Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[N:7]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:23]([O:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[N:7]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:6]1=[O:5])[CH2:24][CH2:8][CH2:9][CH2:21][CH3:22]
Reactant: O=C(O)CCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21
Solvent: O=S(Cl)Cl
Product: CCCCCCOC(=O)CCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 cc. of thionylchloride are added to 1 g. of 8-(2-oxo-3-phenyl-benzimidazolin-1-yl)-caprylic acid and the mixture is stirred at room temperature for 2 hours. Unreacted thionylchloride is evaporated in a vacuum, the residue is dissolved in a small amount of anhydrous chloroform and 238 mg. of hexanol are added to the solution. The mixture is stirred at room temperature for 4 hours, consequetively washed with 5% NaHCO3 solution and water, dried over Na2SO4 and evaporated in a vacuum. The residue is further purified chromatographically on silicic acid gel using hexane/ethyl acetate as eluant.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[N:17]=[C:18]([Cl:34])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]=12)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:34].[CH2:27]([N:22]1[C:21]2=[C:16]([NH:7][CH2:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[N:17]=[C:18]([Cl:34])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]1[CH3:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)nc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)n(Cc2ccccc2)c2c(NCc3ccc(F)cc3)nc(Cl)cc12

Procedure:
A solution of (1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 3 in ethyl acetate was saturated with hydrochloric acid gas and then filtered. The resulting solid was dried under reduced pressure to give 23.5 mg of the titled compound as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:11]=[N:12][CH:13]=[CH:14][CH:15]=1>[Cl-].[Zn+2].[Cl-]>[C:2]1([CH:1]=[CH:9][C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccnn1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: C(=Cc1cccnn1)c1ccccc1
Temperature: 150 °C
Yield: 59 %

Procedure:
Zinc chloride (820 mg, 6 mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60 mmol) and 3-methylpyridazine (2.83 g, 30 mmol) and the resulting mixture heated for 20 hours at 150° C. The cool reaction mixture was partitioned between dichloromethane (40 ml) and 2M aqueous sodium hydroxide solution (20 ml), then the organic phase separated, combined with a dichloromethane extract (80 ml) of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (99:1) as eluant, to give the title compound (59%) as a solid. δ (CDCL3): 7.12 (1H,d), 7.34 (3H,m), 7.56 (2H,d), 7.72 (1H,d), 8.37 (1H,s), 8.50 (1H,s), 8.60 (1H,s). LRMS: m/z 183 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18].C(N(CC)CC)C.[C:27]1([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH2:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 18.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10 g), triethylamine (4.8 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (5.4 g) in toluene (300 cc). The mixture is heated for 9 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystalline from boiling acetonitrile (10 cc), 2-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (2.6 g) is obtained, m.p. 101° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:18][C:17](=[O:19])[C@@H:16]1[C@:20]2([CH3:22])[C@H:13]([C@H:12]3[C@H:3]([C:2](=[O:1])[CH2:21]2)[C@:4]2([CH3:24])[C:9](=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
11α-Hydroxypregna-1,4-diene-3,20-dione (120 mmol) in acetone (950 ml) is treated with Jones reagent (38.7 ml) at 0°. Following work-up the title compound is obtained.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)=[N+:2]=[N-:3].[Cl:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1.CCN(CC)CC>CC#N>[N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:36][CH:35]=2)[CH2:30][CH2:31]1)=[N+:2]=[N-:3]
Reactant: Clc1ccc(CC2CCNCC2)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 8.6 %

Procedure:
A murky solution of (±)-trans-4-nitro-benzenesulfonic acid 2-azido-cyclohexyl ester (1.77 g, 5.41 mmol), 4-(4-chlorobenzyl)-piperidine (1.14 g, 5.43 mmol), and Et3N (0.75 mL, 5.4 mmol) in CH3CN (11.2 mL) was stirred at room temperature for 17 hours, 65° C. for 31 hours, and 80° C. for 5 d, allowed to cool to room temperature, and concentrated. The residue was partitioned between CH2Cl2 and 1 N NaOH, the aqueous phase was extracted with CH2Cl2 and the extracts were dried and concentrated. Chromatography of the residue with 98:1.9:0.1–95:4.75:0.25 CH2Cl2:MeOH:NH4OH to 100% MeOH and subsequent chromatography with 10:1 hexanes:EtOAc to 100% EtOAc followed by 95:5 EtOAc:MeOH gave, in order of elution, starting (±)-trans-4-nitro-benzenesulfonic acid 2-azidocyclohexyl ester (1.2 g, 68%), desired product (155 mg, 9%), and starting 4-(4-chlorobenzyl)-piperidine (810 mg, 71%). Product: 1H NMR δ 1.19–1.81 (m, 12H), 1.92–2.08 (m, 3H), 2.22 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 3.02 (m, 2H), 4.05 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 333.2 (M+H)+.
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[NH2:2].[C:16]1([CH:22]([CH:25]=O)[CH:23]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([C:22]2[CH:23]=[N:2][N:1]([CH:3]3[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]3)[CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CC(C=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NN)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccccc3)cn2)CC1
Temperature: 75 °C
Reaction time: 36 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 4-hydrazinopiperidine-1-carboxylate (646 mg) and ethanol (15 mL) was added phenyl malonaldehyde (444 mg), followed by stirring at 75° C. for about 1.5 days. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/chloroform-50/50 to 0/100) to obtain tert-butyl 4-(4-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (226 mg).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)C1C=CC=CC=1>CCOC(C)=O.CC(O)=O.[Pd]>[CH:9]12[NH:8][CH:13]([CH2:14][C:15](=[O:17])[CH2:16]1)[CH2:12][O:11][CH2:10]2
Reactant: O=C1CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirring mixture of 9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (1.1 g, 4.76 mmol) in EtOAc/HOAc (6 mL, 1:1, v/v) was added palladium on carbon (250 mg). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 2 days. The suspension was filtered through Celite and the filtrate was concentrated under vacuum to give a quantitative yield of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a yellow oil. This crude mixture was converted to the corresponding hydrochloric salt by the addition of HCl (3 mL, 1N aqueous HCl). The mixture was concentrated under reduced pressure and this process was repeated twice. Retention time (min)=0.231, Method [1], MS(ESI) 142.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([CH3:15])[CH:9]1C(OCC)=O.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([CH3:15])[CH2:9]1
Reactant: CCOC(=O)C1C(C)=CC(=O)CC1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=CC(=O)CC(c2ccccc2F)C1
Yield: 98.6 %

Procedure:
To 5-(2-fluorophenyl)-3-methyl-4-carbethoxy-2-cyclohexen-1-one (57.3 g, 0.21 mole) was added a solution of sodium hydroxide (11.5 g, 0.29 mole) in 35 ml of ethanol and 80 ml of water. The stirred reaction mixture was heated under reflux for 8 hours. The ethanol was removed by evaporation under reduced pressure, and the residue was extracted with diethyl ether. The ether extract was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 5-(2-fluorophenyl)-3-methyl-2-cyclohexen-1-one (42.3 g).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[C:6]([CH2:10][C:11]#N)[C:5]([CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[O:2]1.N>[Ni]>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]3[CH2:10][CH2:11][NH:15][CH2:14][CH2:13][C:5]=3[CH:4]=2)[O:9]1
Reactant: N#CCc1cc2c(cc1CC#N)OCO2
Agent: [Ni]
Agent: N
Product: c1c2c(cc3c1OCO3)CCNCC2
Yield: 105.5 %

Procedure:
119 g. (0.595 moles) of 4,5-methylenedioxy-1,2-benzenediacetonitrile was hydrogenated in 2.4 l. of ammonia-saturated ethanol at an initial pressure of 1,000 PSI and 100° C in the presence of 24 g of Raney nickel for 4 to 5 hours. The cooled autoclave contents were filtered to remove the nickel, the catalyst washed with 500 ml of hot ethanol, and the filtrate distilled at reduced pressure, leaving 120 g of dark gray oil. This oil was distilled in vacuo using a Claisen still head and several fractions were collected. The low boiling fractions contained the desired produ ct which upon purification yielded the above-named product, m.p. 82°-84°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([O:35]C)=[O:34])[C:23]4=[O:37])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:37])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)NC(=O)C(NC(=O)OC(C)(C)C)C4)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(NC(=O)OC(C)(C)C)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Methyl 8-(3-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (43 mg, 0.083 mmol) was dissolved in MeOH (2 mL) and sodium hydroxide 1M solution in water (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 50° C. for 2 h. After cooling, the MeOH was removed in vacuum. The residue was dissolved in water (5 mL) and then neutralized with 1M HCl (−0.5 mL). The precipitate formed was stirred at room temperature overnight. The mixture was extracted with DCM (3×4 mL). The organic layers were concentrated to afford the title compound as a yellow solid (29 mg, 69%).
Reaction SMILES: I[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([NH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[K]>CO.[Pd]>[C:12]([NH:11][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[C:2]([C:9]([O:8][CH3:7])=[O:10])=[CH:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(I)c2c1OCO2
Agent: [Pd]
Agent: [K]
Solvent: CO
Product: COC(=O)c1ccc(NC(C)=O)c2c1OCO2
Temperature: 150 °C
Reaction time: 16 h
Yield: 128.6 %

Procedure:
A mixture of intermediate 19 (38.8 g), potassium acetae (20 g) and Pd/C (10%; 2 g) in CH3OH (500 ml) was stirred at 150° C. under 4.9×106 Pa (50 kg) pressure of CO, during 16 hours. The reaction mixture was cooled, filtered over dicalite, and the filtrate was evaporated. The residue was diluted with water, then extracted three times with DCM. The combined organic layers were dried, filtered and the solvent evaporated. The residue was dissolved in acetic acid (250 ml) and acetic anhydride (6 ml) was added dropwise. The mixture was stirred for 30 minutes at room temperature, then diluted with water (250 ml) and the resulting precipitate was filtered off, washed with water, then dried, yielding 19.4 g (64.7%) of methyl 7-(acetylamino)-1,3-benzodioxole-4-carboxylate (intermediate 20).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:27]([O:34][C:35]([NH:37][C:38](=NC(OCC1C=CC=CC=1)=O)SC)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:28]1([CH2:27][O:34][C:35]([NH:37][C:38]2[NH:1][C:2]3[CH:3]=[C:4]([C:9]4[CH:10]=[CH:11][C:12]5[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=5[CH:26]=4)[CH:5]=[CH:6][C:7]=3[N:8]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)cc2C1
Temperature: 60 °C
Yield: 45.1 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.0 g, 5.6 mmol) in acetic acid (20 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (2.4 g, 6.7 mmol) and the resulting mixture was heated (60° C.). After 12 h the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was then washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography on silica (0 to 50% ethyl acetate/hexanes) provided 1,1-dimethylethyl 7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.3 g, 45% yield) as a brown solid. MS (EI) for C29H30N4O5: 515 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:24][C@:25]([CH3:76])([CH2:74][I:75])[C:26](=[O:73])[C@H:27]([CH2:69][CH:70]([CH3:72])[CH3:71])[NH:28][C:29](=[O:68])[C@H:30]([CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[NH:31][C:32](=[O:60])[C@H:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[NH:34][C:35](=[O:55])[C@H:36]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[NH:37][C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)(=[O:23])[CH2:9][CH2:10][C:11]([O:13]CC1C=CC(OC)=CC=1)=[O:12]>C(Cl)Cl>[CH2:61]([C@@H:30]([C:29](=[O:68])[NH:28][C@@H:27]([CH2:69][CH:70]([CH3:72])[CH3:71])[C:26](=[O:73])[C@:25]([CH2:74][I:75])([CH3:76])[O:24][C:8](=[O:23])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH:31][C:32](=[O:60])[C@H:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[NH:34][C:35](=[O:55])[C@H:36]([CH2:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[NH:37][C:38](=[O:46])[CH2:39][N:40]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: COc1ccc(COC(=O)CCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@@](C)(CI)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Referring to FIG. 43, TFA (6 mL) was added dropwise to a solution of compound (4S,7S,10S,13S,15S)-10-benzyl-16-iodo-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-15-yl 4-methoxybenzyl succinate (21, 1.7 g, 1.59 mmol) in DCM (30 mL) at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. TFA was removed under reduced pressure and the residue was dissolved in DCM (50 mL). The resulting mixture was washed with water (40 mL×3) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give product (quantitative without further purification).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.O1CCCC1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1nccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nccc2c(N)cccc12
Yield: 88 %

Procedure:
1-Methyl-5-nitroisoquinoline (prepared according to Rathelot, P. et al. Eur. J. Med. Chem. 1995, 30, 503-508.) (2.19 g, 11.64 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL) in a 250 mL stainless steel pressure bottle to which was added 5% Pd—C (0.438 g, 4.12 mmol). The reaction mixture was stirred for 2 h under 30 psi hydrogen at ambient temperature. The mixture was filtered through a nylon membrane and the volatiles evaporated in vacuo. The resulting grayish solid was triturated with 1:1 hexanes-CH2Cl2 (50 mL) and the title compound (1.62 g, 10.24 mmol, 88%) was collected as an off white solid. MS (DCI/NH3) m/z 159 (M+H)+.
Reaction SMILES: C([CH:3]([CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O)[CH:4]=[O:5])C>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[C:16]([C:6]1[CH:3]=[CH:4][O:5][C:7]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C(=O)c1ccc(C)cc1)C(C=O)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccoc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
Ethyl 3-Carboethoxy-4-(4-methylphenyl)-4-(oxo)-butanal (10.00 g), trifluoroacetic anhydride (50 mL) and trifluoroacetic acid (2 drops) were mixed and stirred at 0° over ice and allowed to warm to room temperature. After 3 hours, more trifluoroacetic anhydride (50 mL) together with trifluoroacetic acid (2 drops) were added at room temperature. The next day, the solvent was removed in vacuo and the residue partitioned between 1N NaOH (200 mL) and ethyl acetate (200 mL). The layers were separated and the organic layer washed with 1N NaOH (2×200 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield a brown oil (9.95 g) which was flash chromatographed in 99:1 hexane/ethyl acetate to yield 2.57 g of an off-white solid; m.p. 79.0°-80.5°. NMR (200 MHz, CDCl3) δ7.88 (d, 2H, J=9 Hz); 7.42 (d, 1H, J=2 Hz); 7.26 (d, 2H, J=9 Hz); 6.83 (d, 1H, J=2 Hz); 4.34 (q, 2H, J=7 Hz); 2.40 (s, 3H); 1.34 (t, 3H, J=7 Hz). Anal. Calcd. for C14H14O3 : C, 73.03; H, 6.13. Found: C, 73.52; H, 6.30.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:22])([F:23])[F:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (164.0 mg, 0.47 mmol) and triphenylphosphine (184.2 mg, 0.70 mmol) in methylene chloride (1.2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (141.6 mg, 0.80 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole (140.6 mg, 1.40 mmol). The resulting reaction mixture was stirred at 25° C. for 22 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (47.9 mg, 24%) as a cream solid: mp 189-191° C.; EI-HRMS m/e calcd for C18H19F3N2O3S2 (M+) 432.0789, found 432.0791.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CO>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To an ice-cold solution of 0.158 g (0.5 mM) of 7-amino-4-(3-bromoanilino)-quinazoline [J Med Chem, 1995:3482] and 0.108 g of acrylic acid in 5.0 mL of dry dimethylformamide (DMF) was added 0.288 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDAC). After stirring for 5 minutes, the mixture became a solution, and the ice bath was removed. The reaction continued to stir at room temperature for 3 hours. The reaction was then poured into a mixture of ice and water and made basic with the addition of a saturated solution of sodium bicarbonate. This aqueous mixture was extracted three times with ethyl acetate, and the pooled extracts were dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to afford a light yellow solid. The solid was dissolved in 100 mL of methanol, filtered, and concentrated in vacuo to approximately 10 mL. The solid which precipitated from solution was collected and dried in vacuo at 80° C. to give 50 mg of N-[4-(3-bromo-phenylamino)-quinazolin-7-yl]acrylamide, mp >265° C. Chemical ionization mass spectra: m/e 369.