Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:20]([C:19]3[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:18]=3[F:17])=[O:21])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1c(-c2ccc(N)cc2)csc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(NC(=O)c3cc(C(F)(F)F)ccc3F)cc2)csc1N
Temperature: 25 °C

Procedure:
Crude 2-amino-4-(4-amino-phenyl)-thiophene-3-carboxylic acid amide (0.15 mmoles, 1 eq) is dissolved in 1 mL DMF and added to a solution of 2-fluoro-5-trifluoromethylbenzoic acid (0.20 mmoles, 1.3 equiv) and HBTU (0.20 mmoles, 1.3 equiv) in 1 mL DMF. To this solution is added 0.5 mL triethylamine. The solution is stirred at room temperature until the reaction is complete, as judged by TLC. The crude reaction mixture is purified by preparative HPLC, affording the desired 2-amino-4-{4-[(1-[2-fluoro-5-trifluoromethyl-phenyl]-methanoyl)-amino]-phenyl}-thiophene-3-carboxylic acid amide. Biological Data
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[NH3:24]>O1CCOCC1.CO>[NH2:24][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C(=O)c3ccccc3OC)cc2c1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(N)c(C(=O)c3ccccc3OC)cc2c1

Procedure:
(2-Chloro-6-methoxyquinolin-3-yl)(2-methoxyphenyl)methanone (3.4 g, 10.4 mmol) was dissolved in dioxane (25 mL), mixed with 25% aqueous ammonia solution (15 mL) and heated for 30 hours to 150° C. under intrinsic pressure in the pressurized reactor. After cooling, the reaction mixture was diluted with methanol, prepurified with activated carbon and concentrated after filtration. The crude product was dissolved in dichloromethane and washed with water. The dichloromethane solution was dried (sodium sulfate) and concentrated. The crude product was purified chromatographically (silica gel, dichloromethane, 0-2% methanol). Yield: 1.4 g (4.5 mmol, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1.CCN(CC)CC.[C:21](Cl)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([Br:1])[CH:13]=[N:12][C:5]=2[NH:6][C:7](=[O:11])[CH2:8]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CNCc2cc(Br)cnc2N1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)OCc2ccccc2)Cc2cc(Br)cnc2N1
Reaction time: 8 h
Yield: 31 %

Procedure:
A suspension of 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (1.08 g, 4.46 mmol) in CH2Cl2 (60 mL) was treated with Et3N (0.80 mL, 5.7 mmol) and then cooled in an ice bath. The chilled suspension was treated dropwise with CbzCl (4.5 mmol) to give a clear solution. The ice bath was removed and the solution was allowed to stir overnight. The mixture was diluted with CH2Cl2 (90 mL), washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99.5:0.5 to 99:1) gave the title compound (0.52 g, 31%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.31-8.36 (m, 2H), 7.49-7.71 (m, 1H), 7.34-7.40 (m, 4H), 7.19-7.21 (m, 1H), 5.08-5.12 (m, 2H), 4.43-4.65 (m, 4H); MS (ESI) m/e 376 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH3:4].[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:1][CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH:3]2[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C=CC(C)N(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2C(CCN2Cc2ccccc2)C1C

Procedure:
11.6 g (62.6 mmol) of ethyl N-(1-buten-3-yl)-N -(2-oxoethyl)-carbamate and 10.4 g (62.6 mmol) of N -benzylglycine in 170 ml of toluene are heated under reflux overnight in a water separator. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(CCN1CCCC1)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(CCN3CCCC3)n2c1
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Intermediate 1a (400 mg) was dissolved in THF (20 mL) and cooled in an ice/water bath. Triphenylphosphine (643 mg, 2.45 mmol) was added followed by triethylamine (682 μL, 4.90 mmol) and hexachloroethane (581 mg, 2.45 mmol). The reaction mixture was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH then eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (292 mg, 1.16 mmol, 52%). 1H NMR (400 MHz, CDCl3): 1.80-1.87 (4H, m), 2.60-2.68 (4H, m), 3.00-3.10 (2H, t, J 7.3), 3.24-3.34 (2H, t, J 7.3), 7.13-7.21 (1H, ddd, J 9.9, 7.6, 2.3), 7.70-7.77 (1H, dd, J 9.8, 4.5), 8.00-8.04 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=O)[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.[O:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]([C:16]([NH:28][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:18])[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: NOc1ccccc1
Reactant: O=C(O)c1cc2c(cn1)ncn2Cc1ccc(F)cc1
Product: O=C(NOc1ccccc1)c1cc2c(cn1)ncn2Cc1ccc(F)cc1

Procedure:
The title compound can be prepared from 1-(4-fluoro-benzyl)-1H— imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine under the same conditions as those in step (c) of Example 1.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[CH3:18]O>>[CH3:18][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([Br:6])[CH:8]=1
Reactant: CO
Reactant: O=C(O)C=Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1cccc(Br)c1
Temperature: 25 °C

Procedure:
Add concentrated sulfuric acid (5.0 mL, 90 mmol) to a solution of 3-bromocinnamic acid (25.0 g, 110 mmol) in MeOH (250 mL). Heat the mixture to reflux for 5 h then cool to room temperature and concentrate under reduced pressure. Dilute the residue with water and extract with EtOAc. Concentrate the combined organic phase under reduced pressure and purify the residue by silica gel chromatography to provide 26 g of trans-3-(3-bromo-phenyl)-acrylic acid methyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC[C@H](O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@H]1CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-((S)-3-hydroxypyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (390 mg, 1.61 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (244 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.40-4.33 (m, 1H); 3.70-3.60 (m, 4H); 3.44-3.34 (m, 1H); 2.88-2.77 (m, 1H); 2.73-2.52 (m, 3H); 2.47 (dd, J=10.1, 5.2 Hz, 1H); 2.30-2.12 (m, 2H); 1.84-1.69 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].OO.O.S([O-])(O)=[O:18].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(B(O)O)cc1F
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g of the crude 3-fluoro-4-ethoxyphenyl boronic acid obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 23.6 g (208 mmol) of aqueous 30% hydrogen peroxide was added while being kept at about 35° C. in a warm bath. After addition and after stirring the reaction solution at a room temperature for 24 hours, the reaction solution was poured into 300 ml of water, then sodium hydrogen sulfite was added and stirred at a room temperature for one hour. The reaction solution was extracted with 300 ml of ethyl acetate and the extracted layer was washed with water and then with an aqueous saturated sodium chloride solution successively and, after dying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The concentrated residue was purified by silica gel column chromatography using a ethyl acetate/heptane mixed solvent as an eluent to obtain 17.6 g (113 mmol) of 3-fluoro-4-ethoxyphenol.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)[CH:2]=[CH2:3].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=3)[C:11]2=[O:15])=[CH:21][CH:22]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: C=CCOc1ccc2c(c1)CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O

Procedure:
To a solution of 6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (10.6 g, 52 mmol) and 1-bromo-3-(4-fluorophenyl)-propane (17 g, 78 mmol) and KI (430 mg, 2.6 mmol) in dimethyl formamide (DMF) (125 mL) is added NaH (3.1 g, 78 mmol). After 4 hours the reaction mixture is poured into H2O (500 mL) and the resulting suspension is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with H2O (5×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield 2-[3-(4-fluorophenyl)-propyl]-6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[CH2:5][C:6]1[CH:7]3[O:19][CH:10]([C:11]=1[CH2:12]2)[C:9](=[CH2:20])[C:8]3=[CH2:21].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[CH:5]=[C:6]1[C:11](=[CH:12]2)[CH:10]2[O:19][CH:7]1[C:8](=[CH2:21])[C:9]2=[CH2:20]
Reactant: C=C1C(=C)C2OC1C1=C2Cc2c(OC)ccc(OC)c2C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: C=C1C(=C)C2OC1c1cc3c(OC)ccc(OC)c3cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 2 g (7.1 mmol) of 1,2,3,4,9,10-hexahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene, 1.77 g (7.8 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 30 ml of benzene was stirred at room temperature under nitrogen for 30 minutes. The precipitate formed was filtered off and washed with benzene, the benzene solution was washed with two 30 ml portions of saturated aqueous sodium hydrogen sulphite solution and two 30 ml portions of water, dried over sodium sulphate and concentrated to dryness. By recrystallisation from diethyl ether/tetrahydrofuran/methylene chloride (4:1:2) there were obtained 1.95 g (98%) of 1,2,3,4-tetrahydro-5,8-dimethoxy-2,3-dimethylene-1,4-epoxyanthracene of melting point 205°-206° C. in the form of white crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([Cl:31])[CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([C:29]6[N:34]=[N:35][NH:36][N:30]=6)=[C:25]([Cl:31])[CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C#N)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(-c2nn[nH]n2)c(Cl)c1
Temperature: 110 °C
Yield: 9 %

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)-cyclopropanecarboxamide was added ammonium chloride (0.13 g, 2.4 mmol), sodium azide (0.156 g, 2.40 mmol) and 1 mL of DMF. The mixture was heated at 110° C. in a microwave reactor for 10 minutes. After cooling, the mixture was filtered and purified by preparative HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide (8.6 mg, 9%). ESI-MS m/z calc. 473.1, found 474.3 (M+1)+; retention time 1.86 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ncc(Br)cc2N)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a stirred mixture of 5-bromo-2-(4-methoxyphenyl)-3-nitropyridine (0.19 g, 0.60 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (0.67 g, 3.00 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 20 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The light yellow solid was identified as 5-bromo-2-(4-methoxyphenyl)pyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (1H, d, J=2.0 Hz), 7.57 (2H, d, J=8.8 Hz), 7.35 (1H, d, J=2.0 Hz), 7.01 (2H, d, J=8.8 Hz), 5.36 (2H, s), 3.80 (3H, s).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@:15]2(O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=1.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C@@H:16]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@](O)(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Yield: 74.5 %

Procedure:
To a toluene solution (40 mL) of tert-butyl (3S,4S)-4-(4-fluorophenyl)-4-hydroxy-3-(pivaloyloxy)piperidine-1-carboxylate (2.07 g, 5.23 mmol) synthesized in Reference Synthesis Example 130, methyl N-(triethylammoniosulfonyl)carbamate (1.74 g, 7.32 mmol) was added and the resultant mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with each of saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→3/1) to obtain the title compound (1.47 g, yield 75%).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O:6][CH:7](OC)[CH2:8][CH2:9][CH2:10][CH:11]=O>CCOC(C)=O.CCCCCC>[N+:1](/[CH:4]=[CH:11]/[CH2:10][CH2:9][CH2:8][CH:7]=[O:6])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: C[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCCC/C=C/[N+](=O)[O-]
Yield: 65.9 %

Procedure:
Prepared according to the general procedure A from nitromethane 112a (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 66% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][Mg]Br.O>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]([OH:6])[CH3:12])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1c(F)ccc(Br)c1F
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(F)ccc(Br)c1F
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2,6-difluorobenzaldehyde (5 g) in tetrahydrofuran (50 ml) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 24.9 ml) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.91 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH:31]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Cc1ccc(C2=CCNCC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C2=CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)nc1
Yield: 47.8 %

Procedure:
(2R,3S)-2-(2,4Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-methyl-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.63 g, 9.3 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.63 g of the intended substance (yield 47.8%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][N:5]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl>C1COCC1.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][N:5]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
Add NaH (60% in mineral oil, unwashed; 6.23 g, 156 mmol) in portions to a solution of 1-chloro-4-nitroisoquinoline (26.0 g, 125 mmol) and 1-tert-butoxycarbonyl-4-hydroxypiperidine (27.6 g, 137 mmol) in THF (350 mL) stirred at room temperature under nitrogen flow. Stir the dark reddish mixture at 40° C. for 1.5 hours then 55° C. for 1.5 hours. Add additional NaH (1.3 g), and stir the resulting mixture at 55° C. for 2 hours then cool to room temperature overnight. Add hexanes (75 mL), then add water (600 mL) slowly. Adjust the reaction mixture to pH 7 with aqueous HCl (1 N), then separate layers. Discard the aqueous layer and add hexanes (200 mL) to the organic layer. Partially concentrate the mixture under reduced pressure to a volume of 50-100 mL. Add diethyl ether (150 mL) and hexanes (250 mL), then filter the resultant slurry. Wash the cake with diethyl ether/hexanes (1:1) and air-dry to provide 4-(4-nitro-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (33.84 g, 73% yield) as a tan solid. (ES+): m/z 374 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH:9]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]1[N:18]2[CH:19]([CH3:30])[C:20](=[O:29])[NH:21][N:22]=1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][CH:28]=2)[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:30])[C:20](=[O:29])[NH:21][N:22]=2)[CH:9]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)CN1C(=O)OC(C)(C)C
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(Nc2ccc3c(c2)N2C(=NNC(=O)C2C)CO3)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a mixture of 2-methyl-3-oxo-azetidine-1-carboxylic acid tert-butyl ester (crude, 1.17 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was added 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E, 0.050 g, 0.215 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h then NaBH3CN (0.068 g, 1.076 mmol) was added. The mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 24) to give 2-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.016 g, 18%). LC/MS (Table 1, Method 5) Rt=1.087 min; MS m/z: 424 [M+23]+.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>C1C=CC=CC=1>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:8]2[CH:9]=[N:10][CH:11]=[C:6]([Cl:5])[N:7]=2)[N:13]=1
Reactant: NNc1cncc(Cl)n1
Reactant: C/C=C/C#N
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCO
Product: CC1CC(N)=NN1c1cncc(Cl)n1

Procedure:
A 0.30 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 6.72 g. of 2-chloro-6-hydrazinopyrazine (prepared as described above) is added and after 5 minutes, 4.6 g. of distilled crotononitrile is added. The reaction mixture is refluxed for 6 hours. The solvent is removed in vacuo and water is added to the residue to separate a gum. The gum is dissolved in dichloromethane, dried over magnesium sulfate and filtered. The filtrate is evaporated to give a gum. The gum is treated with benzene to separate yellow crystals. The crystals are collected, dried and recrystallized from acetone-hexane to give 1.4 g of the desired product as yellow crystals, m.p. 147°-148° C.