Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](F)=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:21]([NH:24][C:25]([C@H:27]1[CH2:32][CH2:31][C@@H:30]([NH:33]C2C=C(OCC3C=CC(OC)=CC=3)C=CC=2[N+]([O-])=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22]>>[F:1][C:2]1[C:3]([O:4][CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:13][C:14]([NH:33][C@@H:30]2[CH2:29][CH2:28][C@H:27]([C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH2:32][CH2:31]2)=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCCN2CCOCC2)cc1F
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2)cc1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCOCC3)c(F)cc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-4-(4-Fluoro-5-(2-morpholinoethoxy)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide was prepared from 4-(2-(2,5-difluoro-4-nitrophenoxy)ethyl)morpholine using a procedure analogous to that used to prepare cis-N-isopropyl-4-(5-(4-methoxybenzyloxy)-2-nitrophenylamino)cyclohexanecarboxamide (272 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1(C(OC)=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Cl>O>[O:8]1[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C1(C(=O)OC)CCOCC1
Agent: Cl
Solvent: O
Product: O=C(O)C1CCOCC1
Yield: 101.1 %

Procedure:
To tetrahydro-4H-pyran-4,4-dicarboxylic acid dimethyl ester (4.04 g) was added 20% HCl (20 mL), and the mixture was heated under reflux for 19 hours. Water was added to the reaction mixture, and the thus-obtained mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and hexane was added to the residue. The resultant solid was collected by filtration, and was washed, to thereby give the title compound (2.63 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)[CH3:2].[F:21][C:22]([F:35])([CH:32]([F:34])[F:33])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([F:21])([F:35])[CH:32]([F:33])[F:34])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(OCC(F)(F)C(F)F)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(OCC(F)(F)C(F)F)cc2)cc1)OC

Procedure:
3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 173, Step A) and 4-(2,2,3,3-tetrafluoro-propoxy)-phenol (Step B) were treated under ester K to afford the title compound 1H-NMR (CDCl3, 200.15 MHz): δ 7.13 (d, 2H, J=8.6), 6.85–6.80 (m, 6H), 6.05 (dt, 1H, J=53.2, 5.1), 4.22–4.08 (m, 8H), 3.90 (dd, 1H, J=7.0, 5.6), 3.35 (s, 3H), 3.04–2.86 (m, 2H), 2.22 (qn, 2H, J=6.2).
Reaction SMILES: [CH3:1][S:2][CH:3]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Br:15])=[C:10]([CH3:16])[CH:9]=1)[C:4]([OH:6])=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[Br:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][CH:3]([S:2][CH3:1])[C:4]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:6])=[CH:9][C:10]=1[CH3:16]
Reactant: CC(C)(C)N
Reactant: CSC(Oc1cc(C)c(Br)c(C)c1)C(=O)O
Product: CSC(Oc1cc(C)c(Br)c(C)c1)C(=O)NC(C)(C)C

Procedure:
In a similar procedure to Stage 2 of Example 1, 2-methylthio-2(4-bromo-3,5-dimethylphenoxy)acetic acid was condensed with tert-butylamine to give 2-(4-bromo-3,5-dimethylphenoxy)-2-methylthio-N-(2-methyl-prop-2-yl)acetamide as a colourless solid, m.p. 123-125° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[NH:29][CH2:30][C:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-7-({2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (123 mg, 0.23 mmol) was treated with 10 mL of 1/1 TFA/CH2Cl2 solution and stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to obtain the titled compound as a white solid. MS (ES+): 427.1 (M+H)+. Calc'd for C25H26N6O—426.22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20](=[O:23])[NH:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[N:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Reaction scheme 1 shows that the compounds of formula I can be, for example, prepared starting from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester which is reacted in a first reaction step with tert-butylcarbazate to give 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid tert-butyl ester (starting compound A7). Compound A7 is reduced with, for example, the boran tetrahydrofurane complex to give 4-(N′-tert-Butoxycarbonyl-hydrazino)piperidine-1-carboxylic acid tert-butyl ester (starting compound A6). Treatment of compound A6 with concentrated hydrochloric acid results in the formation of piperidin-4-yl-hydrazine dihydrochloride (starting compound A5).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])=[O:6]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Nc1cc(F)ccc1C(=O)NC1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.8 %

Procedure:
A mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16 mmol) and CDI (2.4 g, 15 mmol) in acetonitrile (30 mL) was stirred at room temperature for 1.5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol) and sodium hydrogen carbonate (1.6 g, 19 mmol), and the mixture was heated at 50° C. for 21 hours. The suspension was cooled to room temperature for 1 hour. The suspension was filtered and washed with acetonitrile (5 mL) and water (2×20 mL). The solid was stirred in methanol (15 mL) overnight. The suspension was filtered and washed with methanol (15 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluorobenzamide as an off-white solid (1.9 g, 45% yield): 1H NMR (DMSO-d6) δ 1.91-1.96 (m, 1H, CH—H), 2.04-2.18 (m, 1H, CHH), 2.50-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H, CHH), 4.67-4.76 (m, 1H, NCH), 6.35 (dt, J=2, 9 Hz, 1H, Ar), 6.48 (dd, J=2, 12 Hz, 1H, Ar), 6.76 (brs, 2H, NH), 7.58 (dd; J=7, 8 Hz, 1H, Ar), 8.50 (d, J=8 Hz, 1H, NH), 10.84 (s, 1H, NH); 13C NMR (DMSO-d6) δ 24.06, 30.91, 48.98, 101.30 (d, JC-F=23 Hz), 101.60 (d, JC-F=22 Hz), 110.60, 130.66 (d, JC-F=11 Hz), 152.16 (d, JC-F=12 Hz), 164.46 (d, JC-F=246 Hz), 167.80, 172.30, 172.94.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[N:7]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:25][N:26]([C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=O)=[CH:32][CH:31]=1)[CH2:27][C:28]#[CH:29].[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.FC(F)(F)C(O)=O.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[N:7]([CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:25][N:26]([C:30]1[CH:42]=[CH:41][C:33]([C:34]([NH:43][CH2:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[O:36])=[CH:32][CH:31]=1)[CH2:27][C:28]#[CH:29]
Reactant: C#CCN(Cc1cc2c(=O)n(CCN(C)C)c(CN3CCCCC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: NCc1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(Cc1cc2c(=O)n(CCN(C)C)c(CN3CCCCC3)nc2cc1Cl)c1ccc(C(=O)NCc2cccnc2)cc1
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
A solution of tert-butyl 4-[N-[7-chloro-3-(2-dimethylaminoethyl)-4-oxo-2-piperidin-1-ylmethyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.100 g, 0.17 mmol) (Preparation Example 32) in dichloromethane (2.5 ml) and trifluoroacetic acid (3.5 ml) was stirred at room temperature for 55 min with protection from the light. The solvent was then removed in vacuo and the residue was triturated with ether and dried in vacuo over P2O5. This solid was dissolved in anhydrous DMF (5 ml) under argon and the solution was placed in an ice-bath. A solution of 3-(aminomethyl)pyridine (0.027 g, 0.25 mmol) in DMF (0.2 nil) was then added followed by PyBOP® (0.092 g, 0.37 mmol) and diisopropylethylamine (0.197 g, 1.53 mmol). Stirring was continued at 0° C. for 15 min; then the ice-bath was removed and the reaction mixture was stirred for an additional 4 h at room temperature. The solvent was then removed in vacuo and the residue was chromatographed on aluminium oxide 90 active (neutral) column eluting first with chloroform and then with 1% methanol in chloroform. The product was obtained as a white solid (0.026 g, 24%), mp 90-93° C.; 1H-NMR (DMSO-d6) 1.40-1.49 (m, 6H, piperidine CH2CH2CH2), 2.20 (s, 6H, Me2N) 2.41 (m, 4H, piperidine CH2NCH2), 2.55 (t (obscured), 2H, Me2NCH2), 3.21(s, 1H, C≡CH), 3.62 (s, 2H, 2-CH2), 4.25 (t, J=7.0 Hz, 2H, N3-CH2), 4.38 (s, 2H, CH2C≡C), 4.45 (d, J=5.7 Hz, 2H, CONHCH 4.78 (s, 2H, 6-CH2), 6.78 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.32 (dd, J=4.8, 7.8 Hz, 1H, pyr 5-H), 7.68 (d, J=8.0 Hz, 1H, pyr 4-H), 7.75 (d, J=8.7 Hz, 2H, 2′,6′-ArH), 7.85, 7.91 (2×s, 2H, 5-H, 8-H), 8.43 (d, J=5.1 Hz, 1H, pyr 6-H), 8.52 (s, 1H, pyr 2-H), 8.74 (t, J=5.9 Hz, 1H, CONH).; MS (FAB, m/z) 626, 628 [(M+H)+, 100%, 35% respectively; Cl isotopic pattern]. FAB-HRMS: measured 626.3025; calculated for C35H41ClN7O2 (M+H)+: 626.3010.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:27]1[CH:28]=[C:29]2[C:24]([CH:23]=[CH:22][NH:21]2)=[CH:25][CH:26]=1)=[O:31]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2cc[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 1H-indole-6-carboxylic acid. MS: 417.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])[N:3]=1.[F:18][C:19]([F:27])([F:26])[C:20](=O)[CH2:21][C:22](=O)[CH3:23].O>C(O)(=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([NH:7][C:4]1[N:3]=[C:2]2[N:1]=[C:22]([CH3:23])[CH:21]=[C:20]([C:19]([F:27])([F:26])[F:18])[N:6]2[N:5]=1)(=[O:9])=[O:10]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)n2nc(NS(=O)(=O)c3ccccc3Cl)nc2n1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A mixture of 2.19 g (8.00 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide and 1.09 ml (1.38 g, 8.96 mmol) of 1,1,1-trifluoro-2,4-pentanedione in 9 ml of glacial acetic acid was heated at reflux for 21 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ice and water. The solid which separated was collected by filtration, washed with water and dried to yield 2.90 g (93 percent) of the desired product as a white solid, mp 203°-204.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)C(C)(C)CCCCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)CCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 103 %

Procedure:
12.3 g of methyl 11-bromo-2,2-dimethylundecanoate in solution in 70 cm3 of N,N-dimethylformamide are added to 8.2 g of potassium phthalimide in 70 cm3 of N,N-dimethylformamide and the mixture is heated for 3 hours at a temperature in the region of 80° C. The solution is cooled to a temperature in the region of 20° C. and then poured into 1400 cm3 of distilled water. Acidification is carried out to a pH in the region of 2 using 4N hydrochloric acid and extraction is then carried out with a total of 1000 cm3 of ethyl acetate. The organic phase is washed with a total of 450 cm3 of distilled water, dried over magnesium sulphate, and then concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 60° C. 15.4 g of methyl 11-phthalimido-2,2-dimethylundecanoate are thus obtained in the form of a pale yellow viscous oil [Rf =0.38; silica thin layer chromatography; eluent: cyclohexane/ethyl acetate 8/2 (by volume)].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1coc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)co3)C[C@H]2OC)nc1Cl
Yield: 42.5 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate obtained in Example (103e) (0.19 g, 0.45 mmol), 2 N lithium hydroxide (2 mL, 4 mmol) and methanol (3 mL), to obtain 76 mg of the title compound as a colorless solid (43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH2:10]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=O)[CH2:12][CH2:11]1.B(F)(F)F.CCOCC>>[NH2:9][C:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]=[C:13]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:21][CH2:10][CH2:11][C:12]=12
Reactant: O=C1CCCCc2ccccc21
Reactant: N#Cc1ccccc1N
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)-c1ccccc1CCC2

Procedure:
2-amino-1-cyano-benzene (2.0 g, 16.9 mmol), 1-benzosuberone (6, 7, 8, 9-tetrahydrobenzocyclohepten-5-one) (3.0 g, 18.7 mmol) and boron trifluoride diethyl etherate(1M, 2.6 ml, 18.7 mmol) were treated according to the general procedure described herein to give the title compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenylboronic acid (5.12 g, 42 mmol), 2-bromophenol (3.55 g, 21 mmol), Cu(OAc)2 (7.63 g, 42 mmol), pyridine (8 ml, 103 mmol) and 4 Å molecular sieves (2.1 g) in CH2Cl2 was stirred at r.t. overnight. The mixture was diluted with CH2Cl2, filtered through celite, washed with 1M NaOH, brine and dried. Removal of solvent gave 1-bromo-2-phenoxybenzene, crystals (1.40 g, 27%). LRMS (ESI+): 248 (M+1). 1-Bromo-2-phenoxybenzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+) 255 (M+1)
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[OH:21][CH2:22][CH2:23][NH:24][C@@H:25]([CH3:31])[C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:24]([CH2:23][CH2:22][OH:21])[C@@H:25]([CH3:31])[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: C[C@H](NCCO)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N(CCO)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.17 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 79-3 (4.18 mmol, crude form) as starting materials, respectively 0.92 g (Isomer A, colorless solid) and 0.66 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2([O:12][Si](C)(C)C)[C:4]3([CH3:20])[CH:5]=[CH:6][CH:7]([CH2:19][CH:3]13)[C:8]2([CH3:18])[CH3:17].C([O-])(O)=O.[Na+].C(OCC)(=O)C.C(Cl)Cl>C(O)(=O)C.O1CCCC1.O>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2([OH:12])[C:4]3([CH3:20])[CH:5]=[CH:6][CH:7]([CH2:19][CH:3]13)[C:8]2([CH3:17])[CH3:18]
Reactant: CC1(C)C2C=CC3(C)C(C2)C(=O)CCC13O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C2C=CC3(C)C(C2)C(=O)CCC13O
Yield: 94.8 %

Procedure:
A solution of 21 mg of 1,2,3,4,4a,5,6,8a-octahydro-2oxo-4a-trimethylsilyloxy-5,5,8a-trimethyl-1,6-methanonaphthalene in 4 ml of acetic acid/tetrahydrofuran/water (3:1:1) was stirred under argon at 25° C. over 10 hours, then poured into saturated aqueous NaHCO3 solution and extracted with CH2Cl2. After chromatography (SiO2, ethyl acetate/CH2Cl2) and sublimation, there were obtained 15 mg of 1,2,3,4,4a,5,6,8a-octahydro-2-oxo-4a-hydroxy-5,5,8a-trimethyl-1,6-methanonaphthalene (m.p. 112°-115° C., 95% yield).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9]C(O)=O)[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17](=[O:21])[CH2:18][O:19][CH3:20])[CH2:4][C@@H:3]1[NH:22][C:23](=[O:33])[C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:32])[CH:25]=1.O=C1N(C[C:43]([NH:45][C@H:46]2[CH2:50][C:49](=[O:51])[O:48][CH:47]2[O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:44])C2C=CC=CC=2N(C(=O)COC)C[C@@H]1NC(=O)C1C=C(Cl)C(O)=C(Cl)C=1.O=C1N(CC(O)=O)C2C=CC=CC=2N(C(=O)COC)C[C@@H]1NC(=O)C1C=C(Cl)C(O)=C(Cl)C=1>>[O:1]=[C:2]1[N:8]([CH2:9][C:43]([NH:45][C@H:46]2[CH2:50][C:49](=[O:51])[O:48][CH:47]2[O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:44])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17](=[O:21])[CH2:18][O:19][CH3:20])[CH2:4][C@@H:3]1[NH:22][C:23](=[O:33])[C:24]1[CH:25]=[C:26]([CH3:32])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=1
Reactant: COCC(=O)N1C[C@H](NC(=O)c2cc(C)c(O)c(C)c2)C(=O)N(CC(=O)O)c2ccccc21
Reactant: COCC(=O)N1C[C@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21
Agent: COCC(=O)N1C[C@H](NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N(CC(=O)O)c2ccccc21
Product: COCC(=O)N1C[C@H](NC(=O)c2cc(C)c(O)c(C)c2)C(=O)N(CC(=O)N[C@H]2CC(=O)OC2OCc2ccccc2)c2ccccc21

Procedure:
was synthesized from 687b by the method used to prepare 688a from 687a to afford 960 mg of 688b as an off-white solid, 1H NMR (CD3OD) δ2.6(dd, 1H), 2.7(dd, 1H), 3.0(dd, 1H), 3.2(s, 3H), 3.7(m, 3H), 3.9(m, 2H), 4.4-4.5(m, 2H), 4.6(m, 3H), 5.35(s, 1H), 5.55(d, 1H), 7.25(m, 2H), 7.4-7.5 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:22].[K+].[K+].O.[OH-].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(OCc3ccccc3)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(O)c2cccc(OCc3ccccc3)c2n1
Temperature: 140 °C
Yield: 80.9 %

Procedure:
To a mixture of 8-(benzyloxy)-4-chloro-2-methylquinoline (3.09 g, 10.9 mmol), potassium carbonate (3.22 g, 32.8 mmol) in DMSO (30 mL) was added water (1.00 mL) to dissolve the solid. The mixture was heated at 140° C. for 2 h and was added 2N NaOH (12 mL, 24.0 mmol) and heated at 130° C. overnight. The mixture was poured into ice/NaHCO3. Solid precipitated and was filtered, washed with water and dried to give 8-(benzyloxy)-2-methylquinolin-4-ol (2.34 g, 81%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:15]2[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=3)=[C:18]([CH2:19][OH:20])[O:17][N:16]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (5.8 g, 15.6 mmol) in THF (39 mL) was added a solution of lithium hydroxide monohydrate (762 mg, 31.2 mmol) in water (36 mL) and MeOH (10 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified with HCl (1 N, 30 mL) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to afford the title compound (660 mg, 12%) which was obtained as a white solid. MS: m/e=343.0 [M−H]−.