Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:29](=[O:32])[CH2:30][CH3:31])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Reactant: CCC(=O)Cl
Product: CCC(=O)NCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yi)-4-aminomethyl-benzamide and propionyl chloride, the title compound was prepared as off-white crystals (34% yield). MS: m/e=455(M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.[Cl-].[Na+].O>[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc2c(c1)OCC2=O)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-benzofuran-3-one (1.01 g, 6.73 mmol) in dry dichloromethane (18 mL) was added imidazole (0.458 g, 6.727 mmol) followed by tert-butyldiphenylchlorosilane (1.72 mL, 6.73 mmol) at room temperature. The mixture was stirred overnight and poured into brine. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, evaporated in vacuo and the residue was purified by column chromatography (ethylacetate:hexane; 1:9) to give the 6-(tert-butyl-diphenyl-silanyloxy)-benzofuran-3-one as slightly yellow oil (1.34 g, 52%). 1H NMR (CDCl3, 400 MHz) 1.21 (s, 9H), 4.54 (s, 2H), 6.40 (s, 1H), 6.55 (dd, J=1.6, 8.0 Hz, 1H), 7.38-7.50 (m, 7H), 7.67 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>C1COCC1>[C:32]1([S:38][CH:6]2[CH2:5][CH:4]3[CH:8]([C:2](=[O:1])[CH2:3]3)[CH:7]2[C:9]([O:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2CC(=O)C12
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CC2CC(Sc3ccccc3)C(C(=O)OC(c3ccccc3)c3ccccc3)C12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Twenty grams of 7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, 13, were dissolved in 40 mL of THF by gentle warming. To this solution at room temperature was added 1.0 mL of triethylamine and 13.0 mL of thiophenol. The resulting solution was stirred under argon at room temperature for 1 hr, after which time 0.5 mL of acetic acid was added, and the solvent was removed by rotary evaporation at 40°. Crystallization from ether at room temperature afforded 21 g (78%) (total of 2 crops) of 3-phenylthio-7-oxobicyclo[3.2.0]heptan-2-carboxylic acid, diphenylmethyl ester, 14. NMR (220 MHz; CDCl3): δ 2.23 (1H, m), 2.43 (1H, m), 2.84 (1H, m), 3.07 (2H, m), 3.41 (1H, m), 3.80 (2H, m), 6.77 (1H, s), and 7.0-7.3 (15H, m).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:23]([NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:24])=[CH:19][CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reaction time: 2 h

Procedure:
1-{4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]phenyl}methanamine (58 mg, 1.8 mmol) was dissolved in dichloromethane (1.8 mL) and treated with carbonyldiimidazole (0.15 g, 0.93 mmol, 5 equiv). The mixture was stirred at ambient temperatures for 2 hours and then treated with ethyl aminoacetate hydrochloride (0.26 g, 1.8 mmol, 10 equiv). The mixture was stirred until complete, diluted with dichloromethane (30 mL) and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 35:65; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid) to afford the titled compound: 1H-NMR (400 MHz, CDCl3) δ 7.53-7.40 (6H, m); 4.55 (2H, dd, J=6.9, 3.8 Hz); 4.49 (2H, m); 4.25-4.17 (2H, m); 4.02 (2H, s); 1.47-1.38 (1H, m); 1.27 (3H, t, J=6.6 Hz); 0.71-0.66 (2H, m); 0.54-0.49 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 442.1660 [(M+H)+; calculated for C22H25ClN5O3: 442.1640].
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:20][C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:21])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (83.6 g, 0.55 mol) and imidazole (78.69 g, 1.15 mol) were added to a solution of o-cresol (50 g, 0.46mol) in dry DMF (200 mL). The reaction mixture was stirred for 3 h, treated with a 5% aqueous NaHCO3 solution, extracted with petroleum ether and concentrated to obtain the title compound as an oil. Yield: 102 g, (100%); 1H NMR (CDCl3): δ 0.20 (s, 6H, 2CH3), 1.0 (s, 9H, 3CH3), 2.2 (s, 3H, CH3), 6.75 (d, 1H, Ar), 6.85 (q, 1H, Ar), 7.18 (q, 1H, Ar), 7.25 (d, 1H, Ar).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13])(=O)C1C=CC=CC=1.[OH-].[NH4+]>O>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13]
Reactant: CC(C)(NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)CCS)C(=O)O

Procedure:
2.8 g. of the product of Example 45 is treated with a mixture of 20 ml. water and 20 ml. of concentrated ammonium hydroxide solution under an argon blanket for one hour. The benzamide precipitate is filtered and the filtrate is extracted twice with ethyl acetate. The aqueous phase is concentrated in vacuo, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo and the residual product 2-[(3-mercaptopropanoyl)amino]-2-methylpropanoic acid, is crystallized from acetonitrile, yield 1.2 g., m.p. 169°-170°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([NH:31][C:32]([CH2:34][CH2:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH2:34][CH2:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NC(=O)CCc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)NC(=O)CCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 73.5 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (85 mg, 0.2 mmol) and 4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamine (80 mg, 0.34 mmol). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient) to obtain 6-{4-[2-(tert-butylcarbamoyl)-ethyl]benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (75 mg, 74%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:10])[CH2:7]OC.S([O-])([O-])(=O)=[O:12].O[NH3+:17].O[NH3+].O>CO>[C:6](=[O:10])([OH:12])[OH:5].[CH3:4][O:5][CH2:6][C:7]#[N:17]
Reactant: O=S(=O)([O-])[O-]
Reactant: [NH3+]O
Reactant: COCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC#N
Product: O=C(O)O
Reaction time: 2 h

Procedure:
205 g of a 30% solution of sodium methylate in methanol are added dropwise over a period of 4 to 5 hours at 10° C to a mixture of 104 g of methoxy acetic acid methyl ester, 250 ml of methanol and 90 g of freshly precipitated hydroxyl ammonium sulphate. After stirring for 2 hours, another 180 g of sodium methylate solution are added dropwise over a period of 30 minutes. After stirring for another 4 hours at room temperature, 300 ml of water are added and the methanol is distilled off in a water jet pump vacuum. The resulting aqueous solution of the sodium salt of methoxy acethydroxamic acid is acidified to pH 4 with concentrated hydrochloric acid. Following the addition of 350 ml of methylene chloride, 120 g of phosgene are introduced with vigorous stirring at 0° C. At the same time the dropwise addition of a 30% aqueous sodium hydroxide solution ensures that the pH-value of the solution always remains between pH 2.5 and pH 4.5. After stirring for 1 hour, excess phosgene is destroyed by the dropwise addition of more sodium hydroxide solution. The mixture is left standing until phase separation is complete, after which the phases are separated and the aqueous phase extracted with methylene chloride. After drying over zeolite, the solvent is distilled off, 98 g of methoxy acetonitrile carbonate being obtained after distillation in an oil pump vacuum. The yield amounts to 75% by weight of the theoretical yield.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:28]=3)[C:23](O)=[O:24])=[C:17]([Cl:43])[CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48](C)=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34])[CH:28]=3)[C:23]([NH:44][C:45]3[CH:50]=[N:49][CH:48]=[CH:47][N:46]=3)=[O:24])=[C:17]([Cl:43])[CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.073 mL, 0.55 mmol) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (260 mg, 0.5 mmol) in DCM (10 mL) and stirred at RT for 1 hour. 2-Amino-5-methylpyrazine (95 mg, 1 mmol) and pyridine (0.081 mL, 1.0 mmol) were added and the reaction stirred for a further 30 mins. The solvent was removed in vacuo. Water (10 mL) was added and the mixture extracted with ethyl acetate (2×10 mL). The extracts were combined and washed with 1N citric acid, water (10 mL) and brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (37 mg).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]2[CH:21]=[CH:20][C:13]([CH:14]=[CH:15][C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].O.[OH-].[Li+].C1COCC1.O>CO.Cl>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]2[CH:21]=[CH:20][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C=CC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C=CC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 1.0 g (2.71 mmol) of methyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)methylcinnamate and 569 mg (13.57 mmol) of lithium hydroxide, monohydrate, in a mixture of 9 ml of MeOH, 9 ml of THF and 2 ml of water was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 100 ml of 0.5N HCl solution to give a fine white precipitate. The precipitate was isolated by filtration and recrystallized from ethanol to give 750 mg of the title compound as a fine, white cottony solid; mp 203°-204° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][N:9]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)(=O)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C(Cl)Cl.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>[F:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[C:7]1[CH2:8][N:9]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(OS(=O)(=O)C(F)(F)F)=CC(c3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(c3cc(F)ccc3F)=CC(c3ccccc3)C2)cc1

Procedure:
To a flame dried flask equipped with stir bar was added crude 1-[(4-nitrophenyl)sulfonyl]-5-phenyl-1,2,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate (1-5) (376 mg, 0.76 mmol), 2,5-difluorophenyl boronic acid (240 mg, 1.5 mmol), and Na2CO3 (243 mg, 2.3 mmol). The solids were dissolved in 5 mL 4:1 DME/H2O and degassed with N2. Pd(PPh3)4 (9 mg, 0.008 mmol) was added and the reaction was sealed under N2 and heated to 90 C for 2 h. Upon completion, the reaction was diluted with CH2Cl2, washed with 5% NaHCO3 and dried over MgSO4. Following filtration, the organic layer was concentrated and purified via ISCO (SiO2, 0-50% EtOAc/hexanes gradient) to provide 5-(2,5-difluorophenyl)-1-[(4-nitrophenyl)sulfonyl]-3-phenyl-1,2,3,6-tetrahydropyridine (1-6). 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.34 (in, 5H), 7.20 (m, 1H), 7.02 (m, 2H), 6.09 (s, 1H), 4.27 (m, 1H), 3.94 (m, 1H), 3.82 (m, 2H), 2.86 (dd, J=12.0, 8.0 Hz, 1H); MS 457.3 found 457.5 (M+H+) required.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 79.1 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (140 mg, 0.357 mmol) was dissolved in acetonitrile (7 mL), and the solution was added with 1-(2-hydroxyethyl)piperazine (186 mg, 1.43 mmol), acetic acid (0.409 mL, 7.14 mmol) and sodium triacetoxyborohydride (151 mg, 0.714 mmol), followed by stirring at room temperature for 1.3 hours. The mixture was added with sodium triacetoxyborohydride (151 mg, 0.714 mmol) and further stirred for 3.8 hours. Further, the mixture was added with sodium triacetoxyborohydride (76.0 mg, 0.357 mmol) and stirred for 0.6 hours. The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-hydroxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (143 mg, yield 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CC1C=CC(C(C)C)=CC=1.ClCCl.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Agent: [Pd]
Solvent: ClCCl
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)c1ccc2[nH]c3ccc(OC)cc3c2c1
Temperature: 190 °C

Procedure:
A solution of 6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid ethyl ester (3.29 g, 12.1 mmol) in p-cymene (12 mL) was treated with palladium (10% on carbon, 2.25 g) and heated at 190° C. for 20 hours. The mixture was then cooled, diluted with dichloromethane and filtered over a pad of diatomaceous earth. The filtrate was concentrated in vacuo to a low volume and heptane (200 mL) was added to precipitate the title compound as a white solid (2.78 g).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)([CH3:3])[CH3:2].[N-:21]=[C:22]=[O:23].[K+].C(O)(=O)C>O>[CH:1]([N:4]1[C:5]2[C:6](=[CH:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:21][C:22]1=[O:23])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)c(NC(C)C)c1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(-c3ccc(F)cc3)nc(=O)n(C(C)C)c2c1

Procedure:
A solution of 8.5 g. of 2-isopropylamino-4-methyl-4'-fluoro-benzophenone and 4.2 g. of potassium isocyanate in 100 ml. of glacial acetic acid is stirred at 60°-70°C. for 20 hours. The resulting mixture is treated with a mixture of ice and water and extracted three times with methylene chloride. The organic phases are combined, washed twice with water, once with sodium bicarbonate solution and again with water followed by drying and evaporation in vacuo. The residue is dissolved in a small amount of methylene chloride and precipitated by adding pentane. The resulting solid is redissolved in methylene chloride, treated with charcoal and diethyl ether exchanged for the methylene chloride to obtain a solid which is dried in a high vacuum at 60°C. to yield 1-isopropyl-7-methyl-4-(p-fluorophenyl)-2(1H)-quinazolinone, m.p. 172°-174°C.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[N:9]([CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])=[C:10]=[O:11]>C(OCC)(=O)C>[CH:1]([C:4]1[N:5]([C:10](=[O:11])[NH:9][CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CO[Si](C)(CN=C=O)OC
Reactant: CC(C)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: CO[Si](C)(CNC(=O)n1ccnc1C(C)C)OC
Reaction time: 1 h

Procedure:
A stirred solution conditioned at a temperature of 50° C. of 3.00 g of 2-isopropylimidazole in 50 ml of ethyl acetate was admixed dropwise with 4.39 g of (isocyanatomethyl)dimethoxy(methyl)silane and the mixture was stirred for 60 min. This gave 2-isopropyl-1-{[dimethoxy(methyl)silyl]-methylcarbamoyl}imidazole after filtration as a colorless solid in quantitative yield with a purity of >95% (analysis by 29Si and 1H NMR).
Reaction SMILES: C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH2:33]([O:40][C:41](=[O:66])[CH2:42][C@@H:43]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH:48]=1)[C:44](O)=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[NH2:67][C@H:68]([C:73]1[NH:74][CH:75]=[CH:76][N:77]=1)[CH2:69][CH:70]([CH3:72])[CH3:71].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:33]([O:40][C:41](=[O:66])[CH2:42][C@@H:43]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:59]=[CH:60][C:61]([C:64]#[N:65])=[CH:62][CH:63]=3)=[CH:54][CH:53]=2)[CH:48]=1)[C:44]([NH:67][C@H:68]([C:73]1[NH:77][CH:76]=[CH:75][N:74]=1)[CH2:69][CH:70]([CH3:72])[CH3:71])=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@H](N)c1ncc[nH]1
Reactant: N#Cc1ccc(-c2ccc(-n3ccc([C@H](CC(=O)OCc4ccccc4)C(=O)O)c3)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Yield: 49 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester (prepared as described in Example 14(b)) and 2-(1(S)-amino-3-methyl-butyl)-imidazole (see Chen, J. J.; Zhang, Y.; Hammond, S.; Dewdney, N.: Ho, T.; Browner, M. F.; Castelhano, A. L., submitted for publication; and Abel-Meguid, S. S.; Metcalf B. W.; Caw, T. J.; DeMarsh, P.; Des Jarlais, R. L.; Fisher, S.; Green, D. W.; et al. Biochemistry, 1994, 33, 11671-11677) were coupled with TBTU to provide a 49% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid benzyl ester: mp 186-188° C. (dec); 1HNMR (DMSO-d6) δ 11.79 (s, 1H), 8.40 (d, 1H, J=8.5 Hz), 7.92 (s, 4H), 7.85 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.34 (s, 5H), 6.97 (s, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 5.13-5.00 (m, 3H), 3.96 (dd, 1H, J=9.9, 5.5 Hz), 2.99 (dd, 1H, J=16.4, 10.8 Hz), 2.78 (dd, 1H, J=16.4, 5.0 Hz), 1.67-1.60 (m, 2H), 1.55-1.45 (m, 1H), 0.85 (d, 3H, J=6.6 Hz), 0.81 (d, 3H, J=6.3 Hz); Anal. Calculated for C36H35N5O3.H2O: C, 71.62; H, 6.18; N, 11.60. Found: C, 71.50, 71.45; H, 5.97, 6.01; N, 11.51, 11.48.