Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=O)[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:37][OH:38].N1C=CC=CC=1>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:37][OH:38])[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 160 °C

Procedure:
A mixture of 1-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]ethanone (Example 454, 19 mg, 0.0378 mmol), hydroxylamine hydrochloride (2.9 mg, 0.042 mmol), pyridine (0.15 mL), and ethanol (0.15 mL) was heated in a microwave reactor at 160° C. for 10 min. The volatiles were removed, and the residue was triturated with hexane/DCM. The solid was collected and dried to provide the title compound. LC/MS: m/e 504.0 (M+H)+. 1H NMR (500 MHz, acetone-d6): δ 8.88 (1H, s), 8.45 (1H, s), 7.78 (1H, s), 7.73 (1H, d, J=7.5 Hz), 7.64 (1H, d, J=8.5 Hz), 7.27 (1H, d, J=8.4 Hz), 7.20 (2H, d, J=8.0 Hz), 7.14 (1H, d, J=7.3 Hz), 6.97 (2H, d, J=7.8 Hz), 4.70-4.95 (2H, br), 2.05 (3H, s), 1.23 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:27][OH:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(CO)N2CCOCC2)c1)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 1 M morpholine in methanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder from the mixture of isomers as gave ABD785. 1H NMR (300 MHz, CDCl3): δ 2.75-2.81 (3H, m), 3.30 (1H, m), 3.60-3.95 (8H, m), 4.10-4.20 (1H, m), 6.80-7.10 (3H, m), 7.20-7.30 (2H, m), 7.35-7.45 (2H, m), 7.57 (2H, d, J=8 Hz) and 7.91 (2H, d, J=8 Hz). MS, m/z: Calcd, 474.142. Found, 474.58 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>C(O)(C)(C)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][C:11]([C:12]#[N:13])([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CC#N)cc1OC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC)c1
Yield: 65.4 %

Procedure:
A mixture of 25 g. (0.141 mole) of the known compound (3,4-dimethoxyphenyl)acetonitrile and 66 ml. of methyl acrylate in 70 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 21.5 ml. of 40% methanolic Triton B in 32 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at reflux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.20 mm. to give 32.22 g. (65.4% yield) of dimethyl-4-cyano-4-(3,4-dimethoxyphenyl)pimelate, having a boiling point of 210° to 214°C. The NMR spectrum of the compound confirms its expected structure.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2Br)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:3]=1[C:27]([NH2:29])=[O:28].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[O:20]([C:17]1[CH:18]=[CH:19][C:14]([C:4]2[C:3]([C:27]([NH2:29])=[O:28])=[C:2]3[NH:1][C:8]4[CH:9]=[N:10][CH:11]=[CH:12][C:7]=4[N:6]3[N:5]=2)=[CH:15][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2ccncc2Br)c1N
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1cnccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A mixture of 5-amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (3.96 g, 8.8 mmol), CuI (836 mg, 4.4 mmol), N1,N2-dimethylethane-1,2-diamine (77 mg, 0.88 mmol), K3PO4 (5.59 g, 26.4 mmol) in 100 mL of DMF was stirred at 100° C. under N2 for 2 hr, until TLC showed that most of starting material was consumed. After cooling down to RT, the mixture was filtered and concentrated. The residue was chromatographed on 30 g of silica gel using DCM/MeOH (20/1 to 10/1) as eluant to afford 3.2 g (99%) of 2-(4-Phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 7.96 (d, J=4.6 Hz, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.14-7.09 (m, 4H). MS (ESI) m/e [M+1]+ 369.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C1CCC(N=C=NC2CCCCC2)CC1.[F:25][C:26]1[CH:27]=[C:28]([N:38]2[CH:42]=[C:41]([CH2:43][NH2:44])[N:40]=[N:39]2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][S:35][CH2:34][CH2:33]1.O>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([N:38]2[CH:42]=[C:41]([CH2:43][NH:44][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[N:40]=[N:39]2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][S:35][CH2:36][CH2:37]1
Reactant: O=C(O)c1cnccn1
Reactant: NCc1cn(-c2ccc(N3CCSCC3)c(F)c2)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CC#N
Product: O=C(NCc1cn(-c2ccc(N3CCSCC3)c(F)c2)nn1)c1cnccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of pyrazine-2-carboxylic acid (127 mg, 1.02 mmol) and DCC (211 mg, 1.02 mmol) in acetonitrile (5 mL) was added to a stirring solution of C-[1-(3-fluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-yl]-methylamine (200 mg, 0.68 mmol), obtained in Example 19, in dry acetonitrile (10 mL) and allowed to stir at room temperature for 6 h. The reaction mixture was then poured into ice-cooled water and extracted with ethyl acetate (20 mL×2). The organic portion was washed with water followed by brine and dried over sodium sulfate. Upon concentration and purification by silica gel column chromatography (acetone/chloroform, 15:85) the title compound was obtained (245 mg, 90%). Mp. 216–218° C.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1CCCCO1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:14]1=[O:33].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:33]=[C:14]1[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using chloroacetonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, J=17.9 Hz, 2H), 4.73 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 155.8, 148.9, 142.232, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 17 %

Procedure:
6-Amino-9-benzyl-2-butylthiopurine (163 mg, 0.52 mmol) and bromine (0.6 ml) were dissolved in 180 ml of methylene chloride and the solution was stirred at room temperature for 4.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (35 mg, yield 17%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[Cl:23].[Cl:24][C:25]1[C:26](B(O)O)=[CH:27][C:28]([F:31])=[N:29][CH:30]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.COCCOC>[Cl:23][C:3]1[C:2]([C:26]2[C:25]([Cl:24])=[CH:30][N:29]=[C:28]([F:31])[CH:27]=2)=[N:7][C:6]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: CC(C)(C)OC(=O)N(CC1CCCOC1)c1ccc(Cl)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1CCCOC1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Temperature: 90 °C
Yield: 40 %

Procedure:
To a scintillation vial was added racemic tert-butyl 6-bromo-5-chloropyridin-2-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (832 mg, 2.051 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (719 mg, 4.10 mmol) and PdCl2(dppf).CH2Cl2 adduct (167 mg, 0.205 mmol) followed by DME (3 mL) and 2M Na2CO3 aq (2 mL). The mixture was heated at 90° C. for 20 h, then allowed to cool and added water and then extracted with EtOAc (×3). The organics were washed with water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 5% to 15% EtOAc/heptanes) to give racemic tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (374 mg)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:6][C:5]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[NH4+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:6]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc(N)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To N-(6-methyl-4′-nitrobiphenyl-3-yl)-3-(trifluoromethyl)benzamide (375 mg, 0.937 mmol) was added 1,4-dioxane (12 mL) and water (6.2 mL), then ammonium hydroxide (220 μL, 5.6 mmol) followed by sodium dithionite (1.4 g, 7.9 mmol). The reaction was stirred at ambient temperature until LCMS indicated complete reduction, typically 30-60 minutes. The reaction is accompanied by a color change from yellow to colorless. The reaction was partitioned between water and EtOAc and the organic phase was washed with water and saturated aqueous NaCl, then dried (MgSO4) and evaporated to leave the crude product (155 mg, 44.8%) which was used without further purification in the subsequent reaction. MS (EI) m/z=371 (M+H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[O:16][C@@H:15]2[C@@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1[OH:21]>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:21][C@@H:13]2[CH2:12][O:16][C@@H:15]3[C@@H:17]([O:20][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:18][O:19][C@H:14]23)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C

Procedure:
p-Toluenesulfonyl chloride (2722 g, 14.28 mol) was added to a solution of isosorbide (869 g, 5.95 mol) in pyridine (5000 mL) in portions with stirring at 0° C. After the reaction mixture was stirred at ambient temperature overnight, the mixture was poured into ice-water (5000 mL) with stirring, and extracted with DCM (4000 mL×3). The combined organic layers were washed successively with water (3000 mL×3), 1 N aqueous HCl (3000 mL×3, pH=6), and saturated aqueous NaHCO3 (3000 mL×2), and dried over anhydrous Na2SO4. After removal of the solvent via vacuum, ethanol (1000 mL) was added. The resulting precipitate was filtered, and washed with ethanol to give the desired product as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].O>CN(C=O)C>[C:4]([CH2:3][CH2:2][CH2:1][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])#[N:5]
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 157.3 %

Procedure:
A mixture of potassium phthalimide (8.48 g, 0.046 mol) and 4-bromopropylcyanide (6.4 g, 0.043 mol) in 50 ml of anhydrous DMF was stirred at 90° C. for 2 h. After dilution with 300 ml of water, the aqueous solution was extracted with chloroform (80 ml×3). The combined chloroform solution was washed with 0.5% NaOH aqueous solution (80 ml) and water (100 ml), and dried over anhydrous Na2SO4. After evaporation of chloroform, an oil was obtained and 300 ml of water was added. The oil was rapidly solidified. The solid formed was collected by filtration, washed with water, and dried under high vacuum. The product was recrystallized from methanol which was diluted with water, to give white crystals (7.75 g, 84%). 1H NMR (CDCl3) δ 7.87 (dd, 2H), 7.75 (dd, 2H), 3.83 (t, 2H), 2.44 (t, 2H), 2.09 (quintet, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:13]#[C:14][NH2:15].[Na].ClN1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11](=[N:15][C:14]#[N:13])[O-:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N=O)cc1
Reactant: N#CN
Agent: O=C1CCC(=O)N1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+]([O-])=NC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.8 %

Procedure:
4-(N-acetylamino)nitrosobenzene (1.64 g, 10.0 mmol) was dissolved in dimethylformamide (20 ml) and treated with monosodium cyanamide (1.0 g, 15.6 mmol). N-chlorosuccinimide (1.33 g, 10.0 mmol) was added and the mixture stirred for 24 hours at ambient temperature. The mixture was poured on ice-water (100 ml) and the precipitate filtered off to give 1.2 g 4-(N-acetylamino)phenyl ONN-azoxycyanide as a yellow powder, m.pt. 240°-242° C. (Yield: 58.8% of theoretical).
Reaction SMILES: OC[C@H]1[C@@H]2[C@@H]([C@@H](OC)O[C@H]2C)C[C@@H:9]2[C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2.C(N(CC)CC)C.CS(Cl)(=O)=O.CC(C)([O-])C.[K+].[C:37]1([SH:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>C(Cl)CCl.CN(C)C1C=CN=CC=1.CS(C)=O.O>[C:37]1([S:43][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CO[C@H]1O[C@@H](C)[C@H]2[C@@H]1C[C@H]1CCCC[C@@H]1[C@H]2CO
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: c1ccc(Sc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To 460.5 mg(1.81 mmol) of (1S,3S,3aR,4R,4aS,8aR,9aS)-4-hydroxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan in 20 ml of ethylene chloride solution were added 20.3 mg(0.1 equivalent) of 4-(dimethylamino)pyridine and 1.26 ml(5 equivalents) of triethylamine, and, after 420.4 μl (3 equivalents) of methanesulfonyl chloride were added dropwise under cooling with ice and under an atmosphere of argon, the mixture was stirred for about 3 hours while raising temperature naturally. To the reaction mixture were added 20 ml of water to wash, and extraction with methylene chloride(3 ml×3) was performed from the aqueous layer. Combined organic layers were dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain 645.7 mg of O-mesyl form. To 304.7 mg(1.5 equivalents) of potassium t-butoxide in 10 ml of dehydrated dimethyl sulfoxide solution placed in a 25 ml flask were added dropwise 278.8 μl (1.5 equivalents) of thiophenol at room temperature under stirring, and the mixture was stirred for 10 minutes. This was added to previous 645.7 mg of O-mesyl form in 10 ml of dehydrated dimethyl sulfoxide solution, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into 20 ml of cold dilute aqueous solution of sodium hydrogencarbonate, which was extracted with ether(10 ml×3). After washing the organic layer with saturated brine(10 ml×1), it was dried over anhydrous magnesium sulfate, filtered and then solvent was distilled off to obtain phenyl thioether. This was dissolved into 50 ml of methylene chloride and 976.3 mg(2.5 equivalents) of m-chloroperbenzoic acid(80%) and 760.4 mg(5 equivalents) of sodium hydrogencarbonate were added under stirring and cooling with ice. After stirring for 2 hours at room temperature, the reaction mixture was filtered through celite and the residue was washed with methylene chloride(20 ml). Solvent was distilled off under reduced pressure and the residue was diluted with 50 ml of ether, which was washed with saturated aqueous solution of sodium hydrogencarbonate(10 ml×3) and with saturated brine(10 ml×1). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=2:1, then 2:1) to obtain 563.9 mg of (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-(phenylsulfonyl)methyl-dodecahydronaphtho[2,3-c]furan (yield after 3 processes 82%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11](=O)[CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([C:10]1[N:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][C:11]=1[CH:12]([CH3:14])[CH3:13])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C(NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Mixture of 2-benzoylamino-4-methyl-3-oxo-pentanoic acid benzyl ester (1.08 g, 3 mmol), triphenylphosphine (2.01 g, 8 mmol), and iodine (1.62 g, 6.37 mmol) in tetrahydrofuran (60 mL) was cooled to −78 degrees, followed by addition of triethylamine (1.7 mL). The resulted solution was stirred at −78 degrees for about 10 min, and then was warmed up to room temperature. The reaction continued at room temperature for about 1 hr. After the reaction, the solvent was removed, and dichloromethane was added. The resulted solution was washed in sequence with saturated sodium bicarbonate, citric acid (0.5 M), and brine, dried over sodium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-40% ethyl acetate in hexane for 20 min) gave 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (0.84 g, 82%) as a light yellow solid. LCMS calcd for C20H19NO3 (m/e) 321, obsd 322 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][NH2:17])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2].C(N(CC)CC)C.O.[O:40]1CCC[CH2:41]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[O:15][C:41](=[O:40])[NH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
72 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carbohydrazide (compound 133) was dissolved in 4 mL of tetrahydrofuran, and 55 mg of N,N′-carbonyldiimidazole and 47 μL of triethylamine were added to the solution. The mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=5:1), and thus 57 mg (cis:trans=4:1, 75%) of the title compound was obtained as a pale green powder.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=[CH:5][N:4]=1>C(O)(=O)C>[Br:1][C:13]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:8]=2[C:9](=[O:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=1
Reactant: O=c1c2ccccc2ccc2ccncc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1c2ccccc2cc(Br)c2ccncc12

Procedure:
Bromine (4.18 ml.) in acetic acid (50 ml.) is added dropwise to a stirred solution of benzo[5,6]cyclohepta[1,2-c]pyridin-11-one (12.35 g.) in acetic acid (250 ml.). The resulting mixture is heated on the steam bath for 24 hours and the acetic acid is removed under reduced pressure. Saturated Na2CO3 solution (500 ml.) is added to the residue and the deep yellow solid that forms is collected, washed with water, and dried. This crude product is recrystallized from 1-chlorobutane to give 9.3 g., m.p. 167°-169° C.