Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH3:13][NH:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][NH:14][S:15]([N:3]([CH3:2])[O:4][CH3:5])(=[O:17])=[O:16]
Reactant: CNS(=O)(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)N(C)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
5.75 g (58.9 mmol) of N,O-dimethylhydroxylamine hydrochloride was suspended in 300 ml of dichloromethane, and 11.9 g (118 mmol) of triethylamine was added thereto. Then, the mixture was cooled with ice, and a dichloromethane solution of 7.63 g of methylsulfamoyl chloride was dropwise added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. To the residue, 200 ml of benzene was added, and insoluble substance was filtered off. Then, the solvent was distilled off again under reduced pressure. By the distillation under reduced pressure, 4.4 g of N,N'-dimethyl-N'-methoxysulfamide was obtained (boiling point: 85°-88° C./1.9 mmHg).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CCC1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: CCO
Product: OCC1CC(n2c(NC3CCC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (7 mL) and cyclobutylamine (0.41 mL, 4.8 mmol) was added. The solution was refluxed under nitrogen for 18 hours. Volatiles were evaporated and the residue stirred in methanol half-saturated with ammonia at 0° C. (20 mL) for 18 hours. Volatiles were removed in vacuo and the residue crystallized from ethanol-water to give title compound as white solid, m.p. 250° C. dec.; 1H-NMR(DMSO-d6)δ: 7.61 and 7.38 (both s, 1 each, aromatic CH), 7.07 (d, J=7.4 Hz, 1, NH), 5.15 (t, J=3.9 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.71-4.45 (m overlapping d at 4.71, J=3.5 Hz, total 2, OH and NCH), 4.40-4.30 (m, 2. OCH and NCH), 3.82-3.80 (m, 1, OCH), 3.72-3.42 (both m, 1 each, OCH2), 2.32-1.67 (three m, 9, 4CH2 and CH); mass spectrum (CI): 386(M +1).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[NH2:16].O.[NH2:27][NH2:28]>CCO>[NH2:2][C:1]1[NH:28][N:27]=[C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:13]([Cl:12])[CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: NN
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCO
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCOCC3)c(Cl)c2)n[nH]c1N
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 3-Chloro-4-morpholinoaniline (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((3-chloro-4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH2:1]([N:11]1[C:17]([CH3:19])([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH2:20]1[O:23][CH:21]1[CH3:22]>[Cl-].[Li+].CN(C)C=O>[CH2:1]([N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=[O:7])[N:5]([CH2:20][CH:21]([OH:23])[CH3:22])[C:3]1=[O:4])[N:11]1[C:17]([CH3:19])([CH3:18])[C:15](=[O:16])[N:14]([CH2:20][CH:21]([OH:23])[CH3:22])[C:12]1=[O:13]
Reactant: CC1CO1
Reactant: CC1(C)C(=O)NC(=O)N1CN1C(=O)NC(=O)C1(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)N(CN2C(=O)N(CC(C)O)C(=O)C2(C)C)C(C)(C)C1=O
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A mixture of 268.3 g of 1,1'-methylene-bis-(5,5-dimethylhydantoin) [1 mol], 600 ml of dimethylformamide and 2.11 g of lithium chloride is stirred at 60° C. 134.0 g of propene oxide (2.3 mols) are slowly added dropwise to this mixture over the course of 1 hour and 45 minutes. Thereafter the mixture is heated to 100° C. over the course of 1.5 hours and stirred at 100° C. for a further 2 hours. The hot reaction mixture is now filtered and cooled to room temperature, neutralized with 20% strength sulphuric acid and concentrated to dryness on a rotary evaporator. The crude product is recrystallised from ethanol. 327.0 g of pure 1,1'-methylene-bis-(3-β-hydroxy-n-propyl-5,5-dimethylhydantoin) [85.3% of theory] of melting point 131°-133° C. are obtained. Microanalysis shows 14.50% N (calculated, 14.58% N); analysis by gel permeation chromatography shows that the substance is of uniform molecular weight. The N--NMR (nuclear magnetic resonance) spectrum and the IR (infrared) spectrum can be reconciled with the following structure: ##STR9##
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH3:8][SiH:9]([Cl:11])[Cl:10].[CH2:12]([Cl:16])[C:13](=[CH2:15])[CH3:14]>>[CH3:8][Si:9]([CH2:14][CH:13]([CH2:12][Cl:16])[CH3:15])([Cl:11])[Cl:10].[Si:1]([CH2:14][CH:13]([CH2:12][Cl:16])[CH3:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C[SiH](Cl)Cl
Reactant: C=C(C)CCl
Reactant: CC[SiH](CC)CC
Product: CC(CCl)C[Si](C)(Cl)Cl
Product: CC[Si](CC)(CC)CC(C)CCl
Temperature: 50 °C
Yield: 20.9 %
Yield: 67.3 %

Procedure:
In a 100 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH, 11.5 g (0.1 mol) of MeSiHCl2, and 9.1 g (0.1 mol) of methallyl chloride. After heating to 50° C., the heat source was removed and 0.05 ml Pt catalyst solution added, causing an exothermic reaction to 83.5° C. in 4 min. The complete reaction was vacuum distilled, yielding 13.83 g (67.3%) of MeSiCl2CH2CHMeCH2Cl and 4.31 g (20.9%) of Et3SiCH2CHMeCH2Cl. This example shows that while MeSiHCl2 at the equimolar level promotes the reaction between Et3SiH and methallyl chloride, it also competes with Et3SiH, reducing the yield of Et3SiCH2CHMeCH2Cl.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[C:6]([O:8]CC)=O)C.[Cl:16][C:17]1[CH:22]=[C:21]([NH:23]N)[N:20]=[CH:19][N:18]=1.FC(F)(F)C(O)=O>C(O)C>[ClH:16].[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([N:23]2[C:6](=[O:8])[C:5]([N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][NH:2]2)[CH:22]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cl
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1

Procedure:
10.0 g (47.8 mmol) of the compound from Example 5A and 8.3 g (57.3 mmol) of the compound from Example 11A are initially charged in 100 ml of ethanol, and 1.5 ml (2.2 g, 19.0 mmol) of trifluoroacetic acid are added. The mixture is stirred under reflux for 12 h. The precipitated crystals are filtered off, the filter residue is washed with ethanol and the intermediate is dried under reduced pressure overnight. The intermediate is then suspended in 20 ml of methanol, 100 ml of a 4 M solution of hydrogen chloride in dioxane are added and the mixture is stirred at RT for 1 h. The solid is filtered off, the filter residue is washed with dioxane, ethyl acetate and diisopropyl ether and the product is dried under reduced pressure. Yield: 4.6 g (32% of theory)
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][SiH](C)C.C([Si:15]([CH3:18])([CH3:17])Cl)C.[CH2:19]1COC[CH2:20]1>II>[CH2:19]([C:3]1[C:4]([SiH:15]([CH3:18])[CH3:17])=[C:5]([OH:6])[CH:10]=[CH:11][CH:12]=1)[CH3:20]
Reactant: C1CCOC1
Reactant: CC[Si](C)(C)Cl
Reactant: C[SiH](C)Oc1cccc(Br)c1
Agent: II
Agent: [Mg]
Product: CCc1cccc(O)c1[SiH](C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
In a 100 mL flame-dried three-necked flask, fitted with refluxing condenser and dropping funnel, magnesium (92 mg, 3.82 mmol), iodine (1 mg) and dry THF (6 mL) were placed under nitrogen. A light brown solution formed, the mixture was heated to reflux, and a solution of 3-bromophenoxydimethylsilane (0.899 g, 3.47 mmol) in THF (20 mL) was added by dropping funnel over 2 hr. The reaction mixture was refluxed overnight and cooled to room temperature. Ethyldimethylchlorosilane (0.681 g, 0.78 mL, 5.55 mmol) was then added by syringe. The reaction mixture was brought to reflux again for 6 hr, and allowed to stir overnight at room temperature. The reaction was then quenched with 1N HCl, and the reaction concentrated in vacuo. Extraction with CH2Cl2, aqueous workup, and column chromatography (n-hexane/ethyl acetate 8:1) yielded 3-ethyldimethylsilyl phenol (0.130 g, 0.73 mmol, 21%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH3:22])([O-:21])=[O:20].C(O)(=O)C.C(N)CCC>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:22][N+:19]([O-:21])=[O:20])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCN
Product: COc1cc(C=C[N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
23.1 g (95.7 mmol) of 4-benzyloxy-3-methoxybenzaldehyde, 8.76 g (143 mmol) of nitromethane and 250 ml of acetic acid were mixed and 7.07 g (96.7 mmol) of butylamine was added dropwise thereto. The mixture was refluxed for 2 hours by heating, and then cooled and poured into ice-water. The precipitated crystals were dissolved with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 17.0 g of 1-benzyloxy-2-methoxy-4-(2-nitrovinyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](Cl)=[O:34])[CH2:28][CH2:27]1.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([NH:19][C:33](=[O:34])[CH2:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: O=C(Cl)CC1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC1CCOCC1)Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (147 mg), pyridine (62 μL), and dichloromethane (1 mL) was added a solution of the above crude tetrahydro-2H-pyran-4-ylacetyl chloride in dichloromethane (2 mL) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added ethyl acetate (50 mL), the organic layer was washed with a 10% aqueous citric acid solution, and then the solvent was evaporated under reduced pressure. The obtained residue was washed with warmed ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}-2-(tetrahydro-2H-pyran-4-yl)acetamide (176 mg) as a colorless powder.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[H-].[Na+].[CH3:15]I.O>C1COCC1.C(OCC)C>[C:1]([C:3]1([CH3:15])[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2]
Reactant: COc1ccc2c(c1)C(C#N)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)C(C)(C#N)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-cyano-5-methoxybenzocyclobutene (47.3 ml) in THF (300 ml) is added dropwise to a stirred suspension of NaH (23.8 g, 60% in mineral oil) and methyl iodide (37 ml) in THF (300 ml) under nitrogen and the reaction mixture is stirred at RT for three hours. H2O is added to the reaction mixture which is diluted with diethyl ether, washed with water, 10% aq. sodium sulphite, sat'd sodium chloride, dried, filtered and the filtrate evaporated in vacuo affording the desired product as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][PH+](C)C.[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]>COCCOC>[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[CH2:4])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Reactant: C[PH+](C)C
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Into a three-necked flask, 12.1 g of sodium hydride and 580 ml of 1,2-dimethoxyethane were placed, and 108.5 g of trimethylphosphonium bromide was added thereto with stirring at room temperature. Next, after a drop of absolute alcohol was added, the reaction was allowed to proceed at 70° C. for 4 hours. Then, 100.0 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]benzaldehyde was added to the reaction mixture, to carry out reaction at 70° C. for 5 hours, followed by filtration to collect a cake. The cake was extracted with ether and the extract was put together with the filtrate and washed with water. Then, the ether solution was dehydrated with calcium chloride, and thereafter the ether was removed to obtain a crude product. After twice recrystallized from ethanol, acicular 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was obtained in an amount of 84.5 g (yield: 85.0%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[C@H:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[C@H:29]([CH3:30])[CH2:28][N:27]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:26]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 97 %

Procedure:
In the presence of triethylamine, 59 g of benzoyl chloride was reacted at room temperature with 81.4 g of trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine in methylene chloride, whereby 120 g of trans-3-tert-butoxycarbonylamino-4-methyl-1-benzoylpyrrolidine (a) was obtained. Hydrochloric acid was then reacted at room temperature with 123 g of the compound (a) in ethanol, so that 83 g of trans-3-amino-4-methyl-1-benzoylpyrrolidine (b) was obtained. In methylene chloride, 68.4 g of (R)-(-)mandelic acid was then reacted at room temperature with 83 g of the compound (b) in the presence of 87.3 g o 1-hydroxybenzotriazole, 87.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 46.5 g of triethylamine. 34 g of trans-3-(2-(R)-2-phenyl-2-hydroxyacetylamino)-4-methyl-1-benzoylpyrrolidine diastereomer (A), (c) was obtained. Acetic acid and hydrochloric acid were then reacted with the compound (c) under reflux, whereby 16.8 g of (-)-trans-3-amino-4-methylpyrrolidine dihydrochloride was obtained as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCc1ccccc1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 28.9 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 1 g (0.01 mol) of benzylamine were refluxed with heating together with 200 ml of DMF for 5 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 4.8 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 1.2 g of the subject compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-])=O)[C:3]=1[NH2:4].O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:11])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(F)c(F)c(Br)c1N
Temperature: 25 °C

Procedure:
3-Bromo-4,5-difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25: 839 (1984)). A mixture of 2-bromo-3,4-difluoro-6-nitroaniline (700 mg, 2.78 mmol) and SnCl2.2H2O (3.14 g, 13.9 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75 ° C. for 2 h. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The thick yellow white emulsion was then extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown oil which crystallized on standing to yield 410 mg (66%). 1H NMR (CDCl3) δ 3.59 (br s, 4H, 2(NH2)); 6.52 (m, 1H, H-6).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([C@H:16]([CH3:20])[C:17](O)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.CN(C)CCCN=C=NCC.[C:33]([CH2:35][C@@H:36]1[CH2:44][C@@H:43]2[C@@H:39]([CH2:40][NH:41][CH2:42]2)[C@@:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[O:52][CH3:53])([OH:45])[CH2:37]1)#[N:34]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[C:33]([CH2:35][C@@H:36]1[CH2:44][C@@H:43]2[C@@H:39]([CH2:40][N:41]([C:17](=[O:18])[C@H:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:20])[CH2:42]2)[C@@:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[O:52][CH3:53])([OH:45])[CH2:37]1)#[N:34]
Reactant: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CNC[C@H]21
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CN(C(=O)[C@@H](C)c3ccccc3)C[C@H]21
Temperature: 20 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
0.87 cm3 of diisopropylethylamine, 0.75 g of (S)-2-phenylpropionic acid, 0.02 g of hydroxybenzotriazole hydrate and 1.05 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to a solution of 1.43 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol in 20 cm3 of dichloromethane. The reaction mixture is stirred at 20° C. for 20 hours and then washed twice with 30 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 32 cm, diameter 2.8 cm), eluting under a pressure of 0.6 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 25 cm3. Fractions 19 to 35 are concentrated to dryness under reduced pressure (2.7 kPa). 1.20 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-[(S)-2-phenylpropionyl]perhydroisoindol-4-ol in the form of a thick white foam are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=3)[N:10]=2)[N:7]=1.CC(O)=O>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[C:13]([CH:12]=3)[NH2:19])[N:10]=2)[N:7]=1
Reactant: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Iron powder (4.61 g, 0.0825 mol) is added to a mixture of 6-chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (5.0 g, 0.0165 mol) in EtOH—H2O (150 mL, 4:1)containing AcOH (5.66 mL, 0.099 mol) at 80° C. The mixture is stirred at 80° C. for 4 hrs. The reaction mixture is cooled to room temp, filtered through celite, washed with EtOAc and concentrated. The oily residue is dissolved in EtOAc (200 mL) and washed twice with 100 mL Sat. NaHCO3. Compound is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound (4.02 g, 89%). LCMS m/z=273.3, 275.3 [M+H]+, tR=1.93 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][NH2:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:22]=2[C:23]([F:26])([F:25])[F:24])[O:11][N:10]=1.[CH:34](OC)(OC)OC>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[O:15][CH:34]=[N:17][N:16]=2)=[C:12]([C:18]2[CH:19]=[N:20][N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:22]=2[C:23]([F:25])([F:26])[F:24])[O:11][N:10]=1
Reactant: NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Reactant: COC(OC)OC
Product: Fc1ccccc1-n1ncc(-c2onc(-c3c(F)cccc3Cl)c2-c2nnco2)c1C(F)(F)F
Yield: 46.4 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (0.076 g, 0.157 mmol) in 4 g trimethyl orthoformate was kept in a sealed tube at 125° C. for 3 days. The solution was evaporated to dryness and the residue was crystallized from heptane to give 36 mg (46%) of a yellowish solid of example 15. Result of LC/MS MH+: 493.75; 1H NMR (methanol-d4; 400 MHz) δ ppm: 7.30-7.35 (1H, m, CH-arom.), 7.42-7.48 (3H, m, CH-arom.), 7.60-7.70 (3H, m, CH-arom.), 8.51 (1H, s, CH-oxadiazole), 8.93 (1H, s, CH-pyraz.)