmol) in THF (5 mL) and water (1.0 mL) was added potassium osmate(VI) dihydrate (10.2 mg, 27.6 μmol). The reaction was stirred for 5 minutes and then NMO (64.6 mg, 0.55 mmol) was added. The reaction was stirred for 3 hours and then it was diluted with ethyl acetate (80 mL) and 1.0 M aqueous citric acid (40 mL). The separated aqueous layer was extracted with ethyl acetate (140 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and evaporated in vacuo to give 2-((S)-1-(8-chloro-2-(1,2-dihydroxyethyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione. The product was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (1H, d, J=11.7 Hz), 7.61-7.88 (6H, m), 7.49 (1H, q, J=8.1 Hz), 5.95-6.17 (1H, m), 5.22-5.32 (1H, m), 4.02-4.26 (2H, m), 1.94-1.97 (3H, m). Mass Spectrum (ESI) m/e=396.9 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[C:7](OC(C)=C)(=[O:9])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:7]([O:5][CH:4]=[CH:3][C:2]([CH3:6])=[CH2:1])(=[O:9])[CH3:8]
Reactant: C=C(C)OC(C)=O
Reactant: CC(C)=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(C)C=COC(C)=O

Procedure:
Prenal (0.332 mol) was run gradually into isopropenyl acetate (0.532 mol) in which paratoluenesulphonic acid (1% by weight) had been dissolved. The acetone was distilled off as it was formed. The temperature of the mixture was 93°-94° C. at the beginning and 118° C. after heating for 1 hour 50 minutes. The 1-acetoxy-3-methylbutadiene was then purified by distillation. The boiling point of the product was 48°-52° C./13 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:27])=O.C(=O)([O-])[O-].[K+].[K+]>>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][Cl:27])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CO)ccn12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CCl)ccn12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-amino-6-[2-(7-hydroxymethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.5 g) and thionyl chloride (5 ml) was stirred for 40 minutes under ice-cooling. The reaction mixture was poured into ice-water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The aqueous mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and triturated with diethyl ether to give 2-amino-6-[2-(7-chloromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.42 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[N:61]1([CH2:67][C:68](O)=[O:69])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:68](=[O:69])[CH2:67][N:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[C:21]([CH3:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)CN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1NC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0 %

Procedure:
To a solution of (4-amino-3-methylphenyl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (15.2 mg, 40 mol) in DMF (100 μL) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 27.4 mg, 72 mol) in DMF (100 μL), followed by i-Pr2NEt (25 μL, 144 mol) and piperidin-1-yl-acetic acid (8.6 mg, 60 mol). The resulting mixture was shaken at room temperature for 3 hours after which it was diluted with ethyl acetate (10 mL), washed with saturated aqueous ammonium chloride (2×10 mL), dried over sodium sulfate, and evaporated. The residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield [3-methyl-4-(2-piperidin-1-yl-acetylamino)-phenyl]-(4-trifluoromethylbenzyl)-carbamic acid tert-butyl ester as a white solid (10.7 mg, 53%). This was dissolved in dichloromethane (200 μL) and trifluoroacetic acid (200 μL), and the solution was kept at room temperature for 30 minutes, after which volatiles were evaporated and the residue was dried in vacuo at 0.1 mmHg and +40° C. for 1 hour. The resulting trifluoroacetic acid addition salt of the title compound was obtained as a yellow semisolid in quantitative yield.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([CH:9]=[O:10])=[C:7]([F:15])[C:6]=1[F:16].CO>O>[C:1]([CH:9]([OH:10])[C:8]1[C:7]([F:15])=[C:6]([F:16])[C:5]([CH3:4])=[C:12]([F:13])[C:11]=1[F:14])#[N:2]
Reactant: Cc1c(F)c(F)c(C=O)c(F)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(F)c(F)c(C(O)C#N)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
1.66 g of sodium cyanide were introduced into a mixture of 4 g of 4-methyl-2,3,5,6-tetrafluorobenzaldehyde, 4 g of 4-methyl-2,3,5,6-tetrafluorobenzaldehyde, 70 ml of methyl alcohol and 20 ml of water and the mixture was cooled to 0° C. The reaction mixture was stirred for 1 hour at 0° C. and was poured into water. Extraction was carried out with ether and the ethereal phases were dried and evaporated to dryness under reduced pressure to obtain 4.54 g of the product melting at 124° C.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]=[C:11]=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:16]=1[NH2:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=[C:15]([O:14][CH3:13])[C:16]=1[NH:17][C:11]([NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:12]
Reactant: CC(C)C1CCC(N=C=O)CC1
Reactant: COc1cc(OC)c(N)c(OC)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(NC(=O)NC2CCC(C(C)C)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 1.6 g of 4-isopropylcyclohexylisocyanate in chloroform is added a solution of 1.8 g of 2,4,6-trimethoxyaniline in chloroform dropwise in the presence of pyridine. The mixture is stirred at room temperature until starting compounds disappear on TLC. The resultant mixture is concentrated and the residue is dissolved in ethyl acetate. The solution is washed with diluted hydrochloric acid, aqueous sodium hydrogencarbonate solution and brine. The organic layer is dried over magnesium sulfate and filtered off. The filtrate is distilled away and the resulting residue is crystallized to give N-(2,4,6-trimethoxyphenyl)-N'-(4-isopropylcyclohexyl)urea.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]#[N:12].[NH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>C(#N)C>[C:11]([CH2:10][CH2:9][CH2:8][NH:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)#[N:12]
Reactant: NC1CCc2ccccc21
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCNC1CCc2ccccc21

Procedure:
Potassium carbonate (15.5 g, 112 mmole) and 4-chlorobutyronitrile (11.58 g, 112 mmole) was added to a solution of 1-aminoindan (5.0 g, 37.6 mmole) in acetonitrile (50 ml), and the mixture refluxed for 2 hr. A second portion of 4-chlorobutyronitrile (5.0 g) was then added, the mixture further heated for 24 hr, filtered and the filtrate evaporated to dryness. Unreacted 4-chlorobutyronitrile was removed by treating the residue (20 g) with isopropanolic HCl (16.7 ml, 24%) followed by successive extractions with ether (3×150 ml). The crude product thus obtained was further purified by column chromatography (Silica, CH2Cl2 :MeOH 98:2) to afford 3.7 g (49%) of tan-colored crystalline mass.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11](O)[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>>[C:13]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]([N:24]3[CH2:25][CH2:26][N:21]([CH:19]=[O:20])[CH2:22][CH2:23]3)[CH:10]=[CH:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1C=CCC1(c1ccccc1)c1ccccc1
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(C2C=CC(c3ccccc3)(c3ccccc3)C2)CC1

Procedure:
1-(4,4-Diphenyl-2-cyclopentenyl)piperazine dihydrochloride was obtained by reacting 5,5-diphenyl-2-cyclopenten-1-ol and 1-formylpiperazine according to a similar manner to that of Example 11 to give 1-(4,4-diphenyl-2-cyclopentenyl)-4-formylpiperazine, then eliminating formyl group thereof in a conventional manner.
Reaction SMILES: N[C:2]1([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]1[NH2:17])[NH2:3].O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22]>Cl>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:2]2[C:4]=1[NH:17][C:20](=[O:24])[C:21](=[O:22])[NH:3]2
Reactant: O=C(O)C(=O)O
Reactant: NC1C(C(F)(F)F)=CC(C(F)(F)F)=CC1(N)N
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 1,2-diamino-3,5-bis(trifluoromethyl)aniline (94 mg, 0.38 mmol) and oxalic acid dihydrate (53 mg, 0.42 mmol, used as received) in 4N HCl (2 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 45 mg of crude 5,7-bis(trifluoromethyl)-1,4-dihydro-2,3-quinoxalinedione (40%) as a yellow powder. The crude compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=5, affording 23 mg of pure 5,7-bis(trifluoromethyl)-1,4-dihydro-2,3-quinoxalinedione. Mp: 305°-8° C. (dec. from 295° C.). IR (KBr, cm-1) 3421, 3235, 1749, 1690, 1631. 1H NMR (DMSO-d6): δ7.654 (s, 1H); 7.687 (s, 1H); 11.584 (s, 1H); 12.311 (s, 1H). HRMS: calcd for C10F6H4N2O2 (M+) m/z: 298.0176; found: 298.0170.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[Cl:12].[NH2:13][CH2:14][CH:15]1[CH2:30][CH2:29][CH2:28][C:17]2([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][CH:15]2[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:18]3)[CH2:16]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1F
Reactant: CC(C)(C)CN1CC2(CCCC(CN)C2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)CN1CC2(CCCC(CNc3cc(Br)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A rt suspension of 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (0.600 g, 2.36 mmol) in MeCN (8 mL) was treated with 7-(aminomethyl)-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.400 g, 1.57 mmol) and potassium carbonate (0.543 g, 3.93 mmol). The reaction was stirred for 18 h, and the solids were filtered off and washed with EtOAc. The filtrate was concentrated and purified on a 40 g silica gel column (0-100% DCM/hexanes, 20 min gradient; 100% DCM, 15 min; 40 mL/min elution; 254 nm detection) to provide the title compound (0.340 g, 44% yield) as an orange solid. MS (m/z) 488.1, 490.1 (M+H+).
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+].Cl>CCOCC.N1C=CC=CC=1>[CH2:23]([O:22][C:20]([S:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:21])[CH3:24]
Reactant: O=C(O)C(S)c1ccc(-c2ccccc2Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A solution of α-mercapto-2'-chloro-4-biphenylylacetic acid 5.6 g. (0.02 moles) in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 ml. (0.022 moles) of ethyl chloroformate. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([S:9][C:5]2[N:4]=[C:3]([C:1]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:2]=3)[CH:8]=[CH:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(Sc2ccncc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Sc3ccncc3)n2)sc2ccccc12
Yield: 2.1 %

Procedure:
2-Cyano-6-(4-pyridylthio)pyridine (1.54 g, 7.22 mmol) and methyl thiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (50 ml), and triethylamine (1.52 ml, 10.83 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.053 g, 2%) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1[C@@H]1CCCC[C@@H]1O
Temperature: 7.5 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a suspension of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (679 mg) in 14 ml of tetrahydrofuran was added lithium tri-tert-butoxyaluminohydride (676 mg) at 5° C. The reaction mixture was allowed to stir at 5-10° C. for 45 minutes, then the solvent was removed in vacuo. To the residue was added 20 ml ice-water. Then, the mixture was acidified with 1N hydrochloric acid and extracted with dichloromethane (25 ml×2). The combined extracts were washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30 g) eluted with a mixture of dichloromethane and ethyl acetate (10:3) to give pale yellow crystals of cis-3-[2-(2-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (677.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH:22](Br)([CH3:24])[CH3:23].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH:22]([CH3:24])[CH3:23])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)n(C)c(OC(C)C)n2)cc1OC
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.0 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% oil suspension, 0.50 g). The mixture was heated at 60° C. with stirring for 20 minutes and cooled to ambient temperature. To the mixture was added isopropyl bromide (15 ml) with stirring, which was continued at ambient temperature for 5 hours, and at 50° C. for 25 hours. To the reaction mixture was added water, and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4-(3H)-pyrimidinone (2.73 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:20]([S:24](Cl)=[O:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([S:24]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)S(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Ethyl 4-amino-1-piperidinecarboxylate (300 mg) and triethylamine (258 mg) were dissolved in 5 ml of dichloromethane. To the mixture, 2 ml of solution of t-butylsulfinyl chloride (222 mg) in dichloromethane was added and the mixture was stirred at room temperature for 4 hours. The solution was partitioned into an aqueous solution of potassium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 378 mg of 4-t-butylsulfinylamino-1-ethoxycarbonyl piperidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=O)[NH:20][C:19]=1[CH3:26])=[O:17]>>[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:20][C:19]=1[CH3:26])=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2ccccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)NCCN(C)C

Procedure:
1,3-Dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide to give the title compound.