Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].C(OO)(=[O:19])C>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C:8]1[CH:9]=[N+:10]([O-:19])[CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2cccnc2)c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CCOc1cccc(Oc2ccc[n+]([O-])c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 85 g of 3-(3-ethoxyphenoxy)pyridine in 500 ml of glacial acetic acid is treated with four 20 g portions of 40% peracetic acid in acetic acid. The mixture is stirred at 25° C. for 24 hours and is refluxed for 16 hours. The mixture is concentrated at reduced pressure, dissolved in 500 ml of dichloromethane and washed with excess 25% sodium hydroxide solution. The organic layer is dried, concentrated and distilled to yield 3-(3-ethoxyphenoxy)pyridine 1-oxide, bp 175°-177° C. at 0.4 mM.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17]>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1Br
Product: Cc1noc(NS(=O)(=O)c2ccccc2Br)c1Br
Yield: 31 %

Procedure:
2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-bromobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 84°-86° C., yield 31%.
Reaction SMILES: C(OC(C)(C)C)(=[O:4])NN.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](Cl)=[O:23])=[CH:19][CH:20]=2)[C:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:14]1)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:4])=[O:23])=[CH:19][CH:20]=2)[C:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:14]1)(=[O:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: c1ccncc1
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing tert-butyl carbazate (0.79 g, 0.006 mol) in pyridine (30 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (1.7 g, 0.005 mol). The reaction mixture was allowed to stir at ambient temperature for 18 hours. Solvent was removed and water was added to the mixture. The reaction was extracted with ethyl acetate. Some 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid was isolated. The reaction mixture was treated with an equivalent of tert-butyl carbazate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dichloromethane and allowed to stir overnight. The reaction was extracted with ethyl acetate. The product was taken up in a solution of 0.3% ammonia in methanol (˜50 mL) and allowed to stir overnight. The reaction mixture was extracted with dichloromethane, dried with magnesium sulfate, and concentrated. The material was purified by silica gel chromatography using 2% methanol in dichloromethane. The product was taken up in ethanol and gaseous hydrochloric acid was bubbled into solution. A solid precipitated out and was collected by filtration. This material was dried to provide the title compound (0.91 g, 56% yield). ES-MS (m/z) 271 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C@:13]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]([C:18](=[O:20])[CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:22]=3[F:28])[CH2:14]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li]CCCC.Cl[Si:41]([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C@:13]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]([C:18](=[O:20])[CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[C:25]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:24]=[CH:23][C:22]=3[F:28])[CH2:14]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)N1CCN(CCC[C@@]2(c3ccccc3)CC(c3cc(Br)ccc3F)=NN2C(C)=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(CCC[C@@]2(c3ccccc3)CC(c3cc([Si](C)(C)C)ccc3F)=NN2C(C)=O)CC1
Temperature: 25 °C

Procedure:
To a solution of 53 mg (0.100 mmol) 3-7 in 0.75 mL anhydrous THF at −78° C. under N2 was added 60 μL (0.150 mmol) 2.5 M n-BuLi in hexanes dropwise. Immediately following this addition, 51 μL (0.400 mmol) chlorotrimethylsilane was added, the cooling bath was removed, and the reaction warmed to room temperature. After 30 min the reaction was quenched with saturated aqueous NH4Cl solution and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water, brine, dried with Na2SO4 and concentrated. The residue was purified by reverse-phase preparatory HPLC with CH3CN/H2O (with 0.1% TFA). The fractions containing the desired product were poured into saturated aqueous NaHCO3 solution and extracted with EtOAc and concentrated to yield the freebase 3-8 as a clear, colorless oil.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:21][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccccc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a mixture of cyclohexyl(3-methyl-1-benzofuran-2-yl)methanol (843 mg) synthesized above and toluene (20 mL) was added thionyl chloride (256 μL), and the mixture was stirred at room temperature for 2.5 hr and at 50° C. for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (862 mg, 95%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[N:4]=1.[CH3:18][O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1>>[CH3:18][O:19][CH2:20][CH2:21][C@@H:22]1[NH:23][CH2:24][CH2:25][N:17]([C:6]2[C:5]3[N:4]=[C:3]([CH3:2])[S:12][C:11]=3[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH2:27]1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)nc32)CCN1

Procedure:
In a manner such as that described in Example 300, combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.437 g, 1.64 mmol) and (S)-2-(2-methoxyethyl)piperazine (0.474 g, 3.29 mmol) to obtain the title compound: mass spectrum (APCI): m/z=358.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:24]([CH3:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CNc1cccc(C)c1
Product: Cc1cccc(N(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-methylphenyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-N-(3-methylphenyl)amine using method M. NMR; δH [2H6]—DMSO 7.85,(1H, dd), 7.64,(1H, d), 7.49,(1H, d), 7.34,(2H, d), 7.25,(2H, d), 7.15,(1H, t), 7.04,(1H, s), 7.00-6.94,(2H, m), 3.38,(3H, s), 2.55,(3H, s), 2.20,(3H, s), 2.19,(3H, s). LCMS; retention time 3.50 min, MH+ 398.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:15])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C(N(C(C)C)C(C)C)C.[O:29]=[C:30]1[NH:35][C:34]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][S:40]([C:37]3[CH:38]=[CH:39][C:33]4[O:32][CH2:31][C:30](=[O:29])[NH:35][C:34]=4[CH:36]=3)(=[O:42])=[O:41])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1COc2ccc(S(=O)(=O)Nc3cc(-c4cc5ccccc5s4)c4[nH]ncc4c3)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a mixture of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 32 mg, 0.12) and ethyl-diisopropylamine (0.032 mL, 0.18 mmol) in DMF (1 mL) at room temperature and under an inert atmosphere was added 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl chloride (33 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated under reduced pressure. The crude material was purified by preparative HPLC (20% to 80% acetonitrile/0.05 M aqueous ammonium acetate, buffered to pH 4.5 over 30 min at 20 mL/min; Hyperprep C18, 300 Å, 8 μm, 250×21.1 mm column) to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amide as a white solid (34 mg, 58%). LC/MS (Table 1, Method e) Rt 1.75 min; ESI−MS [M+H]+=475.3.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH2:36]Cl)=[N:34][N:35]=[C:31]3[CH2:30][N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[C:27]=2[CH:45]=1)([O-:22])=[O:21]>CC(N(C)C)=O>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH2:36][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:34][N:35]=[C:31]3[CH2:30][N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[C:27]=2[CH:45]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-nitro-6-(o-chlorophenyl)- 1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-nitro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]([C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:12][CH:13]=O)=[O:2].[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>CCO>[OH:2][CH:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:9]([O-:11])=[O:10])[N:12]=[CH:13][N:20]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=CNc1cccc([N+](=O)[O-])c1C=O
Reactant: CCCCCN
Solvent: CCO
Product: CCCCCN1C=Nc2cccc([N+](=O)[O-])c2C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
N-(2-Formyl-3-nitrophenyl)formamide (5a, 20.0 g, 103 mmol) and n-pentylamine (23.9 ml, 206 mmol) were dissolved in EtOH (240 ml) and the mixture stirred at room temperature for 3 h. After the mixture was concentrated under reduced pressure, EtOAc (100 ml) was added to the residue, and the generating yellow crystal was collected by filtration. The crystal was washed with EtOAc and dried under vacuum to obtain 4-hydroxy-5-nitro-3-pentyl-3,4-dihydroquinazoline (6a, 19.6 g, 72%); 1H NMR (270 MHz) δ (CDCl3) 0.91 (t, J=6.7 Hz, 3H), 1.26-1.38 (m, 4H), 1.67-1.78 (m, 2H), 3.21 (dt, J=13.9 and 7.9 Hz, 1H), 3.77 (ddd, J=6.3, 7.6 and 13.9 Hz, 1H), 6.57 (s, 1H), 6.90 (s, 1H), 7.30-7.41 (m, 2H), 7.80 (dd, J=1.7 and 7.6 hz, 1H); MS (ES) m/z 264 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:13][CH:14]=[CH:15][C:8]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: Cc1ccc(C(=O)CC#N)cc1
Reactant: OC1CSC(O)CS1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)c2ccsc2N)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 130.2 %

Procedure:
To a suspension of 4-methylbenzoylacetonitrile (0.325 g; 2.042 mmol) and p-dithiane-2,5-diol (0.155 g; 1.018 mmol) in ethanol (4.3 mL) cooled at 0° C. was added triethylamine (0.283 mL; 2.042 mmol). After 10 min at room temperature, the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10-25%) in heptane to afford the title compound (0.288 g; 65%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H][H]>CCO.[Pd].[C]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][NH:11][C:10]=2[N:9]=1
Reactant: [H][H]
Reactant: COC(=O)CCCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 1-4 (630 mg, 2.58 mmol) and 10% Pd/carbon (95 mg) in EtOH (25 mL) was stirred under a balloon of hydrogen for 72 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70% ethyl acetate/hexanes) to give 1-5 as a colorless oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:12]=[N+:13]=[N-:14])(=[O:3])[CH3:2].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:12]=[N+:13]=[N-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](O)CCC[C@@H]1N=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])CCC[C@@H]1O
Temperature: 50 °C
Yield: 64 %

Procedure:
To a solution of 4 (416 mg, 2.09 mmol) and pyridine (506 μL, 6.27 mmol) in CH2Cl2 (10 mL), Tf2O (421 μL, 2.51 mmol) was dropwise added at −10° C. The mixture was left to react for 10 min when it was diluted (CH2Cl2), washed (HCl(aq) 5%, NaHCO3(aq) sat, brine), dried (MgSO4), filtered and concentrated. The crude was then dissolved in DMF (20 mL). Bu4NNO2 (1810 mg, 6.27 mmol) was added and the mixture was heated to 50° C. After 1 h the mixture was cooled to room temperature. and concentrated. Purification was made by flash chromatography using EtOAc:n-heptan (1:1) as eluent. The reaction yielded 64% of 8. 1H-NMR (CDCl3) 4.79 (dd, J=4.78, 9.75 Hz, 1 H), 4.17 (m, 1 H), 3.83 (ddd, J=4.58, 9.84, 11.29 Hz, 1 H), 2.18 (s, 3 H), 2.00-2.10 (m, 1 H), 1.85-1.95 (m, 1 H), 1.70-1.80 (m, 1 H), 1.50-1.65 (m, 2 H), 1.30-1.45 (m, 1 H)
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[N+:2]=[N-:3].[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33]>C1COCC1>[CH2:30]([NH:34][C:35]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][C@H:5]1[CH2:4][N:1]=[N+:2]=[N-:3])=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
280 mg (0.7 mmol) (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine were treated with 87 μM (0.77 mol, 1.1 eq) butyl isocyanate in 5 ml THF at 0° C., and the solution was stirred at RT for 45 min. The solvent was evaporated, and the residue was purified by flash chromatography yielding 278 mg (80%) (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butylamide as white foam.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.Cl.N>CO.O>[NH2:6][C:5]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[N:20]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Cc1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.40 g (21 mmol) of 4-methylphenylhydrazine hydrochloride with a purity of 98% by weight, 1.4 ml of water, 10 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 15 ml of water and 5 ml of methanol were added to the mixture to cool the same up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 15 ml of cold water and dried under reduced pressure to obtain 3.26 g of 5-amino-1-(4-methylphenyl)-4-nitrosopyrazole (Isolation yield: 67.3%) as a yellowish solid with a purity of 83.5% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24]([O:30][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]5([CH:38]=[O:39])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:41].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24]([O:30][Si:31]([CH2:36][CH3:37])([CH2:32][CH3:33])[CH2:34][CH3:35])([C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]5([C:38]([OH:41])=[O:39])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C=O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
t-Butanol (20 mL) and water (4 mL) were added to rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carb aldehyde (40, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.360 g, 0.642 mmol). After cooling to about 0° C., sodium dihydrogenphosphate (0.770 g, 6.42 mmol), 2-methyl-but-2-ene (0.270 g, 3.85 mmol), and sodium chlorite (0.348 g, 3.85 mmol) were added sequentially. After about 30 min, the ice bath was removed and the reaction was allowed to warm to rt. After about 3 h, a 1:1 solution of sat. aq. Na2SO3 and sat. aq. NaCl (50 mL) was added. Water (30 mL) was added. The mixture was extracted with EtOAc (3×50 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-20% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxylic acid (43, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.267 g, 72% yield); LC/MS, method 4, Rt=2.39 min.; MS m/z: 577 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 8.26 (d, J=0.7 Hz, 1H), 7.90 (s, 1H), 7.82-7.75 (m, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 2H), 2.95-2.71 (m, 2H), 2.60-2.48 (m, 1H), 2.42-2.15 (m, 4H), 2.03-1.78 (m, 3H), 1.73-1.52 (m, 2H), 1.34-1.20 (m, 1H), 0.99-0.90 (m, 9H), 0.69-0.59 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][C@H:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[NH2:19])[CH2:11][C@@H:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@H]2C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 30.6 %

Procedure:
A solution of 4.12 g (14.8 mmol) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluoro-phenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 2.48 g (22.2 mmol) of 4-fluorophenol and 4.65 g (17.7 mmol) of triphenylphosphine in 225 mL of THF was treated with 2.79 mL (17.7 mmol) of diethyl azodicarboxylate and stirred at room temperature for 4 days. The solvent was evaporated, the residue dissolved in 1:1 ethyl acetate:ethyl ether and the solution treated with HCl(g) in ether until precipitation ceased. The mixture was filtered and the solid washed repeatedly with ethyl acetate. The solid was dissolved in a mixture of chloroform and 1M sodium hydroxide, the layers separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 60:40 ethyl acetate:hexane gave 1.69 g (30%) of the title compound. mp (.HCl) 144–149° C. HRMS calcd for C21H25F2N3O: 373.1966, found: 373.1958.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[Cl:20][C:21]1[C:25]([CH2:26][CH3:27])=[N:24][N:23]([CH3:28])[C:22]=1[C:29](O)=[O:30].C(=O)([O-])O.[Na+]>O>[Cl:20][C:21]1[C:25]([CH2:26][CH3:27])=[N:24][N:23]([CH3:28])[C:22]=1[C:29]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:30]
Reactant: CCc1nn(C)c(C(=O)O)c1Cl
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(C)c(C(=O)OCCCCC(C)=C(F)F)c1Cl
Temperature: 100 °C
Reaction time: 7 h
Yield: 73.7 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.45 g (2.4 mmol) of 4-chloro-5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 7 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.52 g (yield: 74%) of 6,6-difluoro-5-methyl-5-hexenyl 4-chloro-5-ethyl-2-methyl-2H-pyrazole-3-carboxylate.