Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]2[C:48]([Cl:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=2[Cl:51])=[CH:35][CH:34]=1)[C:4]([N:6]([CH2:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:26]=1)[O:14][CH2:15][CH:16]1[CH2:18][CH:17]1[C:19]([O:21]CC)=[O:20])[CH:7]1[CH2:9][CH2:8]1)=[O:5].[OH-].[Na+:53]>C(O)C>[NH2:1][CH2:2][CH:3]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][O:42][C:43]2[C:44]([Cl:51])=[CH:45][C:46]([CH3:50])=[CH:47][C:48]=2[Cl:49])=[CH:37][CH:38]=1)[C:4]([N:6]([CH2:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:26]=1)[O:14][CH2:15][CH:16]1[CH2:18][CH:17]1[C:19]([O-:21])=[O:20])[CH:7]1[CH2:9][CH2:8]1)=[O:5].[Na+:53]
Reactant: CCOC(=O)C1CC1COc1cc(CCCOC)cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2CC2C(=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a ethanol solution (0.03 M) of ethyl 2-{[3-{[(3-amino-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}propanoyl) (cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylate from Example 86 was added sodium hydroxide (1 N aqueous solution, 2.2 eq.). The resulting solution was stirred at 80° C. for 18 h. The volatiles were removed in vacuo and the resulting solid residue was suspended in dichloromethane. The insolubles were then filtered off and the filtrate was concentrated in vacuo to afford the title compound as a white solid. MS for the corresponding free acid (ESI+): 713.2. 1H NMR (methanol-d4): 0.41 (m, 1H), 0.70-0.83 (m, 4H), 1.11 (m, 1H), 1.52 (m, 1H), 1.72 (m, 1H), 1.80-1.87 (m, 2H), 2.24 (m, 1H), 2.31 (s, 3H), 2.59-2.62 (m, 2H), 2.75-2.80 (m, 2H), 2.84 (dd, J=13.2, 9.5 Hz, 1H), 2.95 (dd, J=12.7, 7.5 Hz, 1H), 3.31 (s, 3H), 3.37 (t, J=6.4 Hz, 2H), 3.73 (71, 1H), 3.85 (d, J=6.7 Hz, 2H), 4.22-4.45 (m, 4H), 4.48 (d, J=14.6 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 6.58 (s, 1H), 6.62 (s, 1H), 6.65 (s, 1H), 6.78 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 7.22 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCCl>[CH3:27][S:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a 100 mL round-bottomed flask was added tert-butyl 4-(2-aminophenyl)piperidinecarboxylate (Preparation B) (1.93 g, 7.2 mmol) and 1,2-dichloroethane (50 mL). The solution was magnetically stirred under a N2 atmosphere, treated with pyridine (2.9 mL, 36 mmol) and methanesulfonyl chloride (Aldrich) (1.1 mL, 1.7 g, 14 mmol). The vessel was immersed in a 50° C. oil bath for 6 h then cooled to 25° C. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (200 mL) and 1 N HCl (100 mL). The organic layer was washed with satd NaHCO3 (75 mL), satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated to give a foam. The foam was purified by silica gel chromatography (3:/EtOAc:hexane) to provide the title compound as a white foam (2.1 g). MS (ESI, pos. ion) m/z: 355 (M+1); (ESI, neg. ion) m/z: 353 (M−1). Calc'd for C17H26N2O4S: 354.47.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium (10 wt. %) on carbon (50 mg) was added in one portion to a solution of ethyl cis-4-(4-nitrophenoxy)cyclohexanecarboxylate (0.23 g, 0.78 mmol) in a mixture of EtOH (15 mL) and THF (10 mL) and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The reaction mixture was filtered and then concentrated in vacuo to leave the title compound (0.20 g, 100%) as an oil; 1H NMR (CDCl3) δ 1.23-1.28 (3H, t), 1.55-1.63 (2H, m), 1.68-1.74 (2H, m), 1.93-2.03 (4H, m), 2.34-2.40 (1H, m), 4.10-4.17 (2H, q), 4.26-4.30 (1H, m), 6.60-6.63 (2H, d), 6.73-6.78 (2H, d) MS m/e MH+ 264.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].Cl.[NH2:18][OH:19].C(N(CC)CC)C>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:18][OH:19])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1ccc(C=O)cc1C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=NO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a suspension of 4-formyl-2-trifluoromethyl-benzoic acid methyl ester (Example I10) (5.98 g) and hydroxylamine hydrochloride (1.79 g) in methanol (80 ml) was added triethylamine (5.4 ml). The reaction mixture was stirred at ambient temperature for 1 hour. More hydroxylamine hydrochloride (5.4 g) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed and the residue diluted with ethyl acetate (200 ml) and water (150 ml). The phases were separated and the organic layer was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of dichloromethane and heptane and crystallized by slowly evaporating the dichloromethane to give 4-(hydroxyimino-methyl)-2-trifluoromethyl-benzoic acid methyl ester (3.90 g) as a white crystalline powder. 1H-NMR (CDCl3, 400 MHz): 8.18 (s, 1H), 7.97-7.64 (m, 4H), 3.95 (s, 3H).
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:7]=[N:8][CH:9]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([NH:51][NH2:52])[CH:47]=[CH:48][C:49]=1[F:50]>>[Cl:43][C:44]1[CH:45]=[C:46]([N:51]2[C:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[N:52]2)[CH:47]=[CH:48][C:49]=1[F:50]
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC)c1
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cncc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
600 mg (1.33 mmol) of the compound of Example 16A is reacted analogously to the synthesis of the compound of Example 20A with 288 mg (1.46 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, the entire reaction mixture is reduced to the dry state i. vac. 712 mg (37% purity, 57% of theory) of the title compound, which is used without further purification, is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C@H:27]([OH:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:31]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]([CH2:26][C@H:27]([OH:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:31]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C2CCC(N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 4.48 g (5.71 mmol) of ethyl 4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoate and 38 ml of a 1N aqueous sodium hydroxide solution in 114 ml of ethanol is heated at 50° C. overnight. The solvents are evaporated, the medium is taken up in water and a 1N hydrochloric acid solution is gently added to pH=1. The medium is filtered and dried under vacuum. The title compound (4.05 g, 94%) is thus obtained in the form of a white solid (melting point=160° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].CC(O)(C)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:4]3[N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([NH:26][CH3:27])=[O:25])[CH:7]=[CH:6][CH:5]=3)[CH2:9]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(OC2CN(c3cccc(Br)n3)C2)cc1
Reactant: CNC(=O)c1cccc(N)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CNC(=O)c1cccc(Nc2cccc(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a disposable sealed tube was charged 2-bromo-6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (100.0 mg, 0.309 mmol), 3-amino-N-methylbenzamide (69.7 mg, 0.464 mmol), potassium carbonate (59.9 mg, 0.433 mmol) followed by X-Phos (2.95 mg, 6.19 μmol) and Pd2(dba)3 (1.417 mg, 1.547 μmol). The tube was fitted with a septum with an argon inlet for 5-10 min, when t-BuOH (1.0 mL) was added. The reaction mixture was then heated to 100° C. for 7 h, cooled to RT, diluted with EtOAc, and filtered through Celite® (diatomaceous earth) with EtOAc. The filtrate was concentrated and purified using MPLC (5 g cartridge, 12 g column, 0 to 75% EtOAc-hexanes) giving 3-(6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridin-2-ylamino)-N-methylbenzamide (112.8 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[C:14](Cl)(=O)[CH3:15]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCc1ccc(F)c(F)c1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)CCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)propionic acid (1.0 g, 5.4 mmol) in EtOH (10 mL) is added dropwise acetyl chloride (1.0 mL, 14.1 mmol), and the solution is stirred at RT for 2 h. The solvent is rotary evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (4:1) gives 0.99 g of the product 249. 1H NMR (CDCl3) δ 7.10-6.85 (m, 3 H), 4.13 (q, 2 H), 2.90 (t, 2 H), 3.35-2.59 (t, 2 H), 1.23 (t, 2 H); MS: m/z 215 (M++1).
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:47]1([CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=4)=[CH:54][CH:53]=3)[CH2:40][CH2:39]2)=[O:42])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCCCC4CCCCC4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCC1CCCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 68.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(3-cyclohexylpropyl)-1-piperidinecarboxamide (0.23 g, 0.291 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.11 g, 0.199 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([O:13][CH3:17])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(=O)n(-c2ccc(Br)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)nn1-c1ccc(Br)cc1
Yield: 21 %

Procedure:
A mixture of 1-(4-bromophenyl)-3-methyl-pyrazol-5-one (3.6 g), 10N aqueous sodium hydroxide solution (1.57 ml), methanol (5 ml) and dimethylsulphate (1.4 ml) was heated at reflux for 2 hours. The crude product was purified by vacuum flash chromatography on silica gel (Merck Art 7736) using dichloromethane as eluent to give 1-(4-bromophenyl)-5-methoxy-3-methylpyrazole (21% yield) as a solid, m.p. 67°-68° C.; NMR: 2.9(3H,s), 3.4(3H,s), 5.5(1H,s) and 7.4-7.5(2H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]([CH2:33][O:34][CH3:35])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([CH:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:18])[OH:9])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:19]([CH2:33][O:34][CH3:35])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)(=[O:21])=[O:22])[C:5]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:18])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
A mixture of N-{5-chloro-2-[(2-fluoro-6-methoxy-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (0.38 g) and Dess-Martin reagent (0.90 g, 2.1 mmol) in CH2Cl2 (15 mL) at room temperature was stirred for 5 h. A mixture of 10% aqueous Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture vigorously stirred for 30 min. The organic phase was then separated and the aqueous portion was extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel using ethyl acetate-hexane to provide N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z 555.1 (M+Na).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[C:10]([O:12][CH3:13])=[O:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:13][O:12][C:10]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][CH2:9][C:2]2=[O:1])=[O:11]
Reactant: COC(=O)C1CCC2C(O)CCC12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1CCC2C(=O)CCC21
Reaction time: 2 h

Procedure:
A solution of crude 6-hydroxy-2-methoxycarbonylbicyclo[3,3,0]octane (1.98 g; prepared as described in Reference Example 6 and predominantly in the 2β-configuration) in dichloromethane (10 ml) was added to a stirred suspension of pyridinium chlorochromate (3.5 g) in dichloromethane (35 ml), and the mixture was stirred for 2 hours. The mixture was then diluted with diethyl ether (200 ml), and the supernatant liquid was decanted onto a short column of silica gel. The residue was triturated with diethyl ether several times until it became granular in aspect and then all the ethereal washings were added to the column. The column was eluted with diethyl ether and the eluate was evaporated, to give crude 2-methoxycarbonylbicyclo[3,3,0]octan-6-one (1.71 g) [infra-red (I.R.) 1740 cm-1 ], predominantly in the 2β-configuration, and pure enough for use in the next stage.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21](O)=[O:22])[C:2]1=[O:3].S(Cl)([Cl:30])=O>C(Cl)Cl>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([Cl:30])=[O:22])[C:2]1=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Temperature: 35 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, about 5 g (about 13.075 mmol, about 1 eq) coumarin-oxyhexylbenzoic acid (compound 3) was put into about 100 ml of methylene chloride, and about 1.71 g of thionylchloride (about 14.383 mmol, about 1.1 eq) was added thereto, and the mixture was then stirred at about 35° C. for about 5 hours to form a reaction solution. Subsequently, a solvent was removed from the reaction solution, and then the residual was recrystallized using ethylacetate/hexane to obtain coumarin-oxyhexylbenzoyl chloride (compound 4).
Reaction SMILES: [CH2:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(OCC)(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH2:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of tert-butyl 9-propyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (140 mg, 0.480 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (106 mg, 97.2%) as a solid.
Reaction SMILES: [NH2-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH:5]1([CH2:4][O:3][CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: OCC1CCCCCCCCCCC1
Reactant: COS(=O)(=O)OC
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COCC1CCCCCCCCCCC1
Reaction time: 1 h

Procedure:
25 g (0.65 mol) of sodium amide was introduced into 150 ml of xylene and heated to boiling under agitation. Within one hour, 99 g (0.5 mol) of hydroxymethylcyclododecane, dissolved in 750 ml of xylene, was added dropwise to the boiling suspension. To complete the alcoholate formation the mixture was heated for another two hours under reflux. Thereafter 44 g (0.35 mol) of dimethyl sulfate was added dropwise. The reaction mixture was heated under reflux for another four hours and then poured into a mixture of ice and 35 g of sodium hydroxide. The organic phase was washed with water, dried with Na2SO4, and then distilled.
Reaction SMILES: [OH:1][C:2]([C:4]1[C:5]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[C:16]([CH2:18][C:19]3[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=3[CH3:25])[CH:15]=[CH:14][C:13]=2[O:32]C(=O)C)=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])O.[Na+]>CO.Cl>[OH:3][C:2]([C:4]1[C:5]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[C:16]([CH2:18][C:19]3[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=3[CH3:25])[CH:15]=[CH:14][C:13]=2[OH:32])=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:1]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ncccc3C(=O)O)c2)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ncccc3C(=O)O)c2)=C(C)C1=O
Yield: 69.8 %

Procedure:
N-(3-Hydroxycarbonylpyridin-2-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.080 g, 0.162 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with a 2N hydrochloric acid solution and the aqueous layer was rendered acidic (pH=3 to 4) and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.051 g, 0.113 mmol, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:20]([CH3:21])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23]
Reactant: Oc1ccccn1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)OC(C)(C)C)n1ccccc1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 71.7 %

Procedure:
To a stirred solution of 9.5 g (0.10 mol) of 2-hydroxypyridine in 250 mL of DMF was added 16.6 g (0.120 mol) of potassium carbonate followed by 25.0 g (0.120 mol) of 2-bromopropionic acid tert-butyl ester. The resulting mixture was stirred at ambient temperature for 7 h then diluted with 1 L of water. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organics were washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexanes to afford the title compound as a clear gum 16 g (72%). LC-MS: m/z (ES) 224 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a solution of 50 mg (0.25 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 81 mg of TBTU (0.25 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 89 mg (0.25 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 56 mg light yellow amorphous material (38%). MS: 530.1 (M).