Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[C:13]([C:17]1[N:21]=[C:20](Cl)[S:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[C:13]([C:17]1[N:21]=[C:20]([O:9][C:7]2[C:6]([CH3:10])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=2)[S:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(O)c(C)cc1N
Reactant: CC(C)(C)c1nsc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2nc(C(C)(C)C)ns2)c(C)cc1N
Temperature: 100 °C
Yield: 90 %

Procedure:
754 mg (5.50 mmol) of 2,5-dimethyl-4-hydroxyaniline are dissolved in 5 ml of N,N-dimethylformamide and slowly treated with 242 mg (6.05 mmol) of sodium hydride. The reaction mixture is stirred for 15 min, before 972 mg (5.50 mmol) of 3-(tert-butyl)-5-chloro-1,2,4-thiadiazole are added. Subsequently, the reaction mixture is heated at 100° C. for 1 h and then cooled down to AT. After addition of 20 ml of ethyl acetate, the solution is extracted three times with water and dried over MgSO4, and the solvent is removed under vacuum (1.46 g, 94% purity, 90% yield, log P (pH 2.3)=3.29).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH:5]=[CH:6][CH:7]=1.CN>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(/C=C/CCN2C(=O)c3ccccc3C2=O)c1
Agent: CN
Solvent: CCO
Product: NCC/C=C/c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.4 %

Procedure:
A mixture of (E)-N-[4-(3-aminophenyl)-3-butenyl]phthalimide (3.50 g, 12.0 mmol) in ethanol (50 mL) was treated with 50 g of a 25% (w/w) solution of methylamine in ethanol. The resulting yellow solution was stirred at room temperature for 3 h and concentrated on a rotary evaporator. The product was vacuum dried at 50° C. for 1 h to give 4.26 g of a viscous, orange-yellow oil. The oil was purified by column chromatography on silica gel (200 g), eluting with methanol-concentrated ammonium hydroxide (10:1, v/v). Based upon TLC analysis, selected fractions were combined and concentrated on a rotary evaporator. The product was purified by vacuum distillation (bulb to bulb) to give 124 mg (6.4%) of a colorless oil, bp 105-110° C. at 0.075 mm Hg. Purification of a second fraction by vacuum distillation produced an additional 141 mg of a colorless oil, bp 104-105° C. at 0.075 mm Hg, bringing the total yield to 249 mg (12.8%).
Reaction SMILES: [N+:1]([CH:4]([CH3:22])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:6][C:7](OCC)=[O:8])([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C1COCC1.[OH-].[Na+]>C(OCC)C>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH:4]([NH2:1])[CH3:22])[CH2:6][CH2:7][OH:8])=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CC(c1ccc(C(C)(C)C)cc1)C(C)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)C(CCO)c1ccc(C(C)(C)C)cc1

Procedure:
6.5 g (0.021 mol) of the nitro ester prepared as in (b) above was added dropwise to 5 g (0.18 mol) of lithium aluminum hydride suspended in 200 mL of anhydrous diethyl ether, under nitrogen with stirring. The mixture was then refluxed for ten hours. A 50 percent H2O/THF solution was added dropwise and slowly with vigorous stirring until effervescence ceased. 1N sodium hydroxide solution was then added dropwise until the slurry coagulated to a coarse sandy consistency. The mixture was filtered and the solid washed with diethyl ether. The organic fractions were combined, washed with water, dried, filtered and the solvent evaporated off at reduced pressure to afford 4 g (80 percent of theoretical) of the crude product in the form of a gum. The NMR and IR spectra of the product were consistent with the expected structure, and indicated a mixture of the two possible diastereoisomers in a ratio of 2:1.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:28][NH2:29])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH2:28][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: NCc1ccc(OCC(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)F)c(Cl)c1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (225 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol) and (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride (195 mg, 0.75 mmol, Amine-33) in a similar manner to Intermediate-2.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][C:13]1([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: Fc1cccc(CCl)c1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2cccc(F)c2)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
925 mg magnesium were stirred into 19 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 4.95 g 3-fluorobenzyl chloride in 19 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml analytical grade diethyl ether was then added dropwise and the reaction mixture was stirred overnight. For working up, 29 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 50 ml diethyl ether each time and the combined organic phases were washed successively with 20 ml water and 20 ml saturated sodium chloride solution. The crude [8-(3-fluorobenzyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine obtained (5.75 g of yellow solid) was stirred, without further purification, with a mixture of 14 ml conc. hydrochloric acid (32 per cent by weight) and 8 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 30 ml diethyl ether each time and then adjusted to pH 9 by addition of aqueous ammonia (25 per cent by weight), while cooling with ice, and extracted three times with 40 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 4.71 g 4-dimethylamino-4-(3-fluorobenzyl)cyclohexanone were obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[C:30]([F:33])([F:32])[F:31]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[C:23]([C:30]([F:33])([F:31])[F:32])[CH:24]=1)[C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)C(=O)OC(C)(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 6-B (2.0 g, 7.59 mmol) in DMF (20 mL), cooled to 0° C., was added 60% NaH (0.334 g, 8.35 mmol) and the reaction mixture was stirred for 15 minutes. 4-Fluoro-3-trifluoromethyl benzyl bromide (1.26 mL, 8.35 mmol) was added drop-wise at 0° C. and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phase washed with H2O, brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude oil was purified by flash column chromatography (SiO2) eluting with a 0% EtOAc-heptane to 25% EtOAc-heptane gradient to afford compound 6-C as a clear oil. Compound 6-C was used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:15]([O:17]C)=[O:16])[C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[OH-].[K+].O>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: COC(=O)c1cc2nc(C)n(C)c2cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2cc(C(=O)O)c(C(=O)O)cc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of dimethyl 1,2-dimethyl-5,6-benzimidazoledicarboxylate (2.80 g, 10.7 mmol), potassium hydroxide (1.49 g; 26.7 mmol), water and methanol is stirred at room temperature for 16 hours and then concentrated in vacuo. The resultant residue is taken up in a minimal amount of water, cooled, acidified to pH 3 with hydrochloric acid and filtered to give the title product as pink crystals (2.28 g, 91.2%), mp 308°-312° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C>C1COCC1.[Zn]>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)ccc1C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-methyl-5-nitrobenzoate 101 and acetic acid (516 mmol, 29.6 mL) (25.8 mmol, 5.4 g) in THF (129 mL) at 0° C. was added zinc (516 mmol, 33.8 g) and stirred for 1 h. The reaction was filtered, neutralized with 2N NaOH solution and extracted with ethyl acetate (2×). Organic layers were washed with water, brine, dried and concentrated under reduced pressure to give ethyl 5-amino-2-methylbenzoate 102 (4.6 g, 100%).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9]>CC(O)C>[OH:1][CH:6]1[CH2:5][O:4][CH2:3][CH:2]1[NH:9][NH:8][C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C1OCC2OC12
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NNC1COCC1O
Temperature: 90 °C
Reaction time: 72 h

Procedure:
3,4-epoxytetrahydrofuran (3.33 mL) and t-butyl carbazate (6.14 g) were dissolved in 2-propanol (15 mL), and the solution was heated to 90° C. After three days, t-butyl carbazate (6.3 g) was further added. After heating with stirring for further two days, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was partitioned by adding chloroform and brine. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (5.78 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC2C(SC(=O)N(C)C)=C(Cl)C=C(Cl)C=2CC1)=O)(C)(C)C.[OH-].[K+].[Cl-].[NH4+].C1CCN2C(=NCCC2)CC1.[F:67][C:68]1[CH:75]=[CH:74][CH:73]=[CH:72][C:69]=1CBr>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:69]3[CH:72]=[CH:73][CH:74]=[CH:75][C:68]=3[F:67])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1CBr
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: CN(C)C(=O)Sc1c(Cl)cc(Cl)c2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccccc3F)c2CC1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine (102 mg, 0.267 mmol) in methanol (2 ml), add potassium hydroxide pellets (450 mg, 8.02 mmol) and heat the mixture 3 h at 60° C. Cool to ambient temperature, add aqueous saturated ammonium chloride solution, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Dissolve the crude thiophenol thus obtained in dry DCM (2 mL) under nitrogen, and add DBU (80 □L, 0.54 mmol) and 2-fluorobenzyl bromide (65 □L, 0.54 mmol) with stirring. Stir overnight at ambient temperature, dilute with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (31 mg, 25%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 322 (M+H)+.
Reaction SMILES: [I-].[C:2]([C:4]1[CH:5]=[N+:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)#[N:3].[BH4-].[Na+]>CO.O>[C:2]([C:4]1[CH2:5][N:6]([CH3:10])[CH2:7][CH2:8][CH:9]=1)#[N:3]
Reactant: C[n+]1cccc(C#N)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC=C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 (133 g, 0.54 mol) in methanol (1000 ml) and water (200 ml) was added sodium borohydride (41 g, 1.08 mol) in portions at temperatures below 28° C. After the addition the mixture was stirred for 1 hour at room temperature. Most of the methanol was distilled off. To the residue was added saturated ammonium chloride solution (200 ml), and the mixture was extracted three times with ether (300 ml). The combined organic phases were washed once with water and were then extracted three times with 4M hydrochloric acid (300 ml). The colored aqueous phases were kept for 1 hour at room temperature, and pH was then adjusted to 14. The mixture was extracted three times with ether (250 ml), and the combined organic phases were separated from the solid byproducts. The organic phase was washed with 4 portions of saturated sodium chloride solution (200 ml), dried over magnesium sulphate and evaporated. This yielded 17.4 g (0.143 mol, 26%) of crude oily title compound, which was sufficiently pure according to the 1H NMR spectrum.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])([CH3:9])[CH3:8])C>C(O)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:24])([C:20]([F:22])([F:23])[F:21])[C:4]([OH:25])=[O:3])[CH:15]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1[N+](=O)[O-])C(F)(F)F
Solvent: CCO
Product: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
2.4 g of 4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid-ethyl ester is dissolved in 30 ml of ethanol and purified with 60 ml of 1 M sodium hydroxide solution. After 2 days at room temperature, it is concentrated by evaporation, the residue is dissolved in water, acidified at 0° C. and extracted with ethyl acetate. The ethyl acetate phase is washed neutral with water, dried (Na2SO4) and concentrated by evaporation. After crystallization from diisopropyl ether, 4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid with a flash point of 130-131° C. is obtained.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH3:11])[CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([O-:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCOC(C)=O.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>[CH3:11][N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:3]1
Reactant: Cn1cc(Br)c2ncccc21
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc([N+](=O)[O-])cc2)c2ncccc21
Temperature: 100 °C
Yield: 37.1 %

Procedure:
A mixture of 3-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (200 mg), (4-nitrophenyl)boronic acid (175 mg), Pd(PPh3)4 (95 mg) and Na2CO3 (201 mg) in DME (4 mL) and water (2 mL) was heated at 100° C. for 19 h. After this time, the reaction was cooled to room temperature, diluted with AcOEt (100 mL), washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (heptane to 1:1 AcOEt/heptane) to give the title compound (89 mg).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:22])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)=O.[CH3:23][C:24]1[CH:29]=[CH:28][N:27]2[CH:30]=[C:31]([CH2:33][C:34](OCC)=[O:35])[N:32]=[C:26]2[CH:25]=1.N1CCCCC1.C(O)(=O)C>CCO.O>[CH3:23][C:24]1[CH:29]=[CH:28][N:27]2[CH:30]=[C:31]([C:33]3[C:34](=[O:35])[O:22][C:4]4[CH:5]=[C:6]([N:9]5[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]5)[N:7]=[CH:8][C:3]=4[CH:1]=3)[N:32]=[C:26]2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(O)c(C=O)cn2)CC1
Reactant: CCOC(=O)Cc1cn2ccc(C)cc2n1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: Cc1ccn2cc(-c3cc4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4oc3=O)nc2c1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
To a mixture of t-butyl 4-(5-formyl-4-hydroxypyridin-2-yl)piperazine-1-carboxylate (124 mg, 0.40 mmol) and ethyl 2-(7-methylimidazo[1,2-a]pyridin-2-yl)acetate (96 mg, 0.44 mmol) in EtOH (0.2 mL) were added piperidine (0.3 mL) and acetic acid (0.1 mL). The reaction mixture was heated to 120° C. for 15 hours and cooled to room temperature. To the mixture was added water (2 mL) to give a precipitate. The precipitate was filtered and washed with water and then ether. After drying under nitrogen, 115 mg (63%) of t-butyl 4-(3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate was obtained as a yellow solid. MS m/z 462.3 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]O)#[N:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:31]([C:33]1[CH:34]=[C:35]([CH2:36][O:13][C:14]2[CH:15]=[C:16]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:38]=[CH:39][CH:40]=1)#[N:32]
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Reactant: N#Cc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl alcohol (133 mg, 1.0 mmol)(Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofyiran (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated NaHCO3 (2×30 mL), brine (2×30 mL) and dried over Na2SO4. The solvent was removed in vacuo the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (375 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 5.02 (s, 2 H), 6.78 (m, 2H), 6.85 (dd, 1H, J=4.2, 1.3 Hz), 7.20 (t, 1H, J=8.2 Hz), 7.38 (t, 1H, J=5.8 Hz), 7.51 (t, 1H, J=7.7 Hz), 7.59-7.68 (m, 5 H) and 7.93 (dd, 1 H, J=4.0, 0.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:11][CH:20]([CH3:22])[CH3:21])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(N)c(OC(C)C)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Methyl3-hydroxy-4-aminobenzoate (ABCR: 100 mg, 0.60 mmol) & caesium carbonate (396 mg, 1.22 mmol) were taken up in acetone (4 mL) and 2-iodopropane (90 μl, 0.90 mmol) added and reaction heated in microwave (CEM discover; 150 W) to 120° C. and held for 30 mins A further aliquot of 2-iodopropane (90 μl, 0.90 mmol) was added and reaction heated again to 120° C. in microwave, holding for a further 30 mins
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=3)[CH2:7]2)[C:5](=[O:18])[NH:4][C:3]1=[O:19].[N+:20]([O-])(O)=O.OS(O)(=O)=O>>[NH2:20][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[N+:15]([O-:17])=[O:16])[CH2:14][C:6]1([C:5](=[O:18])[NH:4][C:3](=[O:19])[N:2]1[CH3:1])[CH2:7]2
Reactant: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1C(=O)NC(=O)C12Cc1cc(N)c([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (100 mg, 0.432 mmol, described in Intermediate 7) at 0° C. were added 70% HNO3 (1 mL) followed by conc. H2SO4 (1 mL). The resulting mixture was allowed to warm to ambient temperature and stirred for 18 h, then poured onto ice and the precipitate was removed by filtration. The aqueous filtrate was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=277 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>O1CCCC1>[Br:1][C:2]1[N:3]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:4](=[O:13])[C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1nc(Br)cnc1NC1CCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(Br)cnc(NC2CCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a suspension of CaH2 (1.7246 g, 40.96 mmol) in 80.0 mL tetrahydrofuran (0.50 M) was added 5-bromo-2-(N-cyclobutylamino)-3-hydroxypyrazine (EX-115C) (5.0477 g, 20.68 mmol) in 50.0 mL tetrahydrofuran (0.41 M) dropwise via an addition funnel. The resulting suspension was heated to reflux for 30 minutes. To the mixture was then added a solution of tert-butyl bromoacetate (3.40 mL, 23.03 mmol) in tetrahydrofuran (2.3 M). Refluxing of the mixture was continued for 18 hours. The reaction mixture was allowed to cool to room temperature and cautiously poured in to a stirred ice water mixture (600.0 mL). The aqueous layer was extracted with ethyl acetate (4×250 mL). The combined organic solutions were washed with saturated NaHCO3 (1×250 mL) and brine (2×250 mL). The organic solution was dried (MgSO4), filtered, and concentrated. Purification of the crude product by MPLC (20% ethyl acetate/hexanes) afforded pure 6-Bromo-1-t-butoxycarbonylmethyl-3-(N-cyclobutylamino)pyrazinone (EX-115D) in 72% yield as an off white solid: 1H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.18 (br d, J=7.5 Hz, 1H), 4.79 (s, 2H), 4.39-4.29 (m, 1H), 2.41-2.34 (m, 2H), 1.96-1.86 (m, 2H), 1.79-1.68 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.8, 152.5, 149.0, 124.6, 105.1, 83.3, 49.7, 46.3, 31.3, 28.2, 15.6; HRMS (EI) calcd for C14H21N3O3 358.0766, found 358.0746.