Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH:13]=[CH2:14])=[C:11]2[CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[C:17](=[O:18])[C:10]2=[N:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH:13]=[CH:14][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[C:11]2[CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[C:17](=[O:18])[C:10]2=[N:9]1
Reactant: C=Cc1c2c(nn1-c1ccccc1Cl)C(=O)N(C(C)C)C2
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2C=Cc2ccc(Cl)cc2)C1=O

Procedure:
To a stirred solution of 2-(2-chloro-phenyl)-5-isopropyl-3-vinyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 1A-8 (42 mg), palladium acetate (3 mg) and 4-chloroiodobenzene (300 mg) were stirred for 18 hours. The reaction was concentrated and chromatographed on silica gel (gradient 30% to 60% ethyl acetate/hexanes) to afford the title compound (1A-39), 44 mg. 1H NMR in d6-DMSO (ppm): δ 7.78 (d, 1H), 7.63–7.38 (m, 5H), 7.13 (d, 1H), 6.61 (d, 1H), 4.62 (s, 2H), 4.40 (m, 1H), 1.23 (d, 6H); ms (LCMS) m/z=412.3 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: CC(C)CBr
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC(C)C)c1=O
Yield: 69.9 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 69.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:20]=1C)=[O:18].BrC1C=CC(OC)=C([C:39](C2C=CC(NC3C=CC(F)=CC=3F)=CC=2Cl)=[O:40])C=1.C([Si](C)(C)C)#C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:20]=1[O:40][CH3:39])=[O:18]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#C[Si](C)(C)C
Product: COc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 406, using compound 425 (0.99 mmol) and ethynyltrimethylsilane (0.99 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 10:90 as the eluent to afford the title compound as light orange syrup.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=O)(C)(C)C.I[CH3:22].[H-].[Na+]>CN(C=O)C>[CH3:20][C:9]1([CH3:19])[CH:10]([CH3:22])[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8]1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)c2ccccc2NC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.1 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg (86%) of 1,2,3,4-tetrahydro-2,2,3-trimethyl-4-quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 (50 mg, 1.3 mmol) in methanol (5 mL) for 1 h and the reaction mixture was concentrated. Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10% Pd/C (10 mg) in EtOAc (5 mL) under a hydrogen balloon for 15 h. Filtration from the catalyst through a Celite™ pad followed by removal of solvent gave 70 mg (82%) of 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2Cl2 for 30 min. and was quenched with 5% NaOH (6 mL). The mixture was extracted with EtOAc (2×15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil (40 mg, 89%). Data for 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.00-6.91 (m, 2 H), 6.60 (t, J=7.3, 1 H), 6.45 (d, J=7.3, 1 H), 3.61 (br s, 1 H), 2.74 (dd, J=16.6, 5.3, 1 H), 2.47 (dd, J=16.6, 10.3, 1 H), 1.82 (m, 1 H), 1.20 (s, 3 H), 1.05 (s, 3 H), 0.97 (d, J=7.2, 3 H).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:25]1([N:5]2[C:6]3[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=3)[N:12]([C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C@H:3]([CH2:1][CH3:2])[C:4]2=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCC1
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C2CCCC2)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a stirred solution of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) (0.47 g, 1.4 mmol) in tetrahydrofuran (4 mL) under nitrogen at 0° C. was added cyclopentanol (0.20 mL, 0.19 g, 2.2 mmol), triphenylphosphine (0.58 g, 2.2 mmol), and diethyl azodicaboxylate (0.44 mL, 0.46 g, 0.22 mmol). The reaction was warmed to 25° C. and was stirred for 12 h. The solvent was evaporated in vacuo, and the product was purified via Biotage Horizon® (SiO2, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) to yield 0.20 g (36%) of (3R)-1-cyclopentyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 397 ([M+H]+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.CN(C=O)C.Br[CH2:24][C:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH:26]=1>O>[OH:34][C:31]([C@H:28]1[CH2:29][CH2:30][C:25]([CH2:24][N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])=[CH:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(O)[C@@H]1CC=C(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)[C@@H]1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of 2.2 g (16 mmol) K2CO3, 1.2 g (8.4 mmol) phthalimide, and 40 ml DMF was stirred at room temperature for 0.5 hours. Thereafter, 1.7 g (7.4 mmol) (S)-2-(4-bromomethyl-cyclohex-3-enyl)-propan-2-ol (Bull, et. al. Aust. J. Chem., 46 1869, 1993) was added and the resulting mixture was stirred at room temperature for 72 h. Water was added and the mixture was then extracted with ethyl acetate. The ethyl acetate extracts were combined; washed with water and brine; dried (MgSO4); and filtered and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate/hexanes yielded 0.62 g (28%) of the desired product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S(O[CH2:31][C@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:31][C@@H:32]4[CH2:33][O:34]4)[CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(-c3cccc(OC[C@@H]4CO4)c3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a cold (0° C.) solution of sodium hydride (1.83 g, 45.79 mmol) in dimethylformamide (120 mL) and under a nitrogen atmosphere, add a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (50 mL) and stir for 1 hour. Add, dropwise, (2S)-(+)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), over a period of time of 0.5 hours. Let reaction mixture warm to room temperature and stir for 2 days. Quench with water, concentrate and add ethyl acetate/water. Wash with water, saturated sodium chloride and dry (MgSO4) to give the crude compound. Purify by column (silica) chromatography eluting with a graded solvent mixtures of toluene to 1% ether in toluene to give the title compound as a white solid (10.07 g, 81% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. Chiral HPLC, 18.14 minutes [Chiralcel OD (250×4.6 mm), 98:2 heptane/ethanol @ 0.8 mL/min, UV @ 285 nm, 18.14] shows the title compound as 88.3% e.e. mp=83-84° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[C:23]([O-])([O-])=[O:24].[K+].[K+].CO>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([O:24][CH3:23])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(F)cc2F)c(Cl)c1C(F)(F)F
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Yield: 91.9 %

Procedure:
At 35° C., 13.7 g (0.04 mole) 4-chloro-3-(2,4-difluoro-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 5.5 g (0.04 mole) K2CO3, and 100 mL methanol were stirred for 1 hour. The reaction was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was purified chromatographically using 25% ethyl acetate in hexane as the eluent to give 13.0 g (90%) of 4-chloro-3-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a white solid, mp 116° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]2[N:14]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:21][C:19]1[N:20]=[C:13]2[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:17][CH:16]=[CH:15][N:14]2[CH:18]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1cn2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Yield: 25.7 %

Procedure:
A mixture of 4-hydroxyphenylboronic acid (1.1 g), 8-bromo-2-methylimidazo[1,2-a]pyridine (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.28 g), sodium carbonate (3.0 g), DME (35 ml) and water (7 ml) was heated under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (0.46 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[C:19]([C:21](OC)=[O:22])[O:18][N:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[C:19]([CH2:21][OH:22])[O:18][N:17]=1
Reactant: COC(=O)c1cc(OCCc2nc(-c3ccccc3)oc2C)no1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1cc(CO)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a mixture of methyl 3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolecarboxylate (9.2 g) and tetrahydrofuran (200 mL) was added lithium aluminum hydride (1.06 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Dilute hydrochloric acid was added to acidify the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.90 g, 58%) of [3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolyl]methanol from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:13].C(O)(=O)C.BrBr>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cnc2ccccn12
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cnc2ccccn12
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
22.1 g of 3-acetylimidazo[1,2-a]pyridine was dissolved in 220 ml of acetic acid. 35.1 ml of a 30% hydrogen bromide/acetic acid solution was added dropwise to the solution at 0° C. Then 28.6 g of bromine was added dropwise thereto at 40° C. The mixture was stirred at 40° C. for 2 h and crystals thus formed were filtered. The crystals were dissolved in 100 ml of water. The solution was made alkaline with an excess of an aqueous sodium hydrogencarbonate solution and then extracted with ethyl acetate. The organic layer was concentrated and the obtained brown solid was purified according to silica gel column chromatography (eluted with ethyl acetate) to obtain 13.5 g (yield: 40%) of 3-bromoacetylimidazo[1,2-a]pyridine (yield: 40%) in the form of yellow crystals. ii) A suspension comprising 1.91 g (6.0 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 3.0 g of potassium carbonate and 40 ml of dimethylformamide was stirred at 80° C. for 1 h. After cooling to room temperature, 1.99 g of 3-bromoacetylimidazo[1,2-a]pyridine prepared in the above step i) was added thereto and the mixture was stirred at room temperature for 6 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a solid residue, which was then purified according to silica gel column chromatography (chloroform:methanol=96:4). The purified product was converted into its dihydrochloride with ethanolic hydrogen chloride and recrystallized from methanol/acetone to obtain 1.75 g (yield: 58%) of the intended compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.C1(C)C=C(C)C=C(C)C=1S(O)(=O)=[O:24].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:24][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 94.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 56.7 g (0.24 mol) of 2-mesitylenesulfonic acid dihydrate (produced by Aldrich Chemical Co., Inc.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-epoxypyrrolidine (yield 94.7%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl-].[Ca+2].[Cl-].CO.O>[Cl-].[Na+].O.[Fe]>[NH2:15][CH2:14][CH:13]([CH3:18])[CH2:12][C:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: CC(CC(=O)Nc1ccc(C#N)c(Cl)c1)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(CN)CC(=O)Nc1ccc(C#N)c(Cl)c1
Yield: 31.8 %

Procedure:
A solution of the compound obtained in Step 2 (21.2 g, 75.26 mmol), iron powder (21.01 g, 376.29 mmol) and calcium chloride (25.06 g, 225.78 mmol) in a mixed solvent of methanol (100 mL) and water (20 mL) was stirred at 60° C. for 3 hr. To the reaction solution was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give 4-amino-N-(3-chloro-4-cyanophenyl)-3-methylbutanamide (6.02 g, 23.92 mmol, 31.8%) as a brown oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]3=[N:22][CH:23]=[C:24]([CH3:25])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.N(OCCCCC)=O>O1CCCC1>[CH3:25][C:24]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]2=[N:22][CH:23]=1
Reactant: Cc1cnc2n1N=C(c1ccc(N)cc1)c1cc3c(cc1C2)OCO3
Agent: CCCCCON=O
Solvent: C1CCOC1
Product: Cc1cnc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Yield: 71.2 %

Procedure:
200 mg of 5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is mixed in 30 ml of tetrahydrofuran with 1.32 ml of pentyl nitrite and refluxed under argon for 2 hours. After concentration by evaporation, it is chromatographed on silica gel with methylene chloride:ethanol=10:1. 136 mg of 8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:26][C:25](=[O:27])[C:24]3[C:15](=[C:16]4[C:21](=[CH:22][CH:23]=3)[O:20][CH2:19][CH2:18][O:17]4)[N:14]=2)[CH:12]=1)=[O:7])C>C1COCC1>[O:27]=[C:25]1[C:24]2[C:15](=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH2:19][CH2:18][O:17]3)[N:14]=[C:13]([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)[NH:26]1
Reactant: CCOC(=O)c1cnn(-c2nc3c4c(ccc3c(=O)[nH]2)OCCO4)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3c4c(ccc3c(=O)[nH]2)OCCO4)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.1 %

Procedure:
Aqueous potassium hydroxide (1M, 2.6 mL, 2.6 mmol) was added to 1-(8-oxo-2,3,7,8-tetrahydro-1,4-dioxa-5,7-diaza-phenanthren-6-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.298, 0.869 mmol) in THF (2.6 mL). The reaction mixture was allowed to stir at room temperature for 2 days and was then concentrated. The residue was redissolved in water (10 mL) and brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected by filtration to yield the titled compound (0.235 g, 85% yield). MS (ESI/Cl): mass calcd. for C14H10N4O5, 314.1; m/z found, 315.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.01 (s, 1H), 12.73 (s, 1H), 8.86 (d, J=0.7 Hz, 1H), 8.24 (d, J=0.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.40 (s, 4H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]2[CH3:21])=[CH:5][C:4]=1[S:23]([Cl:26])(=[O:25])=[O:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:23]([Cl:26])(=[O:24])=[O:25]
Reactant: CN1C(=Nc2ccccc2)SCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cn1c(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)csc1=Nc1ccccc1

Procedure:
2.5 g (50 mmoles) of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-phenyliminothiazolidin-4-ol hydrobromide are heated rapidly in a jacket, which has been preheated to 220° C., in vacuo (0.1 mm Hg) over phosphorus pentoxide. The substance melts with foaming, as a result of the elimination of water, and solidifies immediately after the end of the reaction, with recrystallization. Slightly green colored crystals; melting point 264° C.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[OH:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:13][O:12][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
An aqueous solution of NaOH (30 g in 60 mL of water) and tert-butyl bromoacetate (3.75 mL, 25.2 mmol) were added into a solution of 4-(hydroxymethyl)benzonitrile (3.0 g, 22.53 mmol) and tetrabutylammonium hydrogen sulfate (765 mg, 2.25 mmol) in toluene (60 mL). The reaction mixture was stirred at RT for 2 hours. The aqueous layer was removed and extracted twice with EtOAc. The organic layers were combined and washed with a saturated aqueous solution of NH4Cl and brine, and then dried (MgSO4) and concentrated to give the title compound as a colorless oil (4.37 g, 78%). HPLC (Method A) Rt 4.7 min (purity: 95.2%). 1H NMR (CDCl3, 300 MHz) δ 7.65 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 4.05 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][CH2:28][CH2:27][CH:26]2[NH2:33]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:33][CH:26]1[C:25]2[C:30](=[CH:31][CH:32]=[C:23]([I:22])[CH:24]=2)[O:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: NC1CCOc2ccc(I)cc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Yield: 84.6 %

Procedure:
An isopropyl alcohol (25 ml) solution of tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate (2.2 g, 7.2 mmol) and 6-Iodo-chroman-4-ylamine (3.0 g, 10.9 mmol) was stirred at 75° C. for 0 h. The IPA was removed in vacuo and the resulting residue dissolved in EtOAc (200 ml). The organic layer was washed with 1 N HCl (4×50 ml), followed by NaHCO3 (2×50 ml), and brine (1×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 3.5 g (85%) of the title compound as an off white solid. MS (ESI+) for C24H29F2IN2O4 m/z 574.8 (M+H)+.