Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]C)=O)[CH:10]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>O>[CH2:1]([N:8]1[CH2:9][C@H:10]2[C@H:11]([C:14](=[O:16])[C:23]3[C:18]2=[CH:19][C:20]([Br:25])=[CH:21][C:22]=3[CH3:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCN(Cc2ccccc2)CC1c1cc(C)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(Br)cc2c1C(=O)[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Temperature: 180 °C
Yield: 6.9 %

Procedure:
A mixture of methyl 1-benzyl-3-(3-bromo-5-methyl-phenyl)piperidine-4-carboxylate (12.2 g, 30.3 mmol) from step B and polyphosphoric acid (124 g) was heated at 180° C. for 3 h then cooled to 0.20° C. To the reaction mixture H2O and saturated NH4Cl aqueous solution were added, successively then extracted with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to obtain the title compound (760 mg, 2.1 mmol): MS (ES) 370.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19]COC4C=CC=CC=4)[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1.BrC[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37]C)=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:32]4[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=4)[C:35]([OH:37])=[O:36])[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCOc3ccccc3)C2=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (500 mg, 1.8 mmol) (example 10-5), methyl 3-(bromomethyl)benzoate (456 mg, 2 mmol), and cesium carbonate (650 mg, 2 mmol) were stirred in DMF (4 mL) in the microwave reactor at 85° C. for 20 minutes. The reaction was cooled, diluted with 1N aqueous HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude ester was dissolved in methanol (5 mL) and aqueous NaOH (50 mL, 10% by wt) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction was acidified with 1N HCl (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The free acid was triturated with ethyl acetate/hexanes (1/9) and dried under vacuum to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (610 mg, 83%) as a white solid. 1H NMR (DMSO-d6, 400 2.13 (s, 3H), 2.29 (s, 3H), 4.00 (s, 2H), 4.59 (s, 2H), 5.18 (s, 2H), MHz): δ 7.46-7.59 (m, 2H), 7.78 (s, 1H), 7.85-7.88 (m, 2H), 8.18 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.8 μM.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][OH:14].[H-].[Na+].Br[CH2:18][CH2:19][OH:20].C[O-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:18][CH2:19][OH:20]
Reactant: OCCBr
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
4.49 g (0.0234 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime (VIII-1) are dissolved in 25 ml of dimethylformamide. 1 g (0.025 mol) of 60% strength sodium hydride is added to this solution which is then stirred at room temperature for one hour. 3.1 g (0.0248 mol) of 2-bromoethanol are added and the mixture is stirred at 25° C. for 12 hours. After the addition of 0.5 g of sodium methoxide and 1.22 g of 2-bromoethanol, the mixture is stirred at room temperature for 2 hours. A further 0.5 g of sodium methoxide and 1.22 g of 2-bromoethanol are added and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate and the organic phase is washed 3 times with 20 ml of 2 N aqueous sodium hydroxide solution. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using diethyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 2.26 g (39.6% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) (II-1) which, according to HPLC, comprises 84.29% of stereoisomer A and 12.58% of stereoisomer B.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].CO>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH2:1])=[C:3]([Cl:11])[CH:4]=1
Reactant: Cc1cc(C#N)cc(Cl)c1N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN)cc(Cl)c1N
Reaction time: 3 h
Yield: 3.8 %

Procedure:
4-Amino-3-chloro-5-methyl-benzonitrile (499.4 mg, 3.00 mmol) and Borane-THF complex (4 eq, 12.04 mmol, 12.04 ml) were added in THF. The reaction mixture was stirred for 3 hrs in reflux. After confirming the completion of the reaction, MeOH was added slowly added in the mixture. MeOH was removed in vacuo. The residue was extracted with ethyl acetate. A combined organic layer was washed with H2O and brine, dried with Na2SO4, concentrated in vacuo to yield 4-Aminomethyl-2-chloro-6-methyl-phenylamine (19.4 mg), as a yellow syrup.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[ClH:17]>C(OCC)(=O)C.CCOCC>[NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[ClH:17]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of ethyl acetate under heating. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. After one hour of standing the mixture is diluted with ether, the separated precipitate is triturated and then filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]=[C:15]=[O:16].O>CS(C)=O>[CH3:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CN=C=O
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1csc(NC(=O)NC)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (27.4 g.) in dimethylsulfoxide (135 ml.) was dropwise added methylisocyanate (13.05 g.) with stirring at room temperature, and the mixture was stirred for 3 hours at 40° C. After the reaction, the reaction mixture was poured into water (500 ml.), and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn and then dried over magnesium sulfate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and then dried to give colorless crystals of ethyl 2-(3-methylureido)thiazol-4-ylacetate (25.7 g.), mp 158° to 159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.CCOC(C)=O>[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCCCN1CCCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCCCN1CCCC1)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-chloro-pyridine-2-carbonyl chloride (8.88 g, 49 mmol) in THF (100 mL) was added at 0° C. 4-pyrrolidin-1-yl-butylamine (7.0 g, 49 mmol). The reaction was stirred for 18 h at RT. The mixture was diluted with EtOAc, washed several time with aqueous 6 N NaOH and then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using a gradient CH2Cl2/MeOH/NH4OH (100%, 0%, 0% to 90%, 10%, 1%). The pure fractions were combined and the solvents removed under vacuum. The title compound was obtained.
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])([CH2:8][CH2:9][CH:10]=[O:11])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].CC([O-])=O.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH2:12]([C:3]([CH2:1][CH3:2])([CH2:8][CH2:9][CH2:10][OH:11])[C:4]([O:6][CH3:7])=[O:5])[CH3:13]
Reactant: CCC(CC)(CCC=O)C(=O)OC
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)(CCCO)C(=O)OC
Reaction time: 0.5 h

Procedure:
Preparation of methyl 2,2-diethyl-5-oxopentanoate 5 To a well stirred mixture of the hydroxyester (1.88 g, 10 mmol), NaOAc (0.82 g, 10 mmol), and celite (1.88 g) in dry CH2Cl2 (50 mL), was added pyridinium chlorochromate (3.24 g, 15 mmol) at 0° C. in a nitrogen atmosphere. After 30 min at 0° C., the dark reaction mixture was stirred at room temperature for 2.5 h, and 100 mL of ether was added to it. Then it was filtered through a plug of silica gel and the solvent removed in vacuo to give 2.00 g of colorless viscous liquid. Column chromatography over silica gel (hexanes-EtOAc, 9:1) afforded the aldehyde (1.45 g, 78%) as a colorless liquid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:30])[CH2:13][CH2:12]1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[ClH:43]>CN(C)C=O.C(O)C>[ClH:43].[ClH:43].[CH2:41]([O:40][C:38]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[N:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH3:3])[CH2:16][CH2:15]2)[C:20]1=[O:30])=[O:39])[CH3:42]
Reactant: CCOC(=O)CCCCCCBr
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2ccccc21
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 60% sodium hydride (0.44 g) in dimethylformamide (50 ml), was added 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione (3.80 g) in a small portion under a nitrogen stream, and the mixture was stirred at room temperature for 30 minutes and at 50° C. for 10 minutes. After cooling to room temperature, a solution of ethyl 7-bromoheptanoate (2.37 g) in dimethylformamide (20 ml) was added to the mixture and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under vacuum and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and dried with sodium sulfate. When the solvent was distilled off under vacuum, an oily substance was obtained and upon column chromatography on silica gel (eluted with a chloroformethanol 25:1 mixture), a pale yellow oil of 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H, 3H)quinazolinedione (3.62 g) was obtained. The oil was dissolved in ethanol (50 ml) and hydrogen chloride gas was introduced into the solution for about 5 minutes. After distilling off the solvent, the crystalline residue was recrystallized from a mixture of ethanol and n-hexane to give colorless needles of 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride (3.45 g) having a m.p. of 109°-111° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:32].[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:30])([CH3:31])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[C:6]([F:32])[CH:7]=4)[CH:22]=[C:21]([O:23][CH3:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-2-fluoro-phenyl}-acetic acid methyl ester (Intermediate 83, 0.12 g, 0.27 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was treated with a 2 M solution of lithium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-8% methanol in ethyl acetate as the eluent to afford the title product as a white amorphous solid (0.041 g, 35%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: Nc1ccccc1
Solvent: CO
Product: N#CNC(=Nc1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.3 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), aniline (0.32 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.63 g, 2.8 mmol, yield: 91%) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:12][N:13]([CH3:18])[S:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)N(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 8.5 g of methyl 4-aminobenzoate 13 and 43 ml of pyridine is added 12.1 g of dimethylsulfamoyl chloride, and the mixture is stirred at 50° C. for 2 hours. The reaction mixture to which is added ice-water is acidified with 6N hydrochloric acid and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is washed with ether-isopropyl ether to give 9.5 g (yield: 65.4%) of methyl 4-(dimethylaminosulfonyl)aminobenzoate 14.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:19].N#N.[OH-].[K+]>O1CCOCC1.C(Cl)Cl.CO>[ClH:19].[CH3:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC1CCCN1C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N#N
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1CCCN1C1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (5.50 g, 21.62 mmol) was treated with 20 mL of 4 M HCl in dioxane at 0° C. The solution was stirred under nitrogen at r.t. overnight. TLC (10% MeOH in DCM) did not detect the starting material. N2 was passed through the solution with stirring. The outlet was passed through KOH solution to absorb HCl for 30 min. The solvent was removed by evaporation to dryness to get the title compound as a hygroscopic gummy material, 5.3 g (˜100%). This material was used without further purification in subsequent steps as illustrated below. LCMS: RT=0.35 minutes, MS: 155 (M+H).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.C1CC[N:19]2[C:14](=[N:15]CCC2)CC1.N#CN.C(O)(=O)C.CS(O)(=O)=O.C([O-])(=O)C.[Na+]>C(#N)C.O>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:15][C:14]([NH2:19])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [O-][n+]1onc2ccccc21
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: N#CN
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 20 °C
Reaction time: 67 h
Yield: 37 %

Procedure:
To a stirred mixture containing 9.5 kg (69.8 moles) of benzofuroxan and 21.3 kg (139.9 moles) of DBU was added a solution containing 5.8 kg (138.0 moles) of cyanamide in 2.7 kg of acetonitrile while maintaining the temperature at 15-25° C. After stirring for 67 hours at 20-25° C. the reaction mixture was diluted with 48 kg of acetonitrile and cooled to 0-10° C. To the cooled mixture was added 8.5 kg (141.5 moles) of acetic acid while maintaining the temperature at 5-15° C. After stirring for 46 hours at 5-10° C., the precipitated product was collected by filtration and washed with acetonitrile (2×15 kg). The resulting solid was suspended in 20 kg of water, stirred for 40 minutes, filtered and the filter cake washed with 10 kg of water. The collected solid was resuspended in 20 kg of water, stirred for 45 minutes, filtered and the filter cake washed with 10 kg of water. The solid collected was suspended in 29 kg of water and to the suspension was added 8.7 kg (90.5 moles) of methanesulfonic acid. The mixture was stirred at 40-50° C. until dissolution was complete. The resulting solution was added to a solution containing 9.2 kg (112.2 moles) of sodium acetate in 49 kg of water and stirred at 10-25° C. for 1.5 hours. The precipitated product was collected by filtration and washed with 10 kg of water. The collected product was suspended in 20 kg of water, stirred for 55 minutes, filtered and the filter cake washed with 10 kg of water. The solid collected was resuspended in 20 kg of water, stirred for 55 minutes, filtered and the filter cake washed with 10 kg of water. The product obtained was dried to constant weight at 50-55° C. to give 4.6 kg of tirapazamine.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]([OH:7])/[CH:4]=[CH:5]/[I:6].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]([CH3:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]([O:7][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:4]=[CH:5]/[I:6]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C)(C)C(O)/C=C/I
Product: CCCCC(C)(C)C(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 11.2 g. (0.396 mole) of 4,4-dimethyl-1-iodo-trans-1-octen-3-ol (Example 151) with 12.8 g. of triphenylmethyl bromide in 50 ml. of pyridine and purification on Florisil®, all as described in Example 127 gives the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][C:20](=[O:26])[NH:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CCO>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[NH:18][CH2:19][C:20](=[O:26])[NH:21]4)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=c1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CNc2c(cccc2Oc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)N1

Procedure:
The title compound was prepared analogous to the methods used in Example 33 using 5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one, (Example 34(b)), (0.25 g, 0.65 mmol) and sodium borohydride (0.11 mg, 2.8 mmol, Aldrich) in EtOH (5 mL). Purification by flash chromatography (0→1.5% 2M NH3/MeOH in CH2Cl2) gave the title compound as a light-yellow powder. Mp: 305° C., MS (ESI, pos. ion) m/z: 387 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][O:3]1.[C:8](=[S:10])=[S:9].N1C=CC=CC=1.C([O-])(=O)C.[Zn+2:21].C([O-])(=O)C>C(Cl)(Cl)Cl.C(O)C>[CH3:1][C:2]1([CH3:7])[N:6]([C:8]([S-:10])=[S:9])[CH2:5][CH2:4][O:3]1.[CH3:1][C:2]1([CH3:7])[N:6]([C:8]([S-:10])=[S:9])[CH2:5][CH2:4][O:3]1.[Zn+2:21]
Reactant: S=C=S
Reactant: CC1(C)NCCO1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)OCCN1C(=S)[S-]
Reaction time: 8 h

Procedure:
While cooling and stirring, 20 g. (0.20 mole) of 2,2-dimethyloxazolidine (preparation described by E. Bergmann et. al., J. Am. Chem. Soc. 75, 358 (1953)) was added to a solution of 15.2 g. (0.20 mole) carbon disulfide in 150 g. pyridine. To the stirring solution was added 18.3 g. (0.10 mole) of anhydrous zinc acetate at 25°-30°C. After standing overnight at room temperature, filtration gave 15.2 g. of the crude product; vacuum-concentration of the filtrate and ethanol-dilution of the residue gave an additional 10.4 g. After combining and vacuum-drying of the crude product at 100°C there was obtained 17.8 g. of the desired carbodithioate melting at 188°- 190°C (decomp.). A small sample, dissolved in hot chloroform and precipitated by hexane (m. 192°- 3°C decomp.) had the following analysis: Found: C, 34.22; H, 4.47; N, 6.84; Zn, 15.20%. Calcd for C12H20N2O2S 4 Zn: C, 34.50; H, 4.79; N, 6.71; Zn, 15.67%.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:13][C:14](=O)[CH:15]([CH3:19])[C:16](=O)[CH3:17])C>CCO.CC(O)=O>[OH:13][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:16]([CH3:17])[C:15]=1[CH3:19]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(-c2cc(C#N)ccn2)c(O)c1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (134 mg, 1 mmol, PREPARATION 2) and 2-methyl-3-oxo-butyric acid ethyl ester (158 mg, 1.1 mmol) in EtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (100 mg, 47%) as an orange solid. [M+H] Calc'd for C11H10N4O, 215; Found, 215.