Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:32])=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1

Procedure:
A suspension of (S)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (7.0 g, 16.3 mmol) in ethanol/water (70 mL/7 mL) was hydrogenated over 10% palladium on carbon (0.41 g) at 55 psi of hydrogen, at 50° C., for 5 hours. The mixture was cooled, and the catalyst was removed by filtration. The solvent was evaporated in vacuo. The residue was dissolved in hot ethanol (30 mL) and treated with a saturated solution of hydrogen chloride in ethanol (3 mL). The product crystallized as the hydrochloride salt, 1.27 g (32%), a colorless solid. MS m/z 207 (MH+). 1H NMR (DMSO-d6) δ 1.92 (m, 3H), 2.43 (m, 1H), 3.28 (m, 2H), 4.31 (m, 1H), 6.77 (d, 2H), 7.47 (d, 2H), 9.44 (br s, 1H) and 10.75 (s, 1H). Anal. calcd for C11H14N2O2: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.28; H, 6.06; N, 11.66.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: COC(=O)CBr
Agent: Cl
Product: COC(=O)CN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 41 %

Procedure:
The title compound (135 mg, 41%) was prepared from 1-(4-Phenoxy-phenyl)-piperazine hydrochloride. (165 mg, 0.9 mmol) and methyl 2-bromo-acetate (140 mg, 0.92 mmol) by the procedure described in step 3 of Example 6 MS (ESI) m/z 327 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.76 (b, 2.67), 3.21 (t, J=3.2 Hz, 4H), 3.29 (s, 2H), 3.75 (s, 3H), 6.92-7.05 (m, 7H), 7.29 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]CC#C)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1[CH2:25][CH2:24][O:23]CC1.O1CCOC[CH2:27]1>>[ClH:19].[ClH:19].[CH2:24]([O:23][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:25]#[CH:27]
Reactant: C#CCCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1COCCO1
Agent: Cl
Product: C#CCOCCN1CCNCC1
Temperature: 60 °C

Procedure:
To a solution of 10.70 g of 1-tert-butoxycarbonyl-4-(2-(2-propynyl)ethyl)piperazine in 1,4-dioxane was added 4N hydrochloric acid/1,4-dioxane, and the mixture was stirred at 60° C. After completion of the reaction, the mixture was concentrated and diethyl ether was added. The solid was collected by filtration and dried to give 11.83 g of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)=[O:3].ClC1C=C(C(OO)=[O:46])C=CC=1>ClCCl>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)(=[O:46])=[O:3]
Reactant: CS(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methanesulfinyl-phenyl)-amide (85 mg, 0.15 mmol) (from Example 81 supra) in dichloromethane (4 mL) was added 3-chloro-benzenecarboperoxoic acid (52.6 mg, 0.3 mmol) (Aldrich). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with 2% of sodium sulfite solution, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methanesulfonyl-phenyl)-amide as a pale yellow solid. (Yield 81 mg, 93%).
Reaction SMILES: [ClH:1].[CH:2]1([C:8]2(O)[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C1COCC1.CO>[ClH:1].[C:2]1(=[C:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(C3CCCCC3)C(C)(C)O4)CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=C3CCCCC3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
Concentrated hydrochloric acid (0.5 mL) was added to a solution of 1-(3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (670 mg, 1.4 mmol) obtained in Example 43 in THF (5 ml) and methanol (5 ml) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was made to basic with 10% aqueous potassium carbonate. The mixture was extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was treated with 4N hydrochloric acid in ethyl acetate solution and the title compound was crystallized from ethanol-diisopropyl ether to obtain 520 mg (yield 75%). mp. 220–222° C.
Reaction SMILES: [P:1]([NH2:17])(=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19].[H-].[Na+]>O1CCCC1>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31]([NH:17][P:1](=[O:16])([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:32])[CH3:19]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
To a suspension of diphenyl phosphoramidate (2.0 g, 8.0 mmol) in tetrahydrofuran (20 mL) at 0° C. is added 2,6-diisopropylphenyl isocyanate (1.7 mL, 8.0 mmol). Sodium hydride (0.32 g, 8.0 mmol) is then added portionwise over 15 minutes. The mixture is allowed to warm to room temperature and stirred for 6 hours. The mixture is partitioned between ethyl acetate and water and the aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated. Flash chromatography (7:3 hexane/ethyl acetate) affords 2.4 g of a white solid which is recrystallized (ethyl acetate/hexane) to afford 1.6 g of the title compound as a white solid; mp 171°-175° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[C:13]([C:17]2[N:18]([CH2:43][CH3:44])[C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[CH:40]=[CH:39][C:38](=[O:41])[NH:37][CH:36]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:22]=[CH:21][C:20]=3[N:42]=2)=[N:14][O:15][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:11][C:12]1[C:13]([C:17]2[N:18]([CH2:43][CH3:44])[C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[CH:36]=[N:37][C:38]([O:41][CH2:3][CH2:4][N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)=[CH:39][CH:40]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:22]=[CH:21][C:20]=3[N:42]=2)=[N:14][O:15][N:16]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(=O)[nH]c4)c3)cc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(OCCN5CCOCC5)nc4)c3)cc21
Temperature: 80 °C
Yield: 29.2 %

Procedure:
2-Chloroethylmorpholine hydrochloride (104 mg, 0.6 mmol) was added to a slurry of the product of Step 2 (135 mg, 0.3 mmol) and powdered K2CO3 (1 g) in DMF (2 mL) and the mixture was heated to 80° C. for 3 h. The mixture was cooled, diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried (MgSO4), filtered and the filtrate was concentrated to give a yellow oil which was purified by reverse phase HPLC to give the title compound (50 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 9.13 (s, 1H), 8.69 (s, 1H), 8.09 (d, J=9.3, 1H); 7.92 (s, 1H), 7.69 (d, J=8.0, 1H), 7.60-7.53 (m, 2H), 7.12 (d, J=8.0, 1H), 6.67 (d, J=9.4, 1H), 4.76 (br q, 2H), 4.53 (br m, 2H), 3.83-3.70 (m, 8H), 3.33 (m, 2H), 1.46 (br t, 3H). MS (ES+) m/e 572 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[Cl:18][C:19]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:18][C:19]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:38][CH:39]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:20]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(-n5ccnc5)cc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A suspension of 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (23 mg), 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide (52.4 mg) and potassium carbonate (42.3 mg) in N,N-dimethylformamide (0.5 ml) was stirred for 3 hours at ambient temperature. Water was added thereto, and the resulting precipitate was collected by filtration. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (60 mg) as colorless amorphous.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:10]([C:3]2[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=2[OH:1])[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: NC1CC1
Product: Cn1ccc(=O)c(O)c1C(NC1CC1)C(F)(F)F
Yield: 40 %

Procedure:
In a similar manner, Apo7074 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and cyclopropylamine (0.62 mL, 9.0 mmol). The title compound Apo7074 (470 mg) was obtained after purification by flash chromatography (5% MeOH in CH2Cl2 as eluant). Yield=40%; 1H NMR (400 MHz, DMSO+a few drops of D2O) δ (ppm): 7.67 (d, J=6.8 Hz, 1H), 6.25 (d, J=7.1 Hz, 1H), 4.70 (q, J=8.1 Hz, 1H), 3.74 (s, 3H), 2.04 (br. s., 1H), 0.34-0.43 (m, 4H); MS m/z 263 [M+1]+, 206 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][N:6]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:7]1[NH:12][C:11](=[S:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[C:9](=[O:26])[CH:8]=1.C(=O)([O-])O.[Na+].I[CH2:50][CH3:51]>C(#N)C>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:6]([CH2:5][C:4]1[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=1[O:2][CH3:1])[C:7]1[N:12]=[C:11]([S:13][CH2:50][CH3:51])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:16][CH:15]=2)[C:9](=[O:26])[CH:8]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2OC)c2cc(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]2)c(OC)c1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSc1nc(N(Cc2ccc(OC)cc2OC)Cc2ccc(OC)cc2OC)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[bis(2,4-dimethoxybenzyl)amino]-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrimidin-4(1H)-one (0.65 g) in acetonitrile (7 mL) were added 1M aqueous sodium hydrogen carbonate solution (1.05 mL) and iodoethane (0.425 mL), and the mixture was stirred at 70° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.68 g).
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16])[CH:5]=[CH2:6].[CH3:17]N(C)C=O.CI>C(OCC)C>[CH3:17][CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:4][CH:5]=[CH2:6])[C:11]1=[O:16]
Reactant: C=CCc1cccc2c1CCC2=O
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: C=CCc1cccc2c1CC(C)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.88 g of sodium methylate in 15 ml of ethyl ether is cooled to 0° C., a solution composed of 2.8 ml of ethyl formiate and 3 g of 4-(2-propenyl)-indanone in 6 ml of ether is introduced over 15 minutes, 5 ml of ether is added, with agitation for 15 minutes, and the suspension is allowed to rise to 20° C. 70 ml of dimethylformamide is added, with agitation for 2 hours, 2.15 ml of methyl iodide and 2 ml of ether are introduced, followed by agitation for 2 hours. The resulting mixture is then poured over 100 ml of ice water and extracted with ethyl ether, the extracts are dried and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (95-5) and 1.62 g of expected product is obtained.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[FH:18].F.F.C(N(CC)CC)C>>[F:18][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2][C@H:1]1[OH:7]
Reactant: F
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@@H](F)[C@H](O)C1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
Racemic benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.00 g, 4.29 mmol) (AMRI, Syracuse, N.Y. E00017 Lot IN-GBG-A-009B) and triethylamine trihydrofluoride (0.699 mL, 4.29 mmol) were combined in a sealed tube and heated to 100° C. overnight. The reaction was cooled and partitioned between water and EtOAc. The aqueous layer was extracted 3×EtOAc, and the organic layer was washed with water once, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 15-50% EtOAc/hexane to give racemic trans-benzyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (0.612 g, 2.42 mmol, 56% yield). MS (ESI, pos. ion) m/z: 254 (M+1).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[ClH:2].[ClH:1].[ClH:2].[CH:26]([NH:29][CH:23]([CH3:24])[CH2:22][O:21][C:15]1[CH:14]=[CH:13][C:12]2[C:17]([CH:16]=1)=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH:4]([NH:18][CH:17]([CH3:12])[CH3:16])[CH3:3])[CH:20]=1)[CH:11]=2)([CH3:28])[CH3:27]
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Reactant: CC(C)N
Agent: Cl
Product: CC(C)NC(C)COc1ccc2cc3ccc(OCC(C)NC(C)C)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and isopropylamine as described in Example 15.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O.P(Cl)(Cl)(Cl)=O>>[N:19]1[CH2:23][CH2:22][CH2:21][C:20]=1[N:6]1[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C1CCCN1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2c(c1)N(C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE as a distillable oil, b.p. 140°-146° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 219.5°-222.5° C. (dec.)(corr.), in a 62% overall yield by triturating with warm benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:18]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=3[CH:18]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CC(C)N1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isopropyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield an off-white solid (67%). mp 195° C.; LCMS: m/z=509.27 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.25 (m, 1H), 6.23 (m, 2H), 4.61 (m, 1H), 4.26 (m, 1H), 3.00 (s, 1H), 2.85 (d, 1H, J=11.9 Hz), 2.66 (s, 3H), 2.47 (d, 1H, J=8.1 Hz), 2.31 (m, 1H), 2.15 (m, 3H), 1.80 (m, 1H), 1.56 (m, 1H), 1.45 (m, 3H), 1.36 (s, 3H), 1.24 (m, 4H), 0.99 (t, 3H, J=6.8 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:35][CH2:2][C:3]2[N:4]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:5]=[C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])[N:7]=2)=[CH:32][CH:31]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: OCc1ccc(Cl)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccc(Cl)cc2)n1
Yield: 22 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 4-chlorobenzyl alcohol instead of 4-methylbenzyl alcohol, was converted to the title compound (28 mg, 22%) which was obtained as a light yellow solid. MS: m/e=501.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[C:30]([C:26]1[CH:25]=[C:24]([CH2:23][CH:15]([NH:14][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])[C:16]([N:18]2[CH2:22][CH2:21][S:20][CH2:19]2)=[O:17])[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N#Cc1cccc(CC(N)C(=O)N2CCSC2)c1
Product: N#Cc1cccc(CC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)C(=O)N2CCSC2)c1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (+)-2-amino-3-(3-cyano-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 183-184° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24]>CN1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CI
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 65.3 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 153 mg, 0.5 mmol) and iodomethane (0.16 mL, 2.55 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown semi-solid which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, and evaporated to give (4R,7S)-2-(2,4-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (104 mg, 65%) as an off-white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28](OC(C)(C)C)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC=O)c[nH]c34)no2)cc1Cl
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (provided by WuxiPharma, China and made in a similar manner to D7) (4.0 g) in DCM (50 mL) at −78° C. under N2 atmosphere was added DIBAL-H (14 ml) dropwise. The reaction was stirred at −78° C. for 6 h. Then MeOH was added at −78° C. to quench the reaction. The resulting solution was concentrated. And the residue was purified by column chromatography on silical gel (15% EtOAc in hexane) to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanal (D92) (1.3 g). δH (CDCl3, 400 MHz): 1.45 (6H, d), 2.90 (2H, t), 3.17 (2H, t), 4.72 (1H, m), 7.07 (1H, d), 7.16 (1H, d), 7.30 (1H, d), 7.78 (1H, d), 8.12 (2H, m), 8.29 (1H, s), 9.63 (1H, br s), 9.89 (1H, s). MS (ES): C22H20ClN3O3 requires 409; found 410 (M+H+).