Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), pyrazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (30 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole as a solid (1.80 g). MS 208.3 (M+H)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1(C(=O)OCC)CCCC1=O
Temperature: 56 °C
Yield: 37.8 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (93.27 g, 597 mmol) and ethyl 2-bromoacetate (144.64 g, 866 mmol) in acetone (1.2 L) was added K2CO3 (165 g, 1194 mmol). The mixture was heated at 56° C. for 24 h. The solid was filtered off and the filtering cake was washed with acetone (3×100 mL). The filtrate was concentrated and the resultant liquid was purified by a silica gel plug to give the title compound as light yellow liquid (54.7 g). LCMS m/z=243.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.14 Hz, 3H), 1.24 (t, J=7.14 Hz, 3H), 1.95-2.03 (m, 1H), 2.06-2.15 (m, 2H), 2.35-2.50 (m, 2H), 2.55-2.60 (m, 1H), 2.80 (dd, J=15.2, 2.09 Hz, 1H), 2.95 (dd, J=15.2, 2.09 Hz, 1H), 4.09 (q, J=7.14 Hz, 2H), 4.12 (q, J=7.14 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:19](=[N:27]O)(Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][O:11][C:9]=2[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: CC(=O)Cc1ccnc(Br)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
To a stirred solution of Compound 16 (1.71 g, 8.0 mmol) and Et3N (2.23 mL, 16 mmol) in EtOH (16 mL) was added a solution of benzoylchloride oxime (1.62 g, 10.4 mmol) in EtOH (16 mL) over 90 min. The solution was stirred at 25° C. for 90 min. Then, the solution was heated to reflux for 24 h. The solution was cooled to 25° C. and concentrated. The crude material was taken up in CH2Cl2 (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), extracted with CH2Cl2 (3×50 mL), dried (Na2SO4), and filtered. Flash chromatography (SiO2, 20% EtOAc-hexanes) provided the title compound (1.32 g, 4.19 mmol, 52%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@:33]1([C@H:36]([OH:38])[CH3:37])[CH2:35][O:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@:33]1([C@@H:36]([OH:38])[CH3:37])[CH2:35][O:34]1
Reactant: C[C@@H](O)[C@]1(c2cc(F)ccc2F)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](O)[C@]1(c2cc(F)ccc2F)CO1
Temperature: 0 °C
Yield: 53 %

Procedure:
DEAD (870 mg; 2 mmol) and p-nitrobenzoic acid (337 mg; 2 mmol) were dissolved in dry THF (3 ml) and the solution was cooled to 0° C. Then 1(R)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (100 mg; 0.5 mmol) and triphenylphosphine (524 mg; 2 mmol) is dissolved in dry THF (10 ml) were added dropwise at such a rate to maintain the temperature below 10° C. The mixture was then allowed to react to completion at 20° C. for 20 hours. Half of the solvent was removed under reduced pressure. The reaction mixture is diluted with diethyl ether (80 ml) and washed with an aqueous saturated ammonium chloride solution. The organic phase is dried over magnesium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The residue is dissolved in methanol (25 ml) and treated with potassium carbonate (450 mg). The reaction mixture is diluted with an aqueous saturated ammonium chloride solution (30 ml). The reaction mixture is extracted with ethyl acetate (2 times 20 ml). The combined organic phases are washed with water (2 times 30 ml) and with brine (2 times 30 ml). The organic phase is dried over magnesium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude residue is purified by chromatography (Petrole ether/ethyl acetate 20:1). 53 mg (yield: 53%) of desired 1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol was obtained as a colorless oil. The HPLC purity is 76%.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCCl

Procedure:
A solution of 32.5 g of the alcohol from Example 1 and 32.5 g triphenylphosphine in 244 ml of carbon tetrachloride was stirred at room temperature and under an atmosphere of nitrogen for 72 hours. Excess carbon tetrachloride was removed in vacuo to give 83 g of a crude yellow oil. Purification by silica gel chromatography (hexanes-20% ethyl acetate) afforded a colorless viscous oil which crystallized on standing. The product was isolated by trituration with hexanes, filtration, and drying. The yield of pure 2-(2-chloroethyl)-N-(1,1-dimethylethyl)benzenesulfonamide, m.p. 64°-65° C., was 15.9 g.
Reaction SMILES: [Br-].[OH:2][CH:3]1[CH2:7][CH2:6][N@@+:5]([CH3:18])([CH2:8][C:9](=[O:17])[NH:10][C:11]2[CH:16]=NC=C[N:12]=2)[CH2:4]1.[Br:19]C[C:21](NC1C=NC=CN=1)=[O:22].BrCC(NC1C=CON=1)=O>>[Br-:19].[OH:2][C@@H:3]1[CH2:7][CH2:6][N+:5]([CH2:8][C:9](=[O:17])[NH:10][C:11]2[CH:16]=[CH:21][O:22][N:12]=2)([CH3:18])[CH2:4]1
Reactant: O=C(CBr)Nc1cnccn1
Reactant: C[N@@+]1(CC(=O)Nc2cnccn2)CCC(O)C1
Agent: O=C(CBr)Nc1ccon1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CC[C@@H](O)C1

Procedure:
This compound is prepared by a method that is analogous to that used to prepare (R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Intermediate B) by replacing 2-Bromo-N-pyrazin-2-yl-acetamide (Intermediate A) with 2-Bromo-N-isoxazol-3-yl-acetamide (Intermediate C).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(O)c1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Oc1cccc(-c2cn3cc(I)ccc3n2)c1
Temperature: 110 °C
Yield: 60.7 %

Procedure:
987 mg (corresponding to 4.55 mmol) of 2-bromo-3′-hydroxyacetophenone and 1.00 g (corresponding to 4.55 mmol) of 2-amino-5-iodopyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 1 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 927 mg (corresponding to 2.76 mmol) of 2-(3′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 2-8, Step 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[SH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CCOC(=O)CCCS
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOC(=O)CCCSc1ccc(Br)cc1C=O
Yield: 78 %

Procedure:
Ethyl 4-(4-bromo-2-formylphenylthio)butyrate was synthesized from 5-bromo-2-fluorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After column chromatography, crystallization from hexane/isopropyl ether yielded ethyl 4-(4-bromo-2-formylphenylthio)butyrate (Yield 78%) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]([O-:16])(=[O:15])[CH3:14].[Br-].[C:18]([Zn+2])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:15][C:13](=[O:16])[CH2:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Zn+2]
Reactant: Fc1cc2ncccc2cc1Br
Reactant: CC(=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cc2cccnc2cc1F
Temperature: 120 °C
Yield: 63 %

Procedure:
To a solution of 6-bromo-7-fluoro-quinoline (1.04 g, 4.6 mmole) in tetrahydrofuran (1 mL) was added a solution of tert-butylzincbromide acetate (20 mL, 10.4 M in tetrahydrofuran) followed by Pd(PPh3)4 (0.58 g, 0.5 mmole). The mixture was heated in a microwave reactor for 35 min at 120° C. The reaction mixture was quenched with a saturated ammonium chloride (60 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (0.75 g, 63%).
Reaction SMILES: N(CCCCN=C=O)=[C:2]=O.N(C[C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])=C=O.N(CCCC[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]=[C:38]=[O:39])=C=O.C(CCN=C=O)CCCN=C=O.N(C1CC(C)(CN=C=O)CC(C)(C)C1)=C=O.[C:68]1([N:77]=[C:78]=[O:79])[CH:73]=[CH:72][C:71]([N:74]=[C:75]=[O:76])=[CH:70][CH:69]=1>>[CH:34]1[C:33]([CH2:23][C:15]2[CH:16]=[CH:17][C:18]([N:19]=[C:20]=[O:21])=[CH:2][CH:22]=2)=[CH:32][CH:31]=[C:36]([N:37]=[C:38]=[O:39])[CH:35]=1.[C:68]1([N:77]=[C:78]=[O:79])[CH:69]=[CH:70][C:71]([N:74]=[C:75]=[O:76])=[CH:72][CH:73]=1
Reactant: O=C=NCCCCCCCCCCN=C=O
Reactant: CC(C)(CCCN=C=O)CN=C=O
Reactant: O=C=NCCCCN=C=O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: O=C=NCCCCCCN=C=O
Agent: O=C=Nc1ccc(N=C=O)cc1
Product: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1

Procedure:
Examples of suitable monomers of the polyisocyanates include, but are not limited to, 1,4-diisocyanatobutane, 1,5-diisocyanato-2,2-dimethylpentane, 2,2,4- and 2,4,4-trimethyl-1,6-diisocyanatohexane, 1,10-diisocyanatodecane, 4,4'-diisocyanato-dicyclohexylmethane, 1,6-hexamethylene diisocyanate, 1,12-dodecane diisocyanate, cyclobutane-1,3-diisocyanate, cyclohexane-1,3- and/or 1,4-diisocyanate, 1-isocyanato-3,3,5-trimethyl-5-isocyanatomethyl cyclohexane (isophorone or IPDI), 2,4-and/or 2,6-hexahydrotoluylene diisocyanate, hexahydro-1,3- and/or 1,4-phenylene diisocyanate, perhydro-2,4'-and/or -4,4'diphenylmethane diisocyanate, 1,3-and/or 1,4-phenylene diisocyanate, 2,4- and/or 2,6-toluylene diisocyanate, diphenyl methane-2,4'-and/or -4,4'-diisocyanate, naphthalene-1,5-diisocyanate, triphenyl methane-4,4',4"-triisocyanate and polyphenyl polymethylene polyisocyanates obtained by phosgenating-aniline/formaldehyde condensation products.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].N12CCCN=C1CCCCC2>O1CCCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:16])[CH2:3]1
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC(F)(F)F)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of 21.9 g (0.100 mole) 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml tetrahydrofuran, was cooled to 0° C. in an ice bath under nitrogen and 24.32 g (0.150 mole) carbonyl diimidazole was added. The reaction was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.55 g (0.100 mole) of 2,2,2-triflouroethylamine hydrochloride, 15.22 g (0.100 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed with 3×150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)CCCCl
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCCCl)cc1
Yield: 93.3 %

Procedure:
6.0 g (29.6 millimoles) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridaz-3-one and 4.6 g (32.6 millimoles) of 4-chlorobutyryl chloride in 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 8.5 g (93% of theory) of 6-[p-(4-chlorobutyrylamino)-phenyl]-5-methyl-4,5-dihydropyridaz-3-one are obtained as beige crystals which, after recrystallization from methanol, melt at 176°-178° C.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[Na].[C:21]([OH:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>O1CCOCC1.C(OCC)(=O)C.O.[Cl-].[Zn+2].[Cl-]>[C:21]([S:28][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: OC(=S)c1cccnc1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1SC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml), the sodium salt of thionicotinic acid (1.94 g) was added. Zinc chloride (1.7 g) was added to the resulting mixture and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulphate, and evaporated in vacuo. The residue was purified by column chromatography to give 1.9 g of the title product (52% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:46]([C:49]1[S:53][CH:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1)([CH3:48])[CH3:47].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:51]3[CH:50]=[C:49]([CH:46]([CH3:48])[CH3:47])[S:53][CH:52]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CC(C)c1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.55 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.32 g), 5-isopropylthiophene-3-carboxylic acid (0.19 g) and triethylamine (0.61 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.4 g.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][CH:11]1[CH2:10][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:12]1)(=[O:21])[CH3:19]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(N)=O)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(N)=O)cs2)C1
Temperature: 80 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (3.04 g, 11.0 mmol) (obtained as described in Reference Example 3(3)) in dimethylformamide (152 ml) was added potassium thioacetate (7.5 g, 65.8 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 10 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→4% methanol in ethyl acetate as the eluant to afford 3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)azetidine (1.97 g, yield 70%) as a pale brown solid.
Reaction SMILES: C(OC(=O)[NH:6][CH2:7][C:8]1[CH:13]=[C:12]([I:14])[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][C:9]=1[Cl:20])(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:6][CH2:7][C:8]1[C:9]([Cl:20])=[CH:10][C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([I:14])[CH:13]=1
Reactant: CC(C)OC(=O)NCc1cc(I)c(NS(C)(=O)=O)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cc(Cl)c(CN)cc1I
Reaction time: 12 h
Yield: 128.7 %

Procedure:
(2-chloro-5-iodo-4-methanesulfonylamino-benzyl)-carbamic acid isopropyl ester (100 mg, 0.22 mmol) was put into a dried 25 ml of round-bottom flask and dissolved in methylenechloride. To the solution were added 5-6 drops of CF3COOH and stirred for 12 hours. After confirming the completion of the reaction with TLC, the resulting solution was concentrated under reduced pressure using toluene to yield a brown syrup (102.1 mg, 130.48%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:22].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:22])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1cc(OC)ccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3ccc(OC)cc3nc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -4-methoxyanthranilic acid (13.3 g, 0.051 mol) and POCl3 (125 ml) was refluxed for 3 hours, then was allowed to sit overnight. The volume of POCl3 was reduced, then ice/water, followed by NH4OH was added. A precipitate formed which was collected by filtration and dried in a vacuum oven at 50° C. to afford 11.51 g (87%) of 1-ethyl-4-chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 95°-98° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.O[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[CH:1]1([O:6][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CC=CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of cyclopent-3-enol (840 mg, 10.0 mmol) in CH2Cl2 (25.0 mL) was added 2-hydroxyisoindoline-1,3-dione (1.96 g, 12.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (740 mg, 32%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57-2.87 (m, 4H) 5.12 (t, J=6.19 Hz, 1H) 5.75 (s, 2H) 7.74 (dd, J=5.68, 3.16 Hz, 2H) 7.79-7.87 (m, 2H). MS (ES) [M+H] calculated for C13H12NO3, 230.07; found 230.20.