Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33]OS(C)(=O)=O)[O:30][N:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:31]2[O:30][N:29]=[C:28]([CH3:27])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: Cc1cc(COS(C)(=O)=O)on1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)on1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid 3-methyl-isoxazol-5-ylmethyl ester (described in Heterocycles, 23(3), 571-83; 1985) gave the title compound. ES-MS m/e (%): 462.2(M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]=[N:10][CH2:11][CH:12](C)C.[CH2:15](OCC(COCC1OC1)(COCC1OC1)COCC1OC1)C1OC1>CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]=[N:10][CH:11]([CH3:12])[CH3:15]
Reactant: C(OCC(COCC1CO1)(COCC1CO1)COCC1CO1)C1CO1
Reactant: CC(C)CN=CCN1CCNCC1C
Solvent: CO
Product: CC(C)N=CCN1CCNCC1C
Temperature: 60 °C

Procedure:
To a 10 mL round bottom flask containing a stir bar was added methyl isobutyliminoethylpiperazine (726 mg, 3.44×10−3 moles, 3 equivalents) and 4 g MeOH. To this mixture at 25° C. was added pentaerythritol tetraglycidyl ether (307 mg, 0.853 mmol, 3.4 mmoles epoxide). This mixture was stirred and heated at 60° C. for 6.5 hours. To this mixture was added ethyl t-piperazine carbamate (537 mg, 3.4 mmol) and this mixture heated at 60° C., 16 hours, 60° C., 54 h with no adduct for the desired product at 906 or 833 (decarboxylated material). Another aliquot of monoblocked piperazine was added (1.5 g) and this mixture was heated at 70° C., 16 hours, 24 hours and 60 hours total with no sign of desired adduct. The 3:1 adduct at 748 amu was completely converted to 4:1 adduct at 993 amu by reaction of remaining equivalent imine in presence of a total of 16 equivalents of ethyl 1-piperazine carboxylate. This mixture was purified by tangential flow ultrafiltration using a 1K regenerated cellulose membrane at 20 psi as a 2-5% w/w mixture in MeOH to give 8-9 recirculations. The retentate was stripped of volatiles on a rotary evaporator followed by high vacuum to give 590 mg. The following scheme illustrates this reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=O)[CH2:22]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:23]3[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:21][CH2:22]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=C1COc2ccccc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3COc4ccccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 2,3-dihydrobenzofuran-3-one using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.NC1C=C(C(C2C=C3C(C(C=CC4C=CC=CC=4)=NN3COCC[Si](C)(C)C)=CC=2)=O)C=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3cccc([N+](=O)[O-])c3)cc21
Agent: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3cccc(N)c3)cc21
Product: Nc1cccc(C(=O)c2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1

Procedure:
(3-Nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone was converted to (3-amino-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone as described in Example 11, step (iv) (102 mg, 84%). LCMS (ESI) [M+H]/z Calc'd 340. found 340.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[N+:26]([C:29]1[CH:34]=[C:33]([S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[CH:32]=[CH:31][C:30]=1Cl)([O-:28])=[O:27]>>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:22]=[CH:23][C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:30]3[CH:31]=[CH:32][C:33]([S:35]([C:38]([F:40])([F:41])[F:39])(=[O:37])=[O:36])=[CH:34][C:29]=3[N+:26]([O-:28])=[O:27])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:12][CH:13]=1)[CH3:21]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1

Procedure:
Using procedure as in example 10, a reaction of ethyl [4-(4-hydroxyphenylsulfonyl)phenoxy]acetate (100 mg, 0.297 mmol), NaH (13 mg, 1.1 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (86 mg, 1 equiv.) afforded{4-[4-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzenesulfonyl]-phenoxy}-acetic acid ethyl ester. 1HNMR (300 MHz, DMSO-d6) δ 8.79 (d, J=2.3 Hz, 1H), 8.29 (dd, J=2.3 & 9.0 Hz, 1H), 8.07 (d, J=8.9 Hz, 2H), 7.92 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.9 Hz, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.14 (d, J=8.9 Hz, 2H), 4.91 (s, 2H, CH2), 4.15 (q, J=7.2 Hz, 2H, OCH2CH3), 1.19 (t, J=7.2 Hz, 3H, OCH2CH3). MS-EI m/z 589 [M+].
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]1([CH3:23])[C:14]([CH3:15])=[CH:13][CH2:12][CH:11]1[C:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH:17]=1>CS(C)=O.C(OCC)C>[CH3:9][C:10]1([CH3:23])[C:14]([CH3:15])=[CH:13][CH2:12][CH:11]1[C:16]1[CH2:21][CH2:20][C:19]2([O:22][CH2:2]2)[CH2:18][CH:17]=1
Reactant: C[S+](C)(C)=O
Reactant: CC1=CCC(C2=CCC(=O)CC2)C1(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC1=CCC(C2=CCC3(CC2)CO3)C1(C)C
Reaction time: 0.5 h

Procedure:
Trimethylsulfoxonium iodide (4.78 g, 21.63 mmol.) is added in portions to a suspension of sodium hydride (60% in mineral oil, 1.00 g, 25.54 mmol.) in DMSO (10 ml). Stirring is carried out for 30 minutes before 4-(2,2,3-trimethyl-cyclopent-3-enyl)-cyclohex-3-enone (XIII, see U.S. Pat. No. 5,189,013, 2.78 g, 13.64 mmol.), dissolved in DMSO (10 ml), is added. When the addition is complete, stirring is continued for a further 30 minutes, and then the reaction solution is poured onto ice (25 ml). The mixture is diluted with diethyl ether (50 ml), the phases are separated, and the aqueous phase is extracted three times with diethyl ether (50 ml each time). The combined organic phases are washed once with saturated NaCl solution before being dried over Na2SO4, filtered off and concentrated in a rotary evaporator. 3.08 g of crude product are obtained, which is then purified by flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.22). 2.21 g of a colourless oil are obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([C:24]1[CH:25]=[C:26]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.O>ClCCl>[C:20]([C:24]1[CH:25]=[C:26]([S:32]([N:17]2[CH2:16][CH2:15][N:14]3[CH2:19][C@H:11]([O:10][C:7]4[CH:6]=[N:5][C:4]([CH:1]5[CH2:3][CH2:2]5)=[CH:9][N:8]=4)[CH2:12][C@H:13]3[CH2:18]2)(=[O:34])=[O:33])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])([CH3:23])([CH3:21])[CH3:22]
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 27B (30 mg, 0.115 mmol) in dichloromethane (1 mL) was added 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride (36 mg, 0.138 mmol) and diisopropylethylamine (0.040 mL, 0.23 mmol). The resulting mixture was stirred at room temperature for 90 minutes. Water (2 mL) was added, and the mixture was extracted with dichloromethane (2×2 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude product. Purification by column chromatography on silica gel eluting with a solvent gradient of 0-60% ethyl acetate in hexanes gave the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.87-1.00 (m, 4H), 1.38 (s, 9H), 1.73-1.87 (m, 1H), 1.91-2.03 (m, 2H), 2.08 (t, J=10.51 Hz, 1H), 2.31 (dd, J=10.17, 5.09 Hz, 1H), 2.37-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.91-3.05 (m, 1H), 3.63 (dd, J=10.17, 6.78 Hz, 1H), 3.68-3.76 (m, 1H), 3.83-3.90 (m, 1H), 3.90 (s, 3H), 5.23-5.35 (m, 1H), 6.94 (d, J=9.16 Hz, 1H), 7.57-7.66 (m, 2H), 7.91 (d, J=1.36 Hz, 1H), 8.02 (d, J=1.70 Hz, 1H); MS (ESI) m/z 487.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]2[N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1)[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]2[N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1ccc2c(n1)N(C(C)=O)CC2)c1cnc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCc1ccc2c(n1)N(C(C)=O)CC2)c1cnc(C)nc1
Yield: 33.5 %

Procedure:
To a solution of 23-10 (0.150 g, 0.34 mmol), ammonium formate (0.192 g, 3.09 mmol), and 10% Pd/C (0.150 g) in EtOH (25 rnL) was refluxed for 15 minutes. Filtration through celite and evaporative removal of the solvent followed by purification by PCTLC (0–10% MeOH-CHCl3) afforded 0.050 g of 23-11.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[CH2:31]([N:38]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:39](Cl)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC1CCCO1>C(OCC)(=O)C.O>[CH2:42]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:39](=[O:40])[O:28][C:27]1[CH2:29][CH2:30][C:23]2[C:24](=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)=[CH:21][CH:22]=2)[N:26]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: O=C(Cl)N(Cc1ccccc1)Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: O=C(OC1=Nc2cc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2CC1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
A mixture of aripiprazole (1.5 g, 3.3 mmol), dibenzylcarbamoyl chloride (1.74 g, 6.7 mmol) silver carbonate (3.75 g, 13.4 mmol) and 2-methyltetrahydrofuran (30 mL) was heated at reflux for 4 days. The reaction mixture was cooled, diluted with ethyl acetate and water, and then filtered through celite. The organic phase was separated, dried over MgSO4 and evaporated. The residue obtained was further purified on silica eluting with ethyl acetate/tetrahydrofuran to give after evaporation of the major product containing fractions, Compound-80 (1.02 g) was a yellow oil.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].Cl.N[OH:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]#[N:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:3]=[C:1]([CH3:2])[O:10][N:25]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5.3 mL triethylamine and 2.6 g hydroxylamine hydrochloride were added to 6.8 g 4-cyano-piperazine-1-carboxylic acid tert-butyl ester in 50 mL ethanol. The reaction was stirred 2 h at 80° C. The solvent was removed and 50 mL pyridine and 3.7 mL acetic anhydride were added to the residue and stirred at 80° C. over night. The mixture was evaporated. Water was added and the precipitate was filtered and purified by chromatography on silica gel (cyclohexane/ethyl acetate: 2/1) to give 3.35 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Nc2nc(Cl)ncc2Cl)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (687.37 mg, 2.86 mmol) in EtOH (20 mL) was added Et3N (552.50 mg, 5.46 mmol) and the reaction mixture was stirred at rt overnight. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 5/1) to give the product as a white solid (930 mg, 88.2%).
Reaction SMILES: C([O:8][C:9]([N:11]1[CH:16]([C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:28][CH:29](OC)OC)=[O:10])C1C=CC=CC=1.[C:34]1([CH3:44])[CH:39]=CC(S([O-])(=O)=O)=C[CH:35]=1.[NH+]1C=CC=CC=1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:34]([O:8][C:9]([N:11]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]1[C:17](=[O:27])[N:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:29][CH2:28]2)=[O:10])([CH3:44])([CH3:39])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC(CC1CCCC(C(=O)NCCc2ccccc2)N1C(=O)OCc1ccccc1)OC
Reactant: [H][H]
Agent: [Pd]
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCCC1C(=O)N(CCc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 1177.2 %

Procedure:
2-(2,2-Dimethoxy-ethyl)-6-phenethylcarbamoyl-piperidine-1-carboxylic acid benzyl ester (Compound 239, 0.297g, 0.65mmol) was dissolved in toluene (15 ml), and the flask was immersed in a 80° C. oil bath. Pyridinium p-toluene sulfonate (0.0120 g, 0.05 mmol) was added and the reaction was stirred at 80° C. for 2 hours. After this time, the reaction was cooled down and the precipitate formed was removed by filtration. The toluene was evaporated and the residue was dissolved in dioxane (10 mL). N-(tert-Butoxycarbonyl anhydride (0.285 g, 1.31 mmol) and palladium 10% on activated carbon (0.1 g) were added. Hydrogen was applied via Parr apparatus and reaction was shaken at 50 psi for 12 hours. The black suspension was then filtered through compacted Celite, and dioxane was removed. Flash chromatographic purification of the residue (1:2 EtOAc/hexanes) gave Compound 240 (0.211 g, 90%). Rf=0.31 (1:2 EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.[N:13]([O-])=[O:14].[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:13]=[O:14])[C:6]=2[CH:12]=1
Reactant: O=N[O-]
Reactant: Fc1ccc2c(c1)NCCCS2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCCSc2ccc(F)cc21
Yield: 92 %

Procedure:
7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (423 mg, 2.3 mmol) was dissolved in acetic acid (1.15 mL)at 0° C. in an ice bath. 2.7 M aqueous sodium nitrite (1 mL) was added and this was stirred over night. Water was added (100 mL) and extracted with dichloromethane (3×50 mL), the organics were combined and concentrated to give 7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 92%). 1H NMR (CDCl3, 300 MHz): δ 7.43 (t, 1H, J=7.1 Hz), 7.30 (dd, 1H, J=9.1 Hz, J=9.2 MHz), 7.26–7.00 (m, 1H), 4.18 (t, 2H, J=5.8 Hz), 2.86 (t, 2H, J=7.2 Hz), 2.17–2.04 (m, 2H) ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[O:4].N([O-])=[O:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:13])[CH:10]=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: O=C(CBr)c1cccc(Br)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CO)c1cccc(Br)n1
Reaction time: 14 h

Procedure:
To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (500 mg, 1.79 mmol) in dimethylformamide (11.5 mL) was added sodium nitrite (124 mg, 1.79 mmol). After 14 hours, the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (2×100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound. 1H NMR (600 MHz, DMSO): δ 7.94 (m, 2H), 7.91 (m, 1H), 5.07 (t, J=5.9 Hz, 1H), 4.85 (d, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([O:32]CC)=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([OH:32])=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCOc4ccccn4)CC3)c2c1
Temperature: 70 °C
Reaction time: 21 h
Yield: 101.4 %

Procedure:
A mixture of 0.12 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yloxy)-ethyl]piperidine-4-carboxylate in 5 cm3 of dioxane, 5 cm3 of methanol and 1 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 21 hours. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 60° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; diameter 1.5 cm; mass 20 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). The fractions containing the product were combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The foam was taken up in 2 cm3 of methanol, filtered, washed with 1 cm3 of methanol and 2 cm3 of diethyl ether and then oven-dried under reduced pressure (10 kPa) at about 50° C. 0.115 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yloxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at about 70° C. and becoming sticky.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]2[CH:22]=[C:21](C(C)(C)C)[C:20](O)=[C:19](C(C)(C)C)[CH:18]=2)=[O:15])[CH:6]=[C:5]([CH3:32])[CH:4]=1.[CH3:33][N:34](C)[C:35]1C=CC(N)=CC=1.C(C1C=C(N)C=C(C(C)(C)C)C=1O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:34]([CH3:35])[CH3:33])=[CH:21][CH:22]=2)=[O:15])[CH:6]=[C:5]([CH3:32])[CH:4]=1
Reactant: Cc1cc(N)nc(CCCCCC(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reactant: CN(C)c1ccc(N)cc1
Agent: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Product: Cc1cc(N)nc(CCCCCC(=O)Nc2ccc(N(C)C)cc2)c1

Procedure:
The experimental protocol used is the same as that described for compound 17, N,N-dimethyl-p-phenylenediamine replacing the 2,6-di-t-butyl-4-aminophenol. Hygroscopic grey solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.CCOCC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1C=CC=CC=1>[CH:29]([O:28][C:26]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)=[O:27])([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)OC(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 58.9 %

Procedure:
To a solution of 3.0 g (0.013 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.4 g (0.013 mole) triethylamine, and 75 ml ether was added 1.6 g (0.013 mole) isopropyl chloroformate. The reaction mixture was refluxed one hour, filtered, and rotary evaporated to give a yellow oil. The oil was distilled (bp1.2 mm 120° C.) to give a cloudy yellow oil. This was taken up in benzene, filtered, and the solvent removed leaving 2.4 g (57% yield) of product. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: Br[C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.C(OCC)(=O)C.Cl>[C:10]([C:4]1[C:3]([OH:13])=[C:2]([C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[C:15]#[N:16])(=[O:12])[CH3:11]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1O
Temperature: 200 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.85 g, 18.4 mmol) and copper cyanide (2.47 g, 27.6 mmol) in N-methylpyrrolidinone (15 mL) was heated at 200° C. for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate and 1 N HCl. The layers were separated and the aqeous layer was extracted with ethyl acetate. The combined organic layers were washed with water, then brine and dried over magnesium sulfate. After concentration to dryness under reduced pressure, the residue was used directly in the next step (3.7 g, 96%). LCMS calculated for C10H9ClNO2 (M+H)+: m/z=210.0; Found: 210.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=1[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CON(C)C(=O)C1CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccc(N)c(C(=O)C2CC2)c1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a stirred solution of p-tolyl-carbamic acid tert-butyl ester (1.0 g, 4.8 mmol) in Et2O (10 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (6.5 mL, 11.1 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopropanecarboxylic acid methoxy-methyl-amide (0.92 g, 6.3 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (15 mL) and TFA (15 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 0.80 g crude (2-amino-5-methyl-phenyl)-cyclopropyl-methanone as a yellow oil.