Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1.Cl>O1CCCC1.COCCOC>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:38](=[O:39])[CH2:3][S:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:6])=[O:5])=[CH:42][CH:43]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is added a solution of 5.0 g. of methyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate in 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 4'-[13-(4-chlorophenyl)tridec-12-ynylamino]-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1[CH:8]=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1/[CH:8]=[CH:24]/[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:25]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OCC(CO)CO)c(C=O)cc1-c1cccs1
Product: COc1cc(OCC(CO)CO)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 2-(3-hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-64B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Light orange solid, mp 219–220° C., 61% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.20 (d, 2H, J=7.5 Hz), 8.05–8.11 (m, 3H), 7.93 (d, 1H, J=16.2 Hz), 7.67 (d, 1H, J=3.0 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.0 Hz), 6.88 (s, 1H), 4.66 (brs, 2H), 4.23 (d, 2H, J=6.3 Hz), 4.01 (s, 3H), 3.55–3.66 (m, 4H), 2.09–2.14 (m, 1H). MS (ESI) m/z=469 ([M+H]+, 100%). Anal. Calcd. for C25H24O7S.H2O: C, 61.72; H, 5.39; S, 6.59. Found: C, 61.93; H, 5.30; S, 7.06.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][CH2:12][C:11]1=O>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1CC=CO1
Reactant: NCc1ccc(F)cc1
Product: O=C1CCCN1Cc1ccc(F)cc1
Yield: 74.8 %

Procedure:
47 g (0.376 mol) of p-fluorobenzylamine, 30.4 g (0.353 mol) of furan-2-one and 0.4 g of hyddroquinone are introduced into a 125 ml autoclave. After driving the air out of the apparatus by passing a stream of nitrogen through it, the mixture is heated to 250° for 6 hours. It is then cooled and distilled under reduced pressure. 51 g (yield=74.8%) of 1-p-fluorobenzyl-pyrrolidin-2-one are collected as a colourless liquid distilling at 103°-105° under a pressure of 0.01 mm of mercury and solidifying slowly. Melting point=37°-38°.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36]I>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH3:36])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: CI
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and methyl iodide.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH2:12][C:13]([C:22](OC)=[O:23])=[C:14]([C:18](OC)=[O:19])[CH2:15][C:16]=1[CH3:17].CO>ClCCl>[OH:19][CH2:18][C:14]1[CH2:15][C:16]([CH3:17])=[C:11]([CH3:10])[CH2:12][C:13]=1[CH2:22][OH:23]
Reactant: COC(=O)C1=C(C(=O)OC)CC(C)=C(C)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1=C(C)CC(CO)=C(CO)C1
Yield: 35 %

Procedure:
To a solution of DIBAL in dichloromethane (1.0M, 45 ml, 0.045 mol) cooled to ice bath temperature under nitrogen was added dimethyl 4,5-dimethylcyclohexa-1,4-diene-1,2-dicarboxylate (2.24 g, 0.01 mol) in dry dichloromethane (30 ml) over 30 min. The resultant solution was stirred for a further 60 mins at this temperature after which methanol (10 ml) was added. The mixture was allowed to come to room temperature, filtered through a "Celite" pad, and the filtrate concentrated in vacuo to give an oil. Crystallisation from ethyl acetate/petroleum ether (40°-60° C.) gave the title compound in 35% yield. N.m.r: δH (90 MHz, CD3OD) 4.15 (s,4H), 3.55 (bs,2H), 2.82 (s,4H), 1.69 ppm (s,6H)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:12]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[C:38]([O:19][CH2:18][CH:16]1[CH2:17][CH:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15]1)(=[O:40])[CH3:39]
Reactant: CC(C)CN(C(=O)OCc1ccccc1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCC1CC(N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 3-{[(benzyloxy)carbonyl](2-methylpropyl)amino}-5-(hydroxymethyl)piperidine-1-carboxylate (4.6 g) and triethylamine (2.3 ml) in ethyl acetate (25 ml) was added acetyl chloride (0.94 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (5.09 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrCCOCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cc2)CCOCC1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 2-(4-bromophenyl)acetonitrile (3.9 g) in tetrahydrofuran (50 mL) was added potassium t-butoxide (4.9 g) in an ice bath, and the mixture was stirred for 1 hr in an ice bath. 1-Bromo-2-(2-bromoethoxyl)ethane (5.8 g) was added thereto at the same temperature, and the mixture was stirred at room temperature for 10 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][NH:27][CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]2)[CH2:17]1.C(#N)C.[CH:48](I)([CH3:50])[CH3:49]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:48]([CH3:50])[CH3:49])[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:17]1
Reactant: CC(C)I
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.06 g, 0.1 mmol) was taken up in acetonitrile (2.6 mL, 50 mmol) and isopropyl iodide (0.098 mL, 0.98 mmol) and triethylamine (0.21 mL, 1.5 mmol) were added. The reaction was heated to 80° C. for 12 hours at which point the reaction appeared to stall. Another 15 equivalents triethylamine and another 15 equivalents isopropyl iodide were added and the reaction continued 8 hours more. Reaction appeared to have stalled again so another 15 equivalents each of isopropyl iodide and triethylamine were added. Upon consumption of the starting material the reaction was concentrated and saturated Na2CO3 (20 mls) and DCM (20 mls) was added. The residue was partitioned between the organic layer and the aqueous layer. The aqueous layer was extracted 3 times with DCM, then the combined organics were dried and purified by FC (DCM/7N NH3 in MeOH 97:3). Product was still contaminated with TEA-H+I−, so to a 30 ml solution of the product in DCM was added 20 mls saturated NaHCO3 and 10 mls 1N NaOH. The mixture was stirred for 15 minutes then the aqueous was extracted with DCM 3 times. The combined organics were dried with MgSO4 and solvent removed to yield pure ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate (0.045 g; 70%) as a brown foam/solid with no more amine salts present by NMR. MS (ESI+) for C35H50N6O6 z 651.3 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]=[C:12]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccccc1

Procedure:
Phenacylbromid (0.1 g, 0.49 mmol) is added to an efficiently stirred suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.1 g, 0.4 mmol) [A. V. Sergievskii, O. A. Krasnoshek, S. F. Mel'nikova, I. V. Tselinskii, Russian Journal of Organic Chemistry, 2002, 38, 915-917] and potassium carbonate (0.172 g, 1.24 mmol) in dry DMF (5 ml) at room temperature. After 4 hours the reaction mixture is diluted with ethyl acetate and the organic phase is washed repeatedly with brine. Drying of the solvent, filtering and evaporation of the solvent under reduced pressure gives the title compound in crude form. The title compound is obtained in pure form by chromatography over silicagel, m.p. 202-204° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])(CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1cncc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cncc3ccccc23)CC1
Reaction time: 1.5 h
Yield: 39 %

Procedure:
A solution of 6.46 gm (31.1 mMol) 4-bromoisoquinoline in 80 mL tetrahydrofuran was cooled to −100° C. under a nitrogen atmosphere. To this solution was added dropwise 28.7 mL (37.3 mmol) sec-butyllithium (1.3 M in hexanes) and the reaction mixture was allowed to stir for 1.5 hours. To the reaction mixture was then added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone in 20 mL tetrahydrofuran dropwise. The reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The organic phases were combined, washed saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 9:1 dichloromethane:methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 3.95 gm (39%) 1-tert-butoxycarbonyl-4-(isoquin-olin-4-yl)-4-hydroxypiperidine as a yellow solid.
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:29])[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25]C)=[C:18]([O:27]C)[CH:17]=1)=[O:15].C(O)C>C(Cl)Cl>[OH:27][C:18]1[CH:17]=[C:16]([C:14](=[O:15])[CH2:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[OH:5])=[O:29])[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]=1[OH:25]
Reactant: COc1cc(C(=O)CC(=O)c2ccccc2O)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: O=C(CC(=O)c1ccccc1O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 1.82 g of boron tribromide in 20 ml of methylene chloride is added dropwise within about 20 minutes to a solution of 500 mg of 1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione in 50 ml of methylene chloride while stirring and under an argon atmosphere at -20°, whereupon the mixture is stirred at room temperature overnight. After cooling to -20° the mixture is treated dropwise with 25 ml of ethanol and evaporated at 40° in a water-jet vacuum. After recrystallization from ethanol, there is obtained 1-(3,4-dihydroxy-5-nitrophenyl)-3-(o-hydroxyphenyl)-1,3-propanedione in the form of yellow crystals of m.p. 251°-252°.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21]N1C(=O)CCC1=O)=O)[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])[CH3:3].[NH2:29][C@H:30]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:62]([OH:64])=[O:63])[C@@H:59]([CH3:61])[OH:60])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:34])[CH2:31][OH:32].C(N(CC)CC)C>CN(C)C=O>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:19]([NH:29][C@H:30]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:62]([OH:64])=[O:63])[C@@H:59]([CH3:61])[OH:60])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:34])[CH2:31][OH:32])=[O:21])[CH2:10][S:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)O)[C@@H](C)O

Procedure:
5.3 g (13 mmols) of BOC-Cys(Bzl)-OSU and 7.4 g (10 mmols) of H-Ser-Asn-Leu-Ser-Thr-OH, 1.93TFA are dissolved in 75 ml of dimethylformamide. From a solution of 150 mmols of triethylamine in 100 ml of dimethylformamide, 18.1 ml (27.2 mmols) are added dropwise while stirring until the reaction mixture shows a pH of 6.4 on moist indicator paper. The solution is stirred for 3 days at room temperature, then evaporated to dryness in a high vacuum. The residue is stirred twice with 250 ml of ethyl acetate and three times with a mixture of 100 ml of ethyl acetate and 20 ml of 5% citric acid solution, filtered, and dried at 40°C under reduced pressure. Melting point: 184°-185°C; [α]D20 -13° (c = 2 in dimethylformamide); Rf6 = 0.45.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH3:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[Br:28]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[C:21]([CH2:22][Br:28])=[CH:20][C:19]3[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C=Cc2cc3c(cc2CBr)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A mixture of 1.0 g (2.76 mmol) of (E)-methyl-4-[2-(3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 0.64 g (3.6 mmol) of N-bromosuccinimide and 0.033 g (0.13 mmol) of benzoyl peroxide in 20 mL of carbon tetrachloride was heated under reflux, under a high intensity lamp. After 2 hours, the reaction was cooled to room temperature and poured into 10% aqueous sodium bisulfite solution. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with methyl alcohol to afford 0.88 g of Methyl-4-[2-(3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (72%) (M+=440).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=[O:2].[CH2:13]([Mg]Br)[CH:14]([CH3:16])[CH3:15]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)C)nc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a −10° C. solution of methyl 6-formylnicotinate (800 mg, 4.8 mmol) in tetrahydrofuran was added isobutylmagnesium bromide (3.6 mL, 7.2 mmol, 2.0M in THF). The resulting mixture was stirred at −10° C. After 2 hours, additional isobutylmagnesium bromide (2.4 mL, 4.8 mmol) was added and the reaction was stirred at −10° C. for another 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to a brown oil. Purification by column chromatography (0-15% ethyl acetate in petroleum ether) gave methyl 6-(1-hydroxy-3-methylbutyl)nicotinate. 1H NMR (400 MHz, CDCl3, δ): 9.14 (s, 1H), 8.29-8.27 (d, 1H), 7.36-7.34 (d, 1H), 4.85-4.83 (m, 1H), 3.78 (s, 3H), 1.95-1.91 (m, 1H), 1.65-1.51 (m, 2H), 1.03-1.01 (d, 3H), 0.96-0.95 (d, 3H).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[S:21][S:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[S:22][S:21][C:15]1[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:35])[CH3:36])([OH:39])=[O:38]
Reactant: Cc1cccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1SSc1c(C)cccc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(CC(C)C)C(=O)O)c1SSc1c(C)cccc1C(=O)NC(CC(C)C)C(=O)O
Yield: 54.9 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-6-methyl-phenyldisulfanyl]-3-methylbenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (0.9 g, 1.3 mmol) from Example 32, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The crude product was recrystallized from dimethylformamide/water to afford 0.4 g of the title compound, mp 210-211° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: [H][H]
Reactant: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccccn2)CCN(C)C1
Yield: 26.1 %

Procedure:
2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole (20 mg, 0.06 mmol) was hydrogenated in methanol (2 ml) with 10% Pd—C (10 mg) at 1 atm of hydrogen to obtain 5 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)propyl)-1H-pyrido[4,3-b]indole after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its HCl salt by treatment of ethanolic HCl.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([CH3:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([CH3:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a mixture of 4-(benzyloxy)aniline hydrochloride (4.10 g) and 2-chloro-5-methyl-3-nitropyridine (3.0 g) in DMF (30 mL) was added TEA (7.27 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was heated to 60° C. After stirring at 60° C. overnight, K2CO3 (4.81 g) was added to the mixture. The mixture was heated to 100° C. and stirred at 100° C. overnight. The mixture was poured into water and the mixture was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-30% AcOEt in hexane) to give N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) as a red solid.