Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][OH:20])[NH:13][CH2:14]2.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].BrC1C=CC=C2C=1C[C@H](CO)N(C(OC(C)(C)C)=O)C2>ClCCl.CN(C)C1C=CN=CC=1>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[NH:13][CH2:14]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1Cc2c(Br)cccc2CN1
Agent: CC(C)(C)OC(=O)N1Cc2cccc(Br)c2C[C@@H]1CO
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[CH:18]1[CH2:20][CH2:19]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30].[F-].[Cs+].COCCOC>O>[CH:18]1([C:8]2[CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:7]=2[C:27]2[CH:26]=[CH:25][C:24]([F:23])=[C:29]([F:30])[CH:28]=2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCOc1cc(C=O)cc(C2CC2)c1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(C=O)cc(C2CC2)c1-c1ccc(F)c(F)c1
Yield: 58.6 %

Procedure:
(1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.30 g) was added to a mixture of 2-cyclopropyl-6-ethoxy-4-formylphenyl trifluoromethanesulfonate (3.00 g), (3,4-difluorophenyl)boronic acid (5.60 g), cesium fluoride (5.39 g), and DME (15 mL), and the resultant mixture was stirred at 100° C. for 15 hours in an argon atmosphere. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.57 g).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][C:29]([O:31]C)=O)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[NH3:33].O>CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][C:29]([NH2:33])=[O:31])[CH:17]=1
Reactant: N
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 50 °C

Procedure:
A mixture of methyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (0.5 g, 0.001 mol) and aq. NH3.H2O (28%, 10 mL) in CH3OH was stirred at 50° C. over night. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with brine, dried and concentrated, purified by column chromatography (PE:EA 5:1˜1:3) to give the title compound, which was dissolved in MeCN, acidified with aq. HCl and freeze-dried to give the product as hydrochloride salt (200 mg, yield 53%). 1HNMR DMSO-d6 400 MH. δ9.85 (s, 1H), 9.17 (s, 1H), 7.43-6.32 (m, 6H), 5.92 (s, 2H), 4.86 (s, 2H), 3.74 (s, 2H). LC-MS m/z 360 (M−H, negative); HPLC purity: 96.93% (220 nm), 99.27% (254 nm).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH:14](Cl)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])C.[Na+].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[CH2:45][N:44]([C:47](=[S:49])[NH2:48])[CH2:43][CH2:42]2)=[O:36]>CCOCC.CCO.CN(C=O)C>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[CH2:45][N:44]([C:47]1[S:49][C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:48]=1)[CH2:43][CH2:42]2)=[O:36]
Reactant: NC(=S)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)propanal (1 g, 5.31 mmol) and ethyl 2,2-dichloroacetate (0.651 mL, 5.31 mmol) in Et2O (4 mL) at 0° was dropwise added sodium ethanolate (0.397 g, 5.84 mmol) in EtOH (4 mL). The reaction mixture was stirred at 0° C. for 1.5 h and diluted with Et2O. The resulting mixture was washed with brine and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was dried in vacuo and dissolved in EtOH (8 mL). To the resulting solution was added Example 49A (1 eq) in DMF. The reaction mixture was heated at 50° C. for 8 hours and concentrated under reduced pressure. The residue was dissolved in DCM and purified by column chromatography on silica gel eluting with 0% to 17% EtOAc in hexanes, then with 0% to 15% EtOAc in DCM to provide the desired product 49B: LCMS (APCI): m/z 623 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[Se:5][C:6]=1[C:7]#[N:8].C([OH:15])C>[OH-].[Na+]>[NH2:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[Se:5][C:6]=1[C:7]([NH2:8])=[O:15]
Reactant: N#Cc1[se]c2ccccc2c1N
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1[se]c2ccccc2c1N
Temperature: 7.5 °C
Yield: 60 %

Procedure:
To a suspension of 3-aminobenzo[b]selenophene-2-carbonitrile (5.0 g) in aqueous sodium hydroxide solution (100 mL, 10%) was added ethanol (60 mL) and the mixture refluxed for 1 h. Ethanol was distilled off under vacuum (appr. 25 mL) and the mixture was allowed to cool to 5-10° C. The separated crystals were filtered off, washed with cold water and dried to give the product as a off-white color solid (3 g, 60%), mp 180-182° C. 1H NMR (400 MHz, DMSO-d6): δ 7.99-8.01 (1H, m, H-7), 7.92-7.94 (1H, m, H-4), 7.40-7.42 (2H, m, H-5,6), 7.21 (2H, s, —CONH2), 6.97 (2H, s, —NH2); LC-MS (positive ion mode): m/z 261, 263 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]([OH:8])[CH:6]([CH3:9])[CH2:5][C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+:16].N.[H][H]>CO.[Ni]>[NH2:16][CH:4]1[CH2:5][CH:6]([CH3:9])[CH:7]([OH:8])[C:2]([CH3:11])([CH3:1])[CH2:3]1
Reactant: CC1CC(=O)CC(C)(C)C1O
Reactant: [H][H]
Reactant: [NH4+]
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Product: CC1CC(N)CC(C)(C)C1O

Procedure:
156 g of 3,3,5-trimethyl-4-hydroxycyclohexanon (formula VIa), 12 g of ammonium acetate and 60 g of Raney Ni in 250 ml methanol were hydrogenated at 100° C. under a hydrogen pressure of 100 bar in the presence of 250 ml of ammonia. When the uptake of hydrogen was complete, the catalyst was filtered off, the filtrate was concentrated under vacuum and the residue was subjected to fractional distillation under a high vacuum. 130 g of the aminoalcohol of formula Ic, which had a melting point of 110 to 112° C., were obtained at 90 to 97° C. (0.1 mbar). According to analysis by gas chromatography, an isomer mixture (four isomers) was present.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:23])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Reaction time: 6 h
Yield: 44.1 %

Procedure:
200 mg (0.850 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 20 ml of dichloromethane were stirred at room temperature, and 92 μl (0.935 mmol) of isopropyl isocyanate were added thereto and stirred for 6 hours. The crystals precipitated were filtered off to obtain 120 mg of the intended compound as colorless crystals. (yield: 44%)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]([CH:20]1[CH2:23][NH:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:21][CH:20]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: c1ccc(OC2CNC2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of methyl 2,5-dichloronicotinate (217 mg, 1.05 mmol) in tetrahydrofuran (5 ml), 3-phenoxyazetidine (D48) (149 mg, 1.05 mmol) and triethylamine (117 mg, 1.16 mmol) were added and the mixture was heated at reflux for 18 hours. The resulting mixture was cooled to room temperature, the precipitates were filtered off and the filtrate was concentrated under vacuo. The residue was dissolved in ethyl acetate (5 ml), washed with water (5 ml) and brine (5 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate from 30:1 to 20:1. Collected fractions after solvent evaporation afforded the title compound (D75) (250 mg) as a white solid.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>C(OCC)C>[P:1]([O:8][Si:17]([CH3:19])([CH3:18])[CH3:16])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOP(OCC)O[Si](C)(C)C
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a mixture of diethyl phosphite (2.8 mL, 0.0217 mol) and triethylamine (9.mL, 0.065 mol, 3.0 equiv.) in dry diethyl ether (250 mL) at 0° C. was slowly added freshly distilled trimethylsilyl chloride (3.3 mL, 0.0260 mol, 1.2 equiv.) via syringe. The resulting slurry was allowed to slowly warm to room temperature, and was then warmed to 45° C. for 14 h. Volatiles were removed by distillation using a 55° C. oil bath. The resulting mixture was diluted with pentane (150 mL), filtered to remove triethylammonium salts, and concentrated at atmospheric pressure using a 55° C. oil bath. Distillation of the resulting oil gave diethyl trimethylsilyl phosphite as a colorless oil (3.64 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@H:6]([NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)[CH3:2].O1CCOCC1>Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@H:6]([NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)O
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate, (65 mg, 0.13 mmol) in 4M HCl in 1,4-dioxane (671 μL, 2.68 mmol) is stirred at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoic acid (23 mg). HPLC retention time=1.66 minutes (condition D); MS (m+1)=432.3; 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.17 (t, J=7.1 Hz, 3 H) 2.21-2.32 (m, 2 H) 2.32-2.40 (m, 2 H) 2.40-2.48 (m, 2 H) 2.77 (d, J=6.8 Hz, 2 H) 3.74 (s, 3 H) 4.03 (q, J=7.1 Hz, 2 H) 4.19-4.33 (m, 1 H) 7.04-7.20 (m, 3 H) 7.23 (d, J=8.1 Hz, 2 H) 7.43 (d, J=8.1 Hz, 2 H) 7.93 (d, J=8.3 Hz, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].Cl[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:18]([CH3:20])=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-(2-ethoxy-5-fluorophenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a4) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][CH:14]=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: [OH-]
Reactant: COc1ccc(C2CC2CC=O)cc1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CC2CC(=O)O)cc1F
Reaction time: 3 h
Yield: 79.6 %

Procedure:
[2-(3-Fluoro-4-methoxy-phenyl)-cyclopropyl]-acetaldehyde (0.088 g, 0.42 mmol) obtained in Step C was dissolved in EtOH (2 mL). AgNO3(0.143 g, 0.84 mmol) dissolved in water (0.26 mL) and NaOH (0.067 g, 1.69 mmol) dissolved in water (0.26 mL) was added thereto in turn, and the mixture was stirred for 3 hours. After the termination of the reaction, the reactant was filtered by using celite to remove solid material, and 1N HCl aqueous solution was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with EtOAc was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.075 g, 79%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[C:22]3[C:14]([C:15]4[CH2:16][CH2:17][C:18]5[CH:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[CH:24][C:19]=5[C:20]=4[NH:21]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.O1CCCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:31][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:19]2[C:20]3[NH:21][C:22]4[C:14]([C:15]=3[CH2:16][CH2:17][C:18]=2[CH:27]=1)=[CH:13][CH:12]=[C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1)[CH:23]=4)=[O:30]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)O)cc2CC4)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)NC)cc2CC4)cc1
Reaction time: 8 h

Procedure:
A sample of 9-(4-Butyl-phenyl)-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid (116.2 mg, 41 μmol) is dissolved in DMF (1 mL) and treated with HATU (16.3 mg, 41 μmol) and a solution of methylamine (2M) in tetrahydrofuran (0.1 mL, 100 μmol). After stirring overnight, the reaction is diluted with ethyl acetate and extracted with water twice. The organics are dried over MgSO4 and the solvent is removed. The resulting residue is purified by mass triggered HPLC to afford the title material as a white solid after lyophilisation. LC/MS calculated for [M+H]+ C28H29N2O: 409.5, found: 409.1
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.[Cl-].[Na+].CS(C)=O.Cl>O>[CH3:32][S:29]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Temperature: 185 °C
Yield: 95.7 %

Procedure:
A mixture of methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate (36.7 g., 0.077 mole), sodium chloride (4.68 g., 0.08 mole), water (1 ml.) and dimethylsulfoxide (60 ml.) is heated in a bath maintained at 185° C. under nitrogen for 5 hours. The resulting reaction mixture is concentrated in vacuo at 100° C. providing an oily residue which is diluted with water. The aqueous mixture is acidified to Congo Red with 6N hydrochloric acid and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo leaving the title compound as a viscous oil (31 g., 95%), pmr (CDCl3) δ2.0 (s, 3H), 2.82 (s, 3H), 3.63 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[CH:30](CNC1C=CC=CC=1[N+]([O-])=O)[C:31]([OH:33])=[O:32])=O)(C)(C)C.[CH3:45]O>[Pd]>[CH3:45][O:33][C:31](=[O:32])[CH2:30][N:21]1[C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Product: COC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Reaction time: 4 h

Procedure:
2(S)-tert-Butoxycarbonylamino-3-(2-aminophenyl-amino)-propionic acid. A mixture of 2-tert-Butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd/C in 100 ml of methanol under hydrogen at 1 atmosphere was stirred for 4 hrs. The solution was filtered through Celite 545 and the filtrate evaporated in vacuo to afford 11.95 g of the title compound in quantitative yield as a dark brown solid that was used without purification. 1H NMR (CD3OD) δ 6.75-6.70 (3H, m), 6.65-6.58 (1H, m), 4.35-4.3 1H, m), 3.6-3.38 (2H, m), 1.45 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].[H][H].C([Li])(C)(C)C.[C:21](=[O:23])=[O:22]>O1CCCC1>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:21]([OH:23])=[O:22])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: O=C=O
Reactant: [H][H]
Reactant: Clc1cc(Br)c2[nH]ncc2c1
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 7-bromo-5-chloro-1H-indazole (23.7 g, 102 mmol) in tetrahydrofuran (400 mL) at 0° C. was added sodium hydride (2.70 g, 113 mmol) in portions to control the release of hydrogen. The ice bath was removed and the reaction was stirred at room temperature for 20 min. The reaction was then cooled to −78° C. and treated with tert-butyllithium (1.7 M, 126 mL, 215 mmol) dropwise over 20 min. The reaction was allowed to gradually warm to −40° C. in the icebath over 1 h. The reaction was re-cooled to −78° C. and treated with an excess of freshly crushed pellets of dry ice. The ice bath was removed and the reaction allowed to gradually warm to room temperature. The reaction was diluted with diethyl ether, and washed with water until most of the insoluble solid was dissolved. The ethereal was washed once more with 1M sodium hydroxide, which was combined with the other aqueous layers. The ethereal was discarded. The combined aqueous washings were cooled to 0° C., and made acidic by the cautious addition of concentrated hydrochloric acid to give a precipitate. The resulting solid was collected by filtration to give the product as a light tan solid. The product was air dried overnight and then pumped under high vaccuum to remove any trace of water to give 15.9 g (79%) which was used without purification. 1H-NMR (d6-DMSO, 500 MHz) δ 13.29 (bs, 1H), 8.18 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H); 13C NMR (126 MHz, d6-DMSO) δ ppm 165.6, 136.5, 133.6, 128.0, 125.5, 124.8, 123.9, 115.5. Mass spec.: 196.97 (MH)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].[OH-].[Na+].Cl>C(O)C.O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NC(N)=S
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCCCCS

Procedure:
11-Bromoundecanoic acid (20.0 g, 0.075 mol) and thiourea (6.3 g, 1.1 equiv.) were refluxed in ethanol (250 mL) overnight. Sodium hydroxide (6.3 g) in water (20 mL) was added and the mixture was further refluxed for 2 hr. The solution was cooled and acidified with 1N HCl. Ethanol was evaporated under reduced pressure and the aqueous residue was extracted With CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated to give white powder. Yield: 15.0 g (91%)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:28])=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[ClH:28].[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)cc1
Product: Cl
Yield: 64.2 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 18.4 g (0.0799 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 32.07 g (0.1598 mol) of p-tert-butylbenzoyl chloride, with the exception that after removing methanol the resultant oil was crystallized from ethyl acetate to provide an oily solid. This solid was purified by filtration through silica gel using 7% methanol in dichloromethane. The filtrate was reduced to dryness under reduced pressure and the resultant residue was recrystallized from an ethyl acetate/methanol/diethyl ether solution containing hydrochloric acid to provide 21.9 g of the desired titled compound (m.p. 207°-211° C.).