Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][CH2:8][N:9]=[N+]=[N-])([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2]
Reactant: [N-]=[N+]=NCCc1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
A mixture of 3-nitrophenethyl azide (0.9 g, 4.69 mmol), triphenyl phosphine (1.22 g, 4.66 mmol) and CH2Cl2 (80 mL) was stirred at room temperature for 3 days. Solvent was removed and the residue was taken up in EtOH (20 mL). The solution was heated to 70° C., added 2M NaOH aqueous solution (10 mL) and stirred at room temperature for 2 hrs. A 10% HCl aqueous solution (20 mL) was then added and refluxed for 2 hrs. After the mixture cool to room temperature, it was washed with benzene, basified with 5N NaOH to pH-12, extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the product (0.63 g) as a yellow oil.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].Br[C:40]1[CH:41]=[C:42]([CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:43]2[CH2:44][CH2:45][CH:46]([NH:50][S:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)(=[O:53])=[O:52])[CH2:47][C:48]=2[CH:49]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([S:51]([NH:50][CH:46]2[CH2:47][C:48]3[C:49]([CH:32]=[CH:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:40][CH:41]=[C:42]([CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:43]=3[CH2:44][CH2:45]2)(=[O:53])=[O:52])=[CH:59][CH:58]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)CCc1cc(Br)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C=CC(=O)OC(C)(C)C)c2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1.25 g (4 mmol) of tri-o-tolylphosphine, 8.5 ml of triethylamine, 230 mg (1 mmol) of palladium acetate and 9 ml of tert-butyl acrylate are added to a solution of 10 g (20.5 mmol) of methyl 3-(3-bromo-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetra-hydro-1-naphthyl)propanoate, described in Application EP 864 561, in 250 ml of DMF. The reaction mixture is stirred at 110° C. for 8 hours. The solvent is then evaporated off, and purification by chromatography on silica gel, using as eluant a cyclohexane/ethyl acetate mixture (80/20), yields the expected product.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:28][CH3:29])[CH:23]=2)[N:18]=1.[K][S:31][C:32](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[S:33][K]>>[CH3:29][O:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:31][C:32](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[S:33][C:26]1=[N:25]2
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: COc1ccc2nc3c(nc2c1)SC(=C(C#N)C#N)S3
Yield: 79 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 0.75 g of 2,3-dichloro-6-methoxyquinoxaline and 0.90 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark yellow powder weighing 0.78 g with a calculated overall yield of 79 percent.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[H][H]>C(O)C.[Rh]>[F:1][C:2]([F:14])([F:15])[CH:3]1[CH2:4][CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)C1CCC(C(F)(F)F)CC1

Procedure:
Ethyl 4-trifluoromethylbenzoate (4.9 g) was dissolved in ethanol (60 ml) and catalyst (5% rhodium on alumina, 0.5 g) added. Reduction with hydrogen gas was effected at ambient temperature at 50 atmospheres pressure until the theoretical quantity of hydrogen had been absorbed. The catalyst was removed by filtration through "hyflo" filter aid and the solvent was removed by evaporation to provide crude ethyl 4-trifluoromethylcyclohexane-1-carboxylate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:9]=2)=[O:4].[OH-].[Na+]>CO>[CH:14]1([N:10]2[CH:9]=[C:8]3[C:12]([CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7]3)=[N:11]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc2cn(C3CCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cn(C3CCCC3)nc2c1

Procedure:
This compound was prepared according to the method of Example 1.D, starting with 3.28 g (13.4 mmol) 2-cyclopentyl-2H-indazole-6-carboxylic acid methyl ester, 100 mL CH3OH and 40 mL 1N NaOH, to give 2.71 g (88%) of light yellow powder: mp 190-193° C.; Anal. calcd for C13H14N2O2: C, 67.79; H, 6.13; N, 12.16. Found: C, 67.40; H, 6.04; N, 12.38.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:35][CH:36]1[C:57](=[O:58])[N:38]2[C:39]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=3)=[O:45])=[C:40]([OH:43])[CH2:41][S:42][C@H:37]12>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:10]([NH:35][CH:36]2[C:57](=[O:58])[N:38]3[C:39]([C:44]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=4)=[O:45])=[C:40]([OH:43])[CH2:41][S:42][C@H:37]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-propoxyiminoacetic acid (syn isomer, 0.515 g.), N,N-dimethylformamide (0.161 g.), phosphoryl chloride (0.0337 g.) and ethyl acetate (7.9 ml.) were treated in a similar manner to that of Example 15-(1) to give the activated acid solution. On the other hand, trimethylsilyacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.60 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.703 g.) in ethyl acetate (10 ml.), and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above at -10° C. all at once, and stirred at the same temperature for an hour. To the resultant solution were added water (20 ml.) and ethyl acetate (20 ml.). The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (8 ml.) and water (14 ml.) and dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was pulverized with diethyl ether, and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[(2-formamidothiazol-4-yl)-2-propoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.75 g.).
Reaction SMILES: CO.[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[CH2:14][C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH:28]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.C=O.[BH3-][C:38]#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[CH2:14][C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]4)[CH:28]=3)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To abs. MeOH (6 mL) stirred at rt were added 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 104 mg, 0.243 mmol), formaldehyde (0.034 mL, 1.216 mmol) and NaBH3CN (76 mg, 1.216 mmol). The RM was then brought to pH 5-6 with addition of acetic acid and stirred at rt for 2 h. It was then taken into DCM and washed with saturated NaHCO3 sol. The organic layer was then washed with brine, dried on Na2SO4, filtered and evaporated. A purification of the crude by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH with ammonia=100:0->90:10) gave the title compound (tR 3.07 min (conditions 3), MH+=442, 1H-NMR in DMSO-d6: 8.82 (d, 1H); 8.49 (s, 1H); 8.33 (d, 1H); 8.10-8.01 (m, 3H), 7.76 (d, 1H); 7.59 (s, 1H); 7.53 (d, 1H); 7.46 (dd, 1H), 4.53 (s, 2H); 4.20-4.10 (m, 1H); 2.85 (d, 2H); 2.18 (s, 3H); 2.06-1.92 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(C(C)C)C(C)C)C>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene (10.0 g, 57.0 mmol), ethyl 3-aminopropanoate hydrochloride (8.75 g, 57.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (36.0 g, 0.285 mol) in tetrahydrofuran (150 mL) was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and then extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (200 mL×3), and then dried over Na2SO4, then filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc:PE=1:2) to afford ethyl 3-[(4-chloro-2-nitrophenyl)amino]propanoate (10.0 g, yield: 64.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru+3].C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Agent: [Ru+3]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)C(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(1-hydroxy-2-methylpropyl)thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide in dichloromethane (2 mL) was added 4 Å molecular sieves (60 mg), N-methyl morpholin-N-oxide (27 mg) and tetrapropyl ammonium ruthenium tetroxide; (n-Pr)4NRuO4 (5 mg). After stirring at room temperature for 1.5 hours, the reaction solution was directly adsorbed onto silica gel, purification by silica gel column chromatography (hexane/ethyl acetate) was carried out, and the title compound (30 mg) was obtained as a yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2)=[O:8].[OH:25]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2)(=[O:25])=[O:8]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCS(=O)c3ccccn3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccn3)ccc2N1

Procedure:
Prepared analogous to Example 3 from 6-[4-(2-pyridyl-sulfinyl)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[C:29](O)=[O:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN(C1C=CN=CC=1)C>[CH2:23]([N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8](=[O:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:11]([C:29]([NH:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:30])[CH2:12]1)=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)NCCN2CCOCC2)C1
Yield: 46.5 %

Procedure:
According to the procedure of Example 1, Step E above, 47 mg (0.09 mmole) of 1-(N,N-diphenylcarbamoyl)-4-(N,N-di-n-pentylcarbamoyl)piperazine-2-carboxylic acid, 3 mg (0.02 mmole) of DMAP, 25 mg (0.13 mmole) of EDAC, and 24 mg (0.18 mmole) of 4-(2-aminoethyl)morpholine after purification by flash chromatography on 16 g of silica gel with 100:3CH2Cl2 :MeOH provided 26 mg (46%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]3)[N:3]=1.[OH-].[Li+].O.CO>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[N:22]=[CH:21]3)[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)c(N)nn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Cl)cc(Cn3nc(N)c4cc(C(=O)O)ccc43)c21
Temperature: 100 °C

Procedure:
A mixture of compound 67 (0.045 g, 0.11 mmol), lithium hydroxide (0.02 g, 0.44 mmol) in a mixture of tetrahydrofuran (2 mL), water (1 mL) and methanol (1 mL) was heated at 100° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1.C=O.O.[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:33]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[C:10]3[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2NC(C(=NO)N2CCOCC2)C1
Agent: C=O
Solvent: CCO
Solvent: O
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-n2cnc(N3CCOCC3)c2C1

Procedure:
A mixture of 3 g (7.1 mmole) of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine 4-oxide, 0.6 g (20 mmole) of paraformaldehyde, 100 ml of ethanol and 250 mg of paratoluene sulfonic acid hydrate was heated to reflux for 16 hours. The crude product obtained after the usual workup was chromatographed over 60 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The clean fractions of product were combined and evaporated. The residue was crystallized from ether and recrystallized from ethyl acetate/hexane for analysis to yield end product as yellow crystals with mp 200°-203° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:24])=[C:14]2[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2ccc(Cl)cc2c1C1CCNCC1
Yield: 23.1 %

Procedure:
4-(5-Chloro-2-methyl-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 107.8 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 6.2 g (95%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C14H17ClN2, 248.11; m/z found, 249.1 [M++H].
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=O.CO.[CH3:26][NH2:27].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[ClH:1].[Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][NH:27][CH3:26]
Reactant: CN
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 121.8 %

Procedure:
2-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (440 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (494 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (144 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:7→0:1), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 308 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>CN(C)C=O.C(OCC)(=O)C.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>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)=[CH2:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of methyl 4-bromo-2-methylbenzoate (compound 152.1, 14.0 g, 61.1 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Tributyl(ethenyl)stannane (29.3 g, 92.4 mmol, 2.00 equiv) and Pd(PPh3)4 (7.10 g, 6.14 mmol, 0.10 equiv) were added to the reaction. The resulting mixture was stirred overnight at 100° C. in an oil bath. After cooling to room temperature, the mixture was diluted with 400 mL of ethyl acetate. The organic layer was washed with 2×400 mL of NH4Cl (aq.) and 2×400 mL of brine, dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude product was purified by CombiFlash with the following conditions (IntelFlash-1): mobile phase, petroleum ether/ethyl acetate=1:0 increasing to petroleum ether/ethyl acetate=100:1 within 20 min; Detector, UV 254 nm. This resulted in 6.81 g (63%) of methyl 4-ethenyl-2-methylbenzoate as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]2[C@@H:3]1[CH2:4][C:5]1[C:6]3[C:19]([NH:20][CH:21]=1)=[CH:18][CH:17]=[CH:16][C:7]=32.[Br:22]C1CC(=O)NC1=O>C(Cl)(Cl)Cl>[Br:22][C:21]1[NH:20][C:19]2[C:6]3[C:5]=1[CH2:4][C@H:3]1[C@H:8]([C:7]=3[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][N:2]1[CH3:1]
Reactant: O=C1CC(Br)C(=O)N1
Reactant: CN1Cc2ccccc2[C@H]2c3cccc4[nH]cc(c34)C[C@@H]21
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2[C@H]2c3cccc4[nH]c(Br)c(c34)C[C@@H]21

Procedure:
4 g of trans-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine are suspended in 300 ml of chloroform, and the stirred suspension is heated to reflux temperature. A solution of 2.7 g of bromosuccinimide in 100 ml of chloroform is quickly added, and the clear reaction solution is then refluxed for a further hour. The cooled reaction solution is extracted with 1n aqueous sodium carbonate solution, the organic phases dried, concentrated and the evaporation residue chromatographed on silica gel with methylene chloride/methanol=95/5 (methylene chloride 10% saturated with NH3). The title compound is obtained. Its bis[base]fumarate is cryst allised from methanol (m.p. 235°-237°).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([C:40](OC)=[O:41])[N:33]=[C:32]2[CH2:44][CH2:45][CH2:46][CH3:47])=[CH:26][CH:25]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O1CCCC1>[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH2:40][OH:41])[N:33]=[C:32]2[CH2:44][CH2:45][CH2:46][CH3:47])=[CH:26][CH:25]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 79.4 %

Procedure:
42 ml of diisobutylaluminum hydride (as a 1.5M solution in toluene) were added dropwise at a temperature between -20° C. and -15° C. to a solution of 16.0 g of dimethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-4,5-dicarboxylate [prepared as described in step (a) above] in 200 ml of tetrahydrofuran, and the resulting mixture was allowed to stand at 0°-5° C. for 16 hours. At the end of this time, the reaction mixture was mixed with an aqueous solution of ammonium chloride and ethyl acetate and was then stirred for 1 hour. After this, precipitates were removed by filtration. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was then purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 12.0 g of the title compound as crystals, melting at 99° C.