Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15]O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>N1C=CC=CC=1.CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][N:29]=[N+:30]=[N-:31])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (123 g, 505 mmol) in pyridine (1 L) was cooled at 4° C. and a solution of p-toluenesulfonyl chloride (125 g, 657 mmol) in pyridine (200 ml) was added below 10° C. The mixture was stirred at ambient temperature for 15 hr and concentrated. After dissolution with EtOAc and H2O, the organic layer was separated. The aqueous layer was extracted with EtOAc (three times), the combined organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated to give a pale yellow oil. To a solution of the above oil in DMF (1.6 L) was added NaN3 (98.8 g, 1.52 mol). The reaction mixture was stirred at ambient temperature for 14 hr and concentrated. After dissolution with CHCl3 and saturated aqueous NaHCO3, the organic layer was separated. The aqueous layer was extracted with CHCl3 (three times), the combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 17% EtOAc in hexane) to give trans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (124 g, 91%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C@@H:29]([OH:31])[CH3:30].N.O>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C@@H:29]([OH:31])[CH3:30])(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: C[C@H](O)c1ccccc1Br
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reaction time: 2 h
Yield: 29.5 %

Procedure:
A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (340 mg, 1.1 mmol), (1S)-1-(2-bromophenyl)ethanol (205 mg, 1.0 mmol) and copper(I) iodide (0.95 g, 4.99 mmol) in dimethyl sulfoxide (10 mL) was degassed and the flask placed in an oil bath at 110° C. The reaction mixture was stirred at this temperature for 2 hours. The cooled reaction mixture was poured into concentrated ammonia/water (1:1; 100 mL) and extracted with diethyl ether (4×50 mL). The extracts were washed with water then brine, combined, dried (MgSO4) and evaporated. The residue was purified by two flash columns, the first eluting with 5-10% diethyl ether/dichloromethane and the second eluting with 40-60% diethyl ether/isohexane, to give the title compound (120 mg, 29%). 1H NMR (500 MHz, CDCl3) δ 8.55 (1H, s), 8.17 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.6 Hz), 8.02 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.5, 8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.69-7.63 (3H, m), 7.49 (1H, t, J=7.2 Hz), 7.19 (2H, t, 8.6 Hz), 5.68-5.62 (1H, m), 2.49 (1H, d, J=3.1 Hz), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 389 [(M-OH)+].
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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:45][C:46]1[CH:47]=[N:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([CH2:56]O)=[CH:51][CH:50]=2>C1COCC1.CCOC(C)=O>[Br:45][C:46]1[CH:47]=[N:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([CH2:56][N:5]1[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]1=[O:6])=[CH:51][CH:50]=2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc2ncc(Br)cc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phthalimide (281 mg, 1.9 mmol), triphenyl phosphine (500 mg, 1.9 mmol) in 10 mL of THF was added DIAD (386 mg, 1.9 mmol) dropwise at 0° C. and the mixture was stirred at this temperature for 10 min. (3-Bromo-quinolin-6-yl)-methanol (413 mg, 1.7 mmol) was added to the above solution in one portion and the resulting solution was stirred at rt for 30 min, then heated at 40° C. for 5 h. After cooling, the reaction mixture was taken up with EtOAc, washed with water, extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (d, 1H), 8.31 (d, 1H), 8.06 (d, 1H), 7.90-7.86 (m, 3H), 7.82-7.73 (m, 3H), 5.04 (s, 2H). LCMS (method A): [MH]+=368/370, tR=5.54 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]([C:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[N:25]([CH3:31])[N:24]=1)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:28]([C:26]2[N:25]([CH3:31])[N:24]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:27]=2)=[O:29])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
4-Trifluoromethylaniline (19.39 g, 120.3 mmol) and triethylamine (13.4 g ,132 mmol) was added to 400 ml of anhydrous dichloromethane in a 1-liter round bottomed flask. This stirred solution was cooled to 4° C. using an ice water bath. 3-tert-Butyl-1-methyl-1H-pyrazole-5-carbonyl chloride 26.57 g (132 mmol) was added drop wise to this cooled solution. The reaction mixture was allowed to warm to room temperature and then was stirred at ambient temperature for 18 hours. The reaction mixture was then placed in an extraction funnel and then extracted first with 400 ml of 1N HCl and subsequently with 300 ml of water. The extraction with water was repeated. The organic layer was then stirred in a 2 liter Erlenmeyer flask and 500 ml of hexane added. The mixture was stirred for 2 hours and provided a precipitate which was collected by filtration on a Buchner funnel. The white solid was then dried in vacuum oven at 40° C. for 24 hours to give 20.63 g of pure product (52% yield). 1H NMR (400 MHz CDCl3) δ: 7.85 (s 1H) 7.74 (s 2H) 7.62 (d 1H) 6.53 (s 1H) 4.16 (s 3H) 1.33 (s 9H). MS: m/z 324.2 (M−1)
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Br[CH:5]([CH3:23])[C:6]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:19]([C:10]1[CH:9]=[C:8]([C:6]2[N:3]=[CH:1][S:2][C:5]=2[CH3:23])[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: NC=S
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1scnc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 39.7 %

Procedure:
A mixture of 0.7 g of thioformamide, 3.4 g of 4-(2-bromopropionyl)-2,6-di-tert-butylphenol, and 15 ml of absolute ethanol was heated to 50°-60° C. for 2-3 hours. After cooling, the reaction mixture poured into a diluted aqueous solution of potassium carbonate. The precipitates thus formed were recovered by filtration and recrystallized from a mixture of cyclohexane and hexane to provide 1.2 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthiazole.
Reaction SMILES: [CH:1]1([S:6][CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH:25]([F:27])[F:26])[N:13]=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:42])C=1.O>C(Cl)Cl>[CH:1]1([S:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH:25]([F:27])[F:26])[N:13]=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)=[O:42])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(NCCSC2CCCC2)nc(N2CCOCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=S(CCNc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1)C1CCCC1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
N-[2-(Cyclopentylsulfanyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (60 mg) was dissolved in methylene chloride (1.2 mL), and m-chloroperbenzoic acid (75% wet) (32 mg) was added thereto at 0° C., followed by stirring for 10 minutes. Water was added thereto, followed by extraction with chloroform. The organic layer was 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=20:80, and subsequently chloroform:methanol=98:2-90:10) to obtain N-[2-(cyclopentyl sulfinyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (53 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:11][N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:11][N:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9]1)[CH2:31][CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4.2 g (10.9 mmol) [(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester, 521 mg (13 mmol) NaH (60%) and 2.54 g (16.3 mmol) iodoethane in 40 mL DMF was stirred for 1 h at 60° C. and evaporated to dryness. The residue was taken up in ethyl acetate and water and extracted further with ethyl acetate. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 2.5 g (55%) of the title compound as light yellow viscous oil. MS m/e: 415.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:35][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(F)c(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(CCCBr)cc1C(F)(F)F
Yield: 73.1 %

Procedure:
Compound 69-2 (3.05 g) was dissolved in methylene chloride (46 ml), triphenylphosphine (4.00 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.86 g) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5](NC(=O)CCCC)=[C:4](Cl)[CH:3]=1>N1C=CC=CC=1>[CH3:4][CH2:3][CH:2]=[CH:14][CH2:3][CH2:4][CH2:5][CH2:13][CH:14]=[CH2:2]
Reactant: CCCCC(=O)Nc1ccc(N)cc1Cl
Solvent: c1ccncc1
Product: C=CCCCCC=CCC

Procedure:
A mixture of 4'-amino-2'-chlorovaleranilide (2.27 g., 0.01 mole) anti-tricyclo[4.2.2.02,5 ]dec-3,9-diene-endo7,endo-8-dicarboxylic anhydride (2.02 g., 0.01 mole) and pyridine (20 ml.) is heated under reflux for twenty-four hours. The solvent is removed in vacuo and the residue (4.35 g., m.p. 120°-136° C.) is recrystallized from butyl chloride to give N-(3-chloro-4-valeramidophenyl)-antitricyclo[4.2.2.02,5 ]dec-3,9-diene-endo-7,endo-8-dicarboximide, m.p. 157.5°-159° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][NH:18][CH2:19]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:32].O>CN(C=O)C>[F:22][C:23]1[CH:28]=[C:27]([NH:29][C:30]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][C:12]([O:11][C:9]4[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=4)=[CH:13][CH:14]=3)[CH2:19]2)=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:32]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CNCC3)ccn1
Reactant: Cc1ccc(N=C=O)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CN(C(=O)Nc2ccc(C)c(F)c2)CC3)ccn1
Reaction time: 24 h

Procedure:
To a solution of N-methyl-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxy)pyridine-2-carboxamide (34 mg, 0.12 mmol) in DMF (1 mL) was added to 2-fluoro-4isocyanato-1-methylbenzene (21.8 mg, 0.144 mmol). The reaction mixture was allowed to stir for 24 h. Water added and the resulting solid was separated and purified by reverse phase HPLC to N-(3-fluoro-4-methylphenyl)-7-({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide (32 mg, 61%). LCMS: (AA) ES+) 435.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:36]1[CH2:37][CH2:38][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:34][CH2:35]1)=[O:26]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 81.8 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2-chloro-5-methylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (72 mg, 0.17 mmol) obtained in step 2 and 4-phenylpiperidine (37 mg, 0.26 mmol), the title compound (72 mg, 84%) was obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]([CH2:15][C:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:28]([N:19]1[CH2:20][CH2:21][C:16]([CH2:15][N:5]([C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (108 mg, 0.281 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added benzaldehyde (35.8 mg, 0.337 mmol) and sodium triacetoxyborohydride (95 mg, 0.450 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 78 mg or product as colorless oil. MS: (M+H)+=475.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.42 (q, 1H), 1.53-1.76 (m, 3H), 2.08-2.34 (m, 4H), 2.42 (ddd, J=10.11, 6.44, 3.66 Hz, 1H), 2.78-2.99 (m, 2H), 3.13-3.24 (m, 1H), 3.53-3.65 (m, 5H), 3.70-3.86 (m, 2H), 7.10 (d, J=7.07 Hz, 2H), 7.18-7.25 (m, 1H), 7.27-7.40 (m, 7H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)([O-:29])=[O:28]
Reactant: NN
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 70.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (568 mg, 1.42 mmol, prepared in Synthetic Example 19) in DMF (14 ml) was added hydrazine monohydrate (80%, 203 μl, 5.07 mmol, 3.6 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (397 mg, 71%).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])[CH2:10][C:9]2=[O:19])=[CH:5][CH:4]=1)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([OH:31])[C:26](=[CH:29][CH:30]=1)[CH:27]=O.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]2[CH:27]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[C:9](=[O:19])[CH2:10]3)(=[O:16])=[O:15])[CH2:18][O:31][C:25]=2[CH:24]=1
Reactant: C=CS(=O)(=O)N1CCN(Cc2ccc(C#N)cc2)C(=O)C1
Reactant: O=Cc1ccc(Cl)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Yield: 39.6 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-4-vinylsulfonyl-2-piperazinone (1.53 g) and 4-chlorosalicylaldehyde (0.94 g) in tert-butanol (20 ml) was added potassium tert-butoxide (187 mg), and the mixture was refluxed for 4 days. The reaction solution was concentrated under reduced pressure, and precipitated crystals were washed with acetone-ethanol to give pale brown crystals of the title compound (0.88 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[O:16]([C:10]1[CH:11]=[CH:12][C:13]([C:3](=[O:4])[CH2:2][Br:1])=[CH:14][CH:15]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:3](=[O:4])[CH2:2][Br:1])=[CH:21][CH:22]=1
Reactant: O=C(Cl)CBr
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Oc2ccc(C(=O)CBr)cc2)cc1
Temperature: -15 °C
Reaction time: 0.05 h
Yield: 66.8 %

Procedure:
Bromoacetyl chloride (2.22 ml, 22 mmol) was added dropwise during 15 min with stirring at −15° C. to a mixture of aluminum chloride (6.0 g, 44.8 mmol) in methylene dichloride (40 ml). The reaction mixture was stirred at −15° C. for an additional 3 min. Diphenyl ether (1.87 g, 11.0 mmol) was added during 30 min with stirring at −15° C. and the reaction mixture was allowed to warm to room temperature and then stirred for 3 h. It was then poured into a mixture of concentrated hydrochloric acid and crushed ice and extracted with methylene dichloride (2×50 ml). The combined organic extracts were washed with 2% aqueous sodium hydrogen carbonate and water and dried over Na2SO4. Evaporation of the solvent under reduced pressure gave desired product 50 3.03 g (67%).
Reaction SMILES: O[Li].O.O.O.O.O.O.[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:36]([O:38]CC)=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([Br:35])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[NH:11]1>O.C1COCC1>[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:36]([OH:38])=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([Br:35])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[NH:11]1
Reactant: CCOC(=O)[C@@H](Cc1ccc(Br)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cc1ccc(Br)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 210 mg (9 mmol) LiOH.6H2O in 40 mL water was added at RT to a solution of 3.64 g (5.83 mmol) of (R)-2-(3,4-dibromo-phenyl)-1-ethoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 70 mL THF and the reaction mixture was stirred for 7 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 100 mL water, 1 M HCl was added until an acid reaction was obtained, the precipitate was filtered off and dried in the vacuum drying chamber at 50° C. The product was reacted further without purification.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[C:6]1([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:13]([O:12][C:6]1[CH:11]=[CH:10][C:9]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COc2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To 0.87 g of dimethylformamide, at 0° C. under an atmosphere of nitrogen, was added 1.61 g of sulfuryl chloride. The mixture was stirred for 15 min and treated with 2.00 g of benzyl phenyl ether. The mixture was then heated at 100° C. for 1.5 h, cooled to about 40° C., poured onto ice, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel chromatography using 10% ethyl acetate in hexane as eluent to provide 0.78 g of the title product as a white solid. TLC: Rf=0.46, 10% ethyl acetate in hexane. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[OH-:19].[Na+].OO.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:19]
Reactant: [OH-]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1F
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(O)c(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a solution of 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.24 g, 8.82 mmol, 1.0 eq) in a mixture of NaOH (1M aqueous solution, 26.4 mL, 26.4 mmol, 3.0 eq) and THF (20 mL) at 0° C. was added H2O2 (3 g, 26.4 mmol, 3 eq). The reaction mixture was stirred at room temperature for 4 h, then the pH of the reaction mixture was adjusted to pH 5 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 50:1) to give the title compound as a colorless oil (850 mg, 65%).