Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[CH:6]2.[Mg].[C:20](=[O:22])=[O:21].[Cl-].[NH4+]>C(OCC)C>[C:13]1([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][C:20]([OH:22])=[O:21])[CH:4]=3)[N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=O
Reactant: BrCc1ccc2nc(-c3ccccc3)ccc2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
The Grignard compound is prepared in the customary manner from 5 g of 6-bromomethyl-2-phenyl-quinoline and magnesium in 30 ml of diethyl ether. It is added to a solution of solid carbon dioxide in 100 ml of diethyl ether. At the same time a further quantity of solid carbon dioxide is added in portions to the reaction solution. Thereafter, aqueous ammonium chloride solution is added to the reaction mixture and the whole is extracted with ethyl acetate. The organic phases are extracted with 2 N sodium carbonate solution. The sodium carbonate extracts are adjusted to pH 6 and extracted with ethyl acetate. These ethyl acetate layers are dried and evaporated. The residue, after recrystallisation from methanol-pentane, yields 2-phenyl-6-quinolineacetic acid of melting point 176-179°C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([OH:17])[CH2:11][CH2:10]1.Cl[C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].[Cl-].[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[O:47]=[C:39]1[NH:40][C:41]2=[N:42][CH:43]=[CH:44][CH:45]=[C:46]2[N:38]1[CH:35]1[CH2:34][CH2:33][N:32]([C:19]([O:17][CH:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:15][CH2:14][C:13]2=[O:16])=[O:20])[CH2:37][CH2:36]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(c2cccc(F)c2F)CCC1O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCC(c2cccc(F)c2F)CCC1OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In an oven-dried 50 mL round-bottomed flask (t=g) was added 5-(2,3-difluorophenyl)-2-hydroxycycloheptanone (22 mg, 0.092 mmol) and 4-Nitrophenyl chloroformate (20.30 mg, 0.101 mmol) in THF (3 mL) to give a colorless solution. DMAP (15.66 mg, 0.128 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC showed a new less polar spot (more polar than the chloride) but mainly starting material. Allowed reaction to stir overnight for 24 hours. To the above reaction mixture was added 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (53.6 mg, 0.184 mmol), followed by Hunig's Base (0.040 mL, 0.230 mmol). The resulted mixture was stirred at room temperature overnight. LCMS showed two close small peaks which has the MW of 484. 22 h: It was diluted with water and extracted with EtOAc. The organic layer was washed 3 times with water, brine, dried with Na2SO4 and concentrated to a tan oil. FCC up to 8% MeOH/CH2Cl2 afforded the desired product as mixture of two diasteromers: 11.7 mg (26%). LCMS: M+H=485.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7]([C:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[C:31]([S:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])(=[O:33])[CH3:32].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1>ClCCl>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[NH:6][C:7]([C:9]1([NH:14][C:36](=[O:37])[C@@H:35]([S:34][C:31](=[O:33])[CH3:32])[CH:39]([CH3:41])[CH3:40])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CC(=O)S[C@H](C(=O)O)C(C)C
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C(C)C)CCCC1
Reaction time: 0.08 h

Procedure:
To a solution of [(1-amino(1-cyclopentyl)carbonyl]-L-tyrosine methyl ester hydrochloride (1.36 g, 3.97 mmol) in dichloromethane (50 mL) is added triethylamine (0.55 mL, 3.97 mmol). The mixture is stirred for 5 minutes and then (S)-2-acetylthio-3-methylbutanoic acid (0.70 g, 3.97 mmol), 1,3-dicyclohexylcarbodiimide (0.82 g, 3.97 mmol) and 1-hydroxy-7-azabenzotriazole (0.54 g, 3.97 mmol) are added. The mixture is stirred for 16 hours and then the solid precipitate is filtered off. The organic phase is washed with a saturated solution of sodium bicarbonate (30 mL), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give a white foam. The foam is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (1:1). The pure fractions are concentrated and the resulting foam is crystallized from ethyl acetate-hexane to afford N-[[1-[(2(S)-acetylmercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]carbonyl]-L-tyrosine methyl ester as a white solid, m.p. 157°-158° C., the compound of formula III wherein R1 is 4-hydroxyphenyl, R2 is methyl, R3 is acetyl and R4 is isopropyl.
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:3][C:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (7.3 g) was dissolved in toluene (30 mL). t-Butyl dicarbonate (9.3 mL) and 1N aqueous sodium hydroxide (10 mL) were added to the solution, followed by stirring for 15 hours at room temperature and then for 4 hours at 50° C. After completion of reaction, the toluene layer was separated and washed with water, followed by drying with sodium sulfate. The desiccant was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel chromatography (hexane:ethyl acetate), to thereby yield the title product (8.745 g, yield: 82%). Notably, when optically active 7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane is treated in accordance with the above-described procedure, the corresponding optically active target product can be yielded without decreasing optical purity.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[O:7]=[C:8](CC1C=CC=CC=1)[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C([O-])=O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1>>[OH:7][C:8]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[C:38]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Nc1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCC(C(=O)[O-])C(=O)Cc1ccccc1
Product: CCCCCCCCc1c(-c2ccccc2)nc2ncnn2c1O

Procedure:
A mixture of 14.0 g (0.17 mol) of 3-amino-1,2,4-triazole, 51.7 g (0.17 mol) of 3-oxo-2-octyl-4-phenylbutanoate and 3. g of p-toluenesulfonic acid was heated under reflux for 6 h. Work-up was carried out analogously to Ex. 1. Drying gave 37 g (0.11 mol) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)C1C=CC=CC=1.CC(O)=O.[H][H]>CO.[Pd]>[F:15][C:14]([F:17])([F:16])[CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1
Reactant: [H][H]
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)C1CNCCN1
Reaction time: 12 h

Procedure:
1-Benzyl-3-(trifluoromethyl)piperazine 34a (4.1 mmol) is dissolved in MeOH (50 mL) followed by addition of AcOH (2.0 mL) and 5% mol of Pd/C. The flask is charged with a hydrogen balloon and stirred for 12 h. The mixture is filtered over celite and the filtrate is concentrated to afford 2-(trifluoromethyl)piperazine 35a, which is used without further purification. MS (m/z) (M+1)+: 155.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6](=O)[NH:7][CH:8]=1.[OH-:10].[Na+]>C(NCC)C>[CH2:6]([N:7]([CH2:2][C:3]1[C:8](=[O:10])[NH:7][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH3:3])[CH3:5]
Reactant: O=c1ccc(CBr)c[nH]1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCNCC
Product: CCN(CC)Cc1ccc[nH]c1=O
Yield: 34 %

Procedure:
The 5-bromomethyl-2-pyridone was taken up in diethyl amine and the solution refluxed for 1 hour. The solution was then treated with 10% sodium hydroxide at 0° C. and washed with chloroform. The aqueous phase was treated with hydrochloric acid to a pH of 6.0 and extracted with chloroform/methanol (5:1). The solution was dried over Na2SO4 and the solvent was then evaporated. The product, (N,N-diethylaminomethyl)-2-pyridone, was obtained in 34% yield. HRMS: m/e, M+ found; 180.1251, 20.8%. Calc. for C10H16N2O; 180.1263, −6.3 ppm. 1H NMR (ppm): 13.1 (broad, 1H, NH), 7.49 (dd, J3-4=9.2 Hz, J4-6=2.4 Hz, 1H, C(4)H), 7.25 (d, J4-6=2.4 Hz, 1H, C(6)H), 6.55 (d, J3-4=9.2 Hz, 1H, C(3)H), 3.30 (s, 2H, CH2O), 2.45 (q, J=7.1 Hz, 4H, N (CH2CH3)2), 1.00 (t, J=7.1 Hz, 6H, N (CH2CH3)2). IR (cm−1): 1660 (vs), υ (C═O).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Cl:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl-:10].[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Reaction time: 56 h

Procedure:
4-(Methylsulfonyl)benzyl chloride (Transworld Chemical) (121 mmol, 24.7 g) and triphenylphosphine (130 mmol, 34.1 g) were heated at reflux in toluene (125 ml) with stirring for 56 hours. The reaction was cooled, and the title compound was collect by filtration (48.0 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[C:10]([Cl:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:15](=[O:17])[CH3:16])[C:10]([Cl:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC

Procedure:
A mixture of 21 g of methyl 2-methoxy-4-amino-5-chlorobenzoate is stirred in 12 ml acetic anhydride and 100 ml acetic acid at 100° C. for 24 hours. The reaction mixture is filtered, diluted with water, filtered and evaporated to dryness to obtain methyl 2-methoxy-4-acetylamino-5-chlorobenzoate which is used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][C:9]([O:11]CC2C=CC=CC=2)=O)[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3]1.C[C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28](O[C:31](=O)[C:26]=12)=[O:29]>C(O)(=O)C.[Pd]>[CH3:31][C:26]1[CH:25]=[CH:35][CH:34]=[C:33]2[C:27]=1[C:28](=[O:29])[N:8]([CH:7]1[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:11]
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)C(=O)NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC1CC(N2C(=O)c3cccc(C)c3C2=O)C(=O)NC1=O
Reaction time: 3 h

Procedure:
A mixture of 2,6-dioxo-3-benzyloxycarbonylamino-5-acetoxypiperidine (9 g, 28.2 mmol) (U. Teubert et al, Arch. Pharm. Pharm. Med. Chem. (1998) 7-12), and Pd/C (10%, 0.9 g) in acetic acid (90 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with acetic acid. To the filtrate is added 3-methylphthalic anhydride (4.56 g, 28.2 mmol) and this mixture is heated at reflux for 18 hours. The solvent is removed in vacuo to give 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.C(OC(C)C)(=O)C.O.[Cu]>[F:16][C:10]([F:17])([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)C(F)(F)c1ccc(C)cc1
Temperature: 55 °C
Yield: 69.8 %

Procedure:
The compound was prepared by modification to the procedure of Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A. Chemical & Pharmaceutical Bulletin 47(7), 1013-1016 (1999). To a solution of 1-iodo-4-methylbenzene (25.1 g, 115 mmol) in DMSO (125 mL) was added ethyl bromo(difluoro)acetate (24.7 g, 122 mmol) and copper (16.8 g, 264 mmol), and the resulting solution was heated to 55° C. After 14 h the reaction was cooled to room temperature and diluted with isopropyl acetate, then cooled to 0° C. and treated with a solution of potassium hydrogen phosphate (23.3 g) in water (250 mL). The mixture was filtered through a pad of Celite, rinsing with isopropyl acetate. The phases were separated and the aqueous layer was washed with isopropyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography (5% methylene chloride, 1-8% ethyl acetate/hexanes gradient) gave the title compound (17.2 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([Li])CCC.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][NH:7]2
Reactant: CCOC(=O)CBr
Reactant: COc1cccc2[nH]ccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c[nH]c2cccc(OC)c12
Reaction time: 2 h

Procedure:
To a solution of 2.94 gm (20 mmol) of 4-methoxyindole in 150 ml of tetrahydrofuran was added slowly 13 ml of n-butyl lithium (1.6M in hexane; 20 mmol) followed by the slow addition of 20 ml of zinc chloride (1.0M in ethyl ether; 20 mmol) at 0-5° C. The cooling bath was removed and the solution stirred for 2 hours and then treated with 2.1 ml (25 mmol) of ethyl bromoacetate for 19 hours, diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/10-50% ethyl ether to give starting material (40%) and then product, 2.3 gm, 50%, as an oil. 1H NMR (CDCl3) δ: 1.25 (t, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 4.10 (q, 2H), 6.45 (d, 1H), 6.90 (d, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 8.00 (br s, 1H).
Reaction SMILES: [C:1]([C:4](C(OC(C)(C)C)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:27][C:28](=[O:30])[CH3:29])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].C(C(C(OC(C)(C)C)=O)(CCCC(OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(=O)C>>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:27][C:28](=[O:30])[CH3:29])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCC(C)(C)C(CCCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OC(C)(C)C)OC(C)=O
Product: CCCCC(C)(C)C(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O

Procedure:
This compound is prepared as described in Example 1, Step C except that ethyl 8-acetyl-8-tert-butoxycarbonyl-12-acetoxy-13,13-dimethylheptadecanoate is substituted for ethyl 8-acetyl-8-tert-butoxycarbonyl-12-acetoxyheptadecanoate. The product, a viscous yellowish oil, is purified by chromatography on silica gel with chloroform as eluant.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(SCC(=O)C(C)(C)C)cc3)c2CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (35 mg, 0.06 mmol) in DCM (0.2 mL). Add 4M hydrogen chloride in dioxane (0.3 mL, 1.3 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and purify by SCX chromatography to obtain the desired intermediate (26 mg, 93%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:18][O:19][CH:20]([O:25][CH3:26])[C:21](OC)=[O:22]>C1COCC1>[CH3:18][O:19][CH:20]([O:25][CH3:26])[C:21]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])=[O:22]
Reactant: COC(=O)C(OC)OC
Reactant: O=C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(=O)C1CCCCC1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclohexanone Compound 2a (1.37 g, 14.0 mMol) in THF (5 mL) was added dropwise to a solution of LHMDS (16.0 mL, 16.0 mMol) in anhydrous THF (25 mL) at −78° C. under a N2 atmosphere. The solution was stirred at −78° C. for about 1 hr. Methyl dimethoxyacetate Compound 11a (1.88 g, 14.0 mMol) in anhydrous THF (5 mL) was then added dropwise. The reaction mixture was stirred while warming to r.t. over a period of about 15 hrs, then the reaction was quenched with water (5 mL). The organic layer was diluted with EtOAc (100 mL) and washed with water and brine. The organic layer was separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude product as an oil. The oil was purified by flash chromatography (eluted with 10% EtOAc in hexane) to afford 2-(2,2-dimethoxy-acetyl)-cyclohexanone Compound 11b (1.82 g, 65%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[Br:15])([CH3:7])[CH3:6]>C(O)(=O)C>[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[C:10]([CH3:14])[C:9]=1[Br:15])([CH3:7])[CH3:6]
Reactant: Cc1cccc(C(C)C)c1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])ccc(C(C)C)c1Br
Temperature: 90 °C

Procedure:
Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in acetic acid (60 mL). The mixture is heated 1 hour at 90° C. and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2Cl2 (3×60 mL). The combined extracts are washed with 1 N NaOH (3×40 mL) and then water (40 mL), dried (Na2SO4), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in AcOH (75 mL)/EtOH (75 mL). To this is added Fe power (5.3 g, 95 mmol) and the mixture is refluxed for 2 hours. The mixture is cooled to room temperature, diluted with water, and neutralized with solid Na2CO3. The mixture is extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H2O (10 mL) is added dropwise at 0° C. to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H2O (15 mL), and the mixture is stirred for 1 hour at 0° C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCl3 (70 mL) at room temperature. The mixture is stirred for 1 hour and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-1H-indazole. 1H NMR (CDCl3) 8.03 (br s, 1H), 7.41 (d, 1H), 7.35 d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12](Br)=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29].CN1CCCC1=O.N>O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:28]#[N:29])=[C:13]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)c(C(=O)c2ccc(C)cc2)cc1OCc1ccccc1
Reactant: N#C[Cu]
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C#N)c(C(=O)c2ccc(C)cc2)cc1OCc1ccccc1
Temperature: 200 °C
Yield: 112 %

Procedure:
A mixture of (5-benzyloxy-2-bromo-4-methoxyphenyl)-p-tolylmethanone (reference example 10-1) (1.11 g), copper(I)cyanide (967 mg) and 1-methyl-2-pyrrolidinone (2 mL) was irradiated with microwave to heat at 200° C. for 10 min while stirring. Water, a 28% ammonia in water and ethyl acetate were added. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (1.08 g).