Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:36][CH2:37][CH3:38])=[C:16]([CH:22]4[CH2:25][N:24](C(OCC5C=CC=CC=5)=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.O>CO.[Pd]>[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:36][CH2:37][CH3:38])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[CH3:21])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (170 mg, 0.32 mmol, racemic intermediate) and 5% palladium (80 mg) were combined in methanol (12 mL), to which was added 0.25 M hydrogen chloride in water (3.2 mL, 0.79 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The suspension was filtered. The filtrate was neutralized with sat. NaHCO3 solution, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and filtered, concentrated to give the desired product (117 mg, 92%). LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2; Found: 401.1.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17]([O:19][C:20](=[O:21])[C:12]=3[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=O)(=O)C.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:26]1[C:20](=[O:21])[C:12]2[C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:4][C:16]=3[CH:15]=[CH:14][C:13]=2[C:17]1=[O:19]
Reactant: CC(=O)n1c2ccccc2c2c3c(ccc21)C(=O)OC3=O
Reactant: CN(C)CCN
Solvent: Cc1ccccc1
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccccc4c3c2C1=O
Yield: 77.9 %

Procedure:
To 100 ml of toluene were added 1.12 g of 9-acetylcarbazole-3,4-dicarboxylic anhydride and 1.06 g of N,N-dimethylethylenediamine. The mixture was azeotropically refluxed for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 960 mg (yield: 78%) of N-(2-dimethylaminoethyl)-carbazole-3,4-dicarboximide as light yellow needles.
Reaction SMILES: [Na+].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH-:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][P:27](=[O:28])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1
Reactant: CCOc1ccc(-c2c(Cl)ncn2-c2ccc(S([NH-])(=O)=O)cc2)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)(OCC)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a suspension of 4-[4-chloro-5-(4-ethoxyphenyl)imidazol-1-yl]benzenesulfonamide sodium salt (2.89 mmol) (obtained in the preceding section) in THF (12 mL), diethyl chlorophosphate (0.42 mL, 2.89 mmol) was added under argon atmosphere. The resulting solution was stirred at room temperature for 15 days. It was then concentrated to dryness and the resulting residue was partitioned between H2O and EtOAc, the suspension was filtered and the phases separated. The organic phase was dried and concentrated to afford a solid which was purified by chromatography on silica gel using mixtures hexane/EtOAc and EtOAc/MeOH of increasing polarity as eluent. The product obtained was then recrystallized from ACN to afford the title compound of the example as a yellowish solid (15% yield).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]=12.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3]([CH:6]=1)=[N:4][O:5][N:1]=2)(=[O:22])=[O:21]
Reactant: OCc1ccc2nonc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2nonc2c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
5-Benzofurazanmethanol (0.6 g, 4 mmol) and triethylamine (0.84 mmol, 0.61 g, 6 mmol) were dissolved in dichloromethane (20 ml) and cooled to -20° C. Methanesulfonyl chloride (0.37 ml, 0.55 g, 4.8 mmol) was added dropwise and the mixture was stirred at -20° C. for 20 minutes, diluted with dichloromethane (30 ml), washed with water (30 ml), dried (Na2SO4), and evaporated under reduced pressure to give the benzofurazan as a white solid (0.91 g, 99%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[N-:9]=[N+:10]=[N-:11].[Na+]>>[N:9]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[N+:10]=[N-:11]
Reactant: O=C(O)CCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCCCCC(=O)O

Procedure:
Reaction of 5-bromopentanoic acid and NaN3, as described for the synthesis of 6, gave 5-azidobutanoic acid 8. Saponification was not necessary. Used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][Al](C)C>C1COCC1.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>[Cl:12][C:4]1[N:3]=[C:2]([CH3:13])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: C[Al](C)C
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc2ccccc12
Temperature: 100 °C

Procedure:
A mixture of 1,3-dichloroisoquinoline (2.0 g, 10.1 mmol), trimethylaluminum (2.0 M in heptane, 6.1 mL, 12.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (117 mg, 0.1 mmol) in THF (8 mL) was heated in a microwave reactor at 100° C. for 15 min. After quenching by addition of water (30 mL), the mixture was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.12 (dd, J=8.5, 0.5 Hz, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.10 (dt, J=8.5, 0.5 Hz, 1H), 7.62-7.60 (m, 2H); 2.97 (s, 3H). LC6: 2.85 min, (M+H): 178.
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7](C(OC)=O)=[CH:6][C:5]=1C1C2C(=CC=CC=2)N=CC=1)([O-])=O.CO.CO[C:27]1[CH:32]=CC(C(C=O)C=O)=C[CH:28]=1>[Pd].CC(O)=O>[N:1]1[C:4]2[N:8]([CH:7]=[CH:6][CH:5]=2)[CH:28]=[CH:27][CH:32]=1
Reactant: COC(=O)c1cc(-c2ccnc3ccccc23)c([N+](=O)[O-])[nH]1
Reactant: COc1ccc(C(C=O)C=O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1cnc2cccn2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 253.9 %

Procedure:
A mixture of methyl 5-nitro-4-quinolin-4-yl-1H-pyrrole-2-carboxylate (23, 90 mg, 0.3 mmol), Pd/C (5%, 45 mg), and MeOH (15 mL) was stirred under argon for 5 min, then under hydrogen for 40 min before removal of the catalyst by filtration through celite. To the orange color filtrate was added 2-(4-methoxyphenyl)malondialdehyde (54 mg, 0.3 mmol) followed by AcOH (2 mL). The resulting reaction mixture was stirred overnight at 82° C., then cooled to rt, quenched with sat. NaHCO3, and extracted with ethyl acetate and CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (90:10) to give 25 as a yellow solid (90 mg, 73%). 1H NMR (DMSO-d6, 500 MHz) δ 9.80 (d, J=3.0 Hz, 1H), 8.97 (d, J=5.0 Hz, 1H), 8.87 (d, J=3.0 Hz, 1H), 8.10 (m, 1H), 8.04 (s, 1H), 7.80 (m, 1H), 7.75 (d, J=5.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.61 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H); nip 230-231° C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].CCN(CC)CC>C(#N)C>[CH3:17][N:18]([CH3:19])[CH:10]([C:3]1[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[C:11]([F:14])([F:13])[F:12]
Reactant: CNC
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(c1c(O)c(=O)ccn1C)C(F)(F)F
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (5.00 g, 22.4 mmol) in 40 mL of acetonitrile at ice-water bath was added Vilsmeier's reagent (4.30 g, 33.6 mmol) portionwise. The resulting mixture was stirred for 2 h before being added to a suspension of dimethylamine hydrochloride (6.00 g, 73.6 mmol) and Et3N (15.0 mL, 107.6 mmol) in 30 mL of acetonitrile. The resulting suspension was stirred at RT for overnight. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (10% MeOH in EtOAc as eluant) to afford title compound, Apo7041 (1.8 g). Yield=32%; 1H NMR (90 MHz, CD3OD-D4) δ (ppm): 7.63 (d, J=7.3 Hz, 1H), 6.41 (d, J=7.3 Hz, 1H), 4.78 (q, J=8.1 Hz, 1H), 3.99 (s, 3H), 2.41 (s, 6H); MS m/z 273 [M+Na]+, 251 [M+1]+, 206 (100%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9]O)([CH2:7]O)[N+:4]([O-:6])=[O:5].C(=O)(O)[O-].[Na+].[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([N:23]1[CH2:9][C:3]([CH2:2][OH:1])([N+:4]([O-:6])=[O:5])[CH2:7][N:26]([CH3:27])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCCNCc1ccccc1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(Cc2ccccc2)CC(CO)([N+](=O)[O-])C1
Temperature: 50 °C

Procedure:
To a mixture of tris(hydroxymethyl)nitromethane (118.9 g), sodium bicarbonate (40 g) and water (1000 ml), N-benzyl-N'-methylethylenediamine (123 g) is added, and the reaction mixture is heated at about 50° C. for 2 hours. After cooling, the solution is extracted with dichloromethane, and the organic layer is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent is evaporated under reduced-pressure to give 1-benzyl-6-hydroxymethyl-4-methyl-6-nitrohexahydro-1H-1,4-diazepine as an oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:37])/[CH:23]=[C:24](\[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)/[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:48]>CO>[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](/[CH:23]=[C:24](\[C:29]2[CH:30]=[C:31]([C:35]([NH2:36])=[NH:48])[CH:32]=[CH:33][CH:34]=2)/[C:25]([F:26])([F:27])[F:28])=[O:37])=[CH:19][CH:20]=1)(=[O:7])(=[O:8])[NH2:5]
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)/C=C(\c2cccc(C#N)c2)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N=C(N)c1cccc(/C(=C\C(=O)Nc2ccc(-c3ccccc3S(N)(=O)=O)cc2)C(F)(F)F)c1
Yield: 61.4 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4,4,4-trifluorobut-2-enamide (90 mg, 0.19 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was placed in the refrigerator at 0° C. over the weekend. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (144 mg, 2 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated then treated with 10 ml trifluoroacetic acid for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}-1-(trifluoromethyl)vinyl)benzenecarboxamidine (57 mg, 47%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 489.15
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@H:23]([NH:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[CH2:27]2)[CH3:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:37][C:34]1[CH:33]=[CH:32][C:31]([C@@H:28]2[CH2:29][CH2:30][C@H:26]([NH:25][C@@H:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH3:24])[CH2:27]2)=[CH:36][CH:35]=1)[CH3:12]
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (5 mL) and ethyl bromoacetate (0.13 mL, 1.2 mmol) were added to 4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenol (331 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. After the extracted solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (NH silica; ethyl acetate/hexane: 5/95-8/92) to give the title compound (298 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1F)=O.O.[NH2:22][NH2:23]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:13]2[C:14](=[C:15]([F:19])[CH:16]=[CH:17][CH:18]=2)[NH:23][N:22]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)c(OC)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Yield: 105.1 %

Procedure:
Prepared as in Example 104 from (2,4-dimethoxyphenyl)[2,3-difluorophenyl]methanone (1.60 g, 5.8 mmol), hydrazine hydrate (1.79 mL, 5702 mmol) and DMAP (0.632 g, 57.5 mmol) to give the product (1.66 g) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.C(Cl)Cl.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[F:26][C:23]([F:24])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1)[C:12]([NH:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:9][CH2:8]1)=[O:27]
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (66 mg, 0.17 mmol) in a 2:1 mixture of CH2Cl2:DMF (3 mL) and TEA (69 μL, 0.50 mmol) was treated with ethyl chloroformate (27 mg, 0.25 mmol). The reaction mixture was allowed to stir overnight, then the solvent was removed in vacuo and the residue was purified by HiTOPs.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[CH:22]=[CH2:21]
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(F)c21
Yield: 68.4 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.108 g, 0.44 mmol), sodium hydride (60% in oil, 0.018 g, 0.45 mmol) and allylbromide (0.043 mL, 0.5 mmol) to give the title compound (0.085 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)c1cccc(CO)c1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of Intermediate 37C (1.079 g, 4.49 mmol) and TBDMS-Cl (1.016 g, 6.74 mmol) in DMF (4 mL) was added imidazole (0.612 g, 8.98 mmol). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The combined extracts were washed with 10% LiCl and brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 40 g column, EtOAc/hexane=0-30%) to afford Intermediate 37D (1.25 g, 79%). HPLC: RT=3.05 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=355.0 [M+H+]. 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J=7.7 Hz, 1H), 7.70-7.62 (m, 1H), 7.47 (d, J=7.7 Hz, 1H), 4.98 (s, 2H), 3.46 (br. s., 3H), 3.36 (br. s., 3H), 0.98 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[O:27])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([NH2:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4].O.C(=O)(O)[O-].[Na+].Cl[CH:30]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:10]([O:16][C@@H:30]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=5)=[CH:36][CH:35]=4)[C:31](=[O:32])[NH:15]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)C
Reactant: O=C(Cl)C(Cl)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (1.8 g) was dissolved in 10 mL EtOAc, 20 mL water and 5.0 g sodium bicarbonate added. 2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride in 10 mL of EtOAc was added and the mixture stirred at rt for 1.5 h. The organic layer was washed with brine, dried and evaporated. The residue was dissolved in 15 mL DMF and potassium carbonate (4.1 g) added. The mixture stirred at r.t. for 3 h and was poured onto water and EtOAc. The organic was washed with 1N HCl, dried and evaporated. The residue was purified over silica (hexanes-EtOAc-2M ammonia in MeOH) to provide (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester 7-methyl ester (2.0 g). LC-MS (m/z) 600.
Reaction SMILES: [ClH:1].[CH:2]1([C:8]2[CH:16]=[CH:15][C:11]([CH:12]([NH2:14])[CH3:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C[CH:19]([NH2:34])[C:20]1C=[CH:24][C:23](CCC2C=CC=CC=2)=[CH:22][CH:21]=1>>[ClH:1].[CH:2]1([C:8]2[CH:9]=[CH:10][C:11]([CH:12]([N:14]=[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:34]3)[CH3:13])=[CH:15][CH:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(N)c1ccc(C2CCCCC2)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C2CCCCC2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting ρ-cyclohexyl-α-methylbenzylamine hydrochloride for the α-methyl-ρ-phenyethylbenzylamine hydrochloride above, results in the formation of 2-(ρ-cyclohexyl-α-methylbenzylimino)hexahydroazepine hydrochloride having a M.P. of 245°-7° C.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.[Li+].[Cl-].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH:23]=O)[CH:14]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH:23]=[CH:3][C:2](=[O:1])[CH3:10])[CH:14]=1
Reactant: COP(=O)(CC(C)=O)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(=O)C=Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl (2-oxopropyl)phosphonate (3.1 g,19.1 mmol), anhydrous LiCl (972 mg, 23 mmol), and 3-quinoline carboxaldehyde 6-1 (3.0 g,19.1 mmol) in anhydrous acetonitrile (70 mL), was treated with DBU (2.9 mL, 19.1 mmol) and the resulting suspension stirred at room temperature for 1 h. The solvent was removed at reduced pressure and the resulting residue partitioned between brine and methylene chloride. The organic layer was removed, dried, and concentrated to afford a yellow solid which was recrystallized from ethyl acetate/hexanes to afford 22-1 as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17]Br)[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1CCBr
Product: CCOP(=O)(CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1)OCC
Temperature: 120 °C
Yield: 34.8 %

Procedure:
3.28 g (10 mmol) of (4S)-3-benzyloxycarbonyl-4-(2-bromomethyl)-1,3-oxazolidin-5-one (from Example 5) are mixed with 3.39 g (20 mmol) of triethyl phosphite and the mixture is heated under argon for 18 hours at 120° C. The excess triethyl phosphite is distilled off under high vacuum and the residue is purified by chromatography on silica gel (mobile phase: dichloromethane/acetonitrile). 1.34 g (34.8% of theory) of (4S)-3-benzyloxycarbonyl-4-[2-(diethoxyphosphinyl)ethyl]-1,3-oxazolidin-5-one are obtained as a colorless oil. Analytical data: