Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])[CH:7]=[C:8]([F:30])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C:25]([F:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=[CH:19][CH:18]=3.CO.Cl>C1COCC1.CCOC(C)=O.O>[F:30][C:8]1[CH:7]=[C:6](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:5]=[C:4]([F:3])[C:9]=1[C@@H:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C@@H:12]([CH3:23])[N:11]1[CH2:24][C:25]([F:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(F)CO)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2c(F)cc(/C=C/C(=O)O)cc2F)N1CC(C)(F)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2M Sodium hydroxide (1.27 mL, 2.54 mmol) was added to a solution of (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate—Isomer 2 (110 mg, 0.23 mmol) in THF (0.529 mL)/methanol (0.529 mL). The reaction was stirred at room temperature for 1 h, then diluted with EtOAc and water. The aqueous was adjusted to pH 6 by addition of 2M HCl, and the layers were separated. The aqueous layer was extracted with EtOAc, then the combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid—Isomer 2 (81 mg, 76%) as a beige solid. 1H NMR (400 MHz, DMSO, 27° C.) 1.02 (2H, s), 1.05 (3H, d), 1.23 (1H, s), 1.90 (3H, s), 2.28-2.46 (1H, m), 2.53-2.7 (1H, m), 2.86-3.03 (2H, m), 3.56 (1H, d), 4.83 (1H, s), 5.17 (1H, s), 6.66 (1H, d), 6.86-7.08 (2H, m), 7.17 (1H, d), 7.40 (1H, d), 7.44 (2H, d), 7.53 (1H, d), 10.54 (1H, s). m/z (ES+), [M+H]+=459.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH2:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:42]=[CH:41][C:29]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([NH:17][S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]3[CH:41]=[CH:42][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:32][CH:33]=2)(=[O:38])=[O:39])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCOCC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminotetrahydropyran-4-carboxylic acid benzyl ester (0.0404 mole) in N,N-dimethylformamide (40 mL) is added triethylamine (5.94 mL, 0.043 mole). Solid 4-(4-fluorophenoxy)benzenesulfonyl chloride (12.165 grams, 0.0424 mole) is added to the above solution in portions. The resulting mixture is stirred at room temperature for 16 hours and then most of the solvent is removed by evaporation under vacuum. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane. The aqueous layer is separated and extracted with dichloromethane. The combined organic layers are washed with brine and dried over sodium sulfate. Evaporation of the solvent under vacuum provided crude 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid benzyl ester. Flash chromatography on silica gel eluting with 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane provided 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid benzyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:40][CH:39]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)nc23)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.065 g, 0.16 mmol) and EtOH (7.5 ml) was added 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.042 g, 0.20 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.65 ml, 0.65 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column which was eluted first with 2% methanol in ethyl acetate/dichloromethane (v:v; 1:1) and then a gradient of methanol (2 to 8%) in chloroform. The titled compound was obtained as a brown solid after trituration with diethyl ether a (0.007 g, 8%). 1H-NMR (500 MHz, CD3OD) 1.55 (d, J=6.4 Hz, 3H, CHCH3), 2.50 (s, 3H, N—CH3), 2.80 (br s, 6H), 2.90 (br s, 2H), 3.42 (br s, 4H) and 3.80 (br s, 4H) (8× piperazine N(CH2)2), 3.70 (m, 1H, CHCH3), 7.10 (d, J=8.9 Hz, 2H) and 8.02 (d, J=8.7 Hz, 2H) (3,5-C6H4—N and 2,6-C6H4—N), 7.31 (t, J=7.2 Hz, 1H, PhH), 7.39 (t, J=7.6 Hz, 2H, PhH), 7.37 (d, J=7.2 Hz, 2H) (PhH), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H);
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[Cl:18][C:19]1[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:27]=[C:28]([O:32][CH2:4][CH:2]2[CH2:3][O:1]2)[C:29]([Cl:31])=[CH:30][C:19]=1[Cl:18]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)COc1cc(O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OCC2CO2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (0.4 g), methyl (2,4-dichloro-5-hydroxyphenoxy)acetate (0.39 g) and Cs2CO3 (0.58 g) in DMF (2 ml) was stirred at r.t. overnight. Water was added and (2,4-dichloro-5-oxiranylmethoxy-phenoxy)-acetic acid methyl ester (0.22 g) was isolated by filtration and dried in vacuo. 5-Chloro-3H-spiro[1-benzofuran-2,4′-piperidine] (0.16 g) in ethanol (5 ml) was added and heated at 70° C. for 2 h. The mixture was allowed to cool and water (1 ml) followed by LiOH (2 eq) was added. Stirred for 3 h. RPHPLC (Xterra, gradient 95-5%, ammonia (0.2% aq.): acetonitrile) gave the title compound (0.1 g) as a white solid.
Reaction SMILES: [K].[CH3:2][CH:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH:8]([C:12]2[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=2)[C:7](=[O:21])[CH2:6]1)[CH3:4].[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C.CCCCCC>[C:22]([O:21][C:7]1[CH2:6][CH:5]([CH:3]([CH3:2])[CH3:4])[CH2:10][C:9](=[O:11])[C:8]=1[C:12]1[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1nc(C)c(C2C(=O)CC(C(C)C)CC2=O)nc1C
Reactant: CCCCCC(=O)Cl
Agent: [K]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OC1=C(c2nc(C)c(C)nc2C)C(=O)CC(C(C)C)C1
Temperature: 25 °C

Procedure:
The subject compound was prepared by reaction of 5-(1-methylethyl)-2-(3,5,6-trimethyl-2-pyrazinyl)-1,3-cyclohexanedione potassium salt (Example 8) with hexanoyl chloride employing the general procedure described in Example 3, but allowing the reaction mixture to stir at room temperature over the weekend. Following the reaction, the ether solution of crude product was extracted quickly with ice-cold 0.25N NaOH, dried (MgSO4), filtered and evaporated to give a residue product showing some acid chloride contamination by IR examination. Dry-column chromatography using 1:1 ethyl acetate/hexane gave analytically pure material as shown by the elemental analysis of Table II.
Reaction SMILES: [Cl:1][C:2]([Cl:22])([Cl:21])[CH2:3][O:4][C:5]([CH2:7][O:8][N:9]=[C:10]([C:18](=[O:20])[CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:6].[Br:23]Br>C(O)(=O)C>[Br:23][CH2:19][C:18](=[O:20])[C:10](=[N:9][O:8][CH2:7][C:5]([O:4][CH2:3][C:2]([Cl:22])([Cl:21])[Cl:1])=[O:6])[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: CC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (29.5 g) in acetic acid (59 ml) was added bromine (23.2 g) at 52° C., and the mixture was stirred at 52° to 68° C. for 15 minutes. After removal of the acetic acid from the reaction mixture under reduced pressure, the residual oil was dissolved in ethyl acetate (400 ml). The solution was washed with 10% hydrochloric acid (20 ml) and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (30.7 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34](OC)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(OCC)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34]([NH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 18) (92 mg, 0.18 mmol) and N-(2-aminoethyl)morpholine (0.25 ml, 1.9 mmol) were heated at 120° C. under a nitrogen atmosphere for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2 ml) added to precipitate the title compound as a white solid which was filtered off and dried (68 mg).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]([C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Cl:22][C:18]1[C:17]([F:23])=[C:16]([C@@H:15]2[C@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12][C@H:11]2[C:9]([N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1CN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CC(C(=O)O)C2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), azetidine-3-carboxylate methyl ester hydrochloride (200 mg, 1.32 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to yield 1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid methyl ester (26 mg, 10.7%). The ester was taken directly to the hydrolysis step by dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid (11.8 mg, 46.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H27Cl2F2N3O3+H [(M+H)+]: 550.1471. found: 550.1471.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[C:18]([O:29]C)=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:1][O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18]=2[OH:29])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C(c1cccc(-c2ccccc2)c1OC)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1c(-c2ccccc2)cccc1C(C)c1cccc(-c2ccccc2)c1O
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 5 (0.74 g, 1.58 mmol) in methanol (25 mL) was treated with 20% palladium on activated carbon (50% wet, 0.07 g) and was hydrogenated at 30 psi in a Parr shaker for 2 hr. The catalyst was filtered out and washed with methanol. The filtrate was stripped and the residue was chromatographed on silica (40 g) with 1% ethyl acetate in hexane (3 L). The relevant fractions were stripped and the residue was triturated with ethanol and dried in a vacuum oven at 65° C. to produce pure B1 (0.49 g, 81%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]4)[N:12]=3)[S:8][C:7]=2[CH:28]=1>Br>[CH3:24][C:22]1([CH3:25])[CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([C:9]3[S:8][C:7]4[CH:28]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=4[CH:10]=3)[CH:16]=[CH:15][N:14]=2)[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21]1
Reactant: COc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Agent: Br
Product: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
Compound of Example 152 (200 mg, 0.5 mmol) was dissolved in 10 ml hydrobromic acid 48% and stirred at 120° C. for 20 hours. Afterwards the mixture was evaporated and the crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:8/2/0.2). Yield: 120 mg (62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1N

Procedure:
The title compound was prepared from (4-chloro-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A6) (16.48 g, 56.7 mmol) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a brown solid (14.78 g).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[ClH:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:11].[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[NH:10])[O:14][CH2:12][CH3:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1

Procedure:
Ethyl 4-methoxybenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, anisonitrile (25.6 g, 0.199 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 40.5 g (94%) of the target compound as pale-red crystals.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C@H:7]([OH:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C@H:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(F)cc2[C@H](O)C[C@@H]1C
Reactant: Oc1ccccc1
Product: CC(=O)N1c2ccc(F)cc2[C@H](Oc2ccccc2)C[C@@H]1C
Yield: 63 %

Procedure:
A compound was produced in the same manner as in Example 12, using 39 mg of cis-1-acetyl-6-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydro quinoline and phenol, and thus 33 mg (63%) of the title compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:55]=[C:54]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[O:53][N:52]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43]>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:59]1[CH2:58][CH2:57][CH:56]([C:54]2[O:53][N:52]=[C:51]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:43])=[O:44])=[CH:46][CH:47]=3)[N:55]=2)[CH2:61][CH2:60]1)=[O:8]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2noc(C3CCNCC3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2noc(C3CCN(C(=O)CCCC(F)(F)F)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-(3-[4-(methylsulfonyl)phenyl-]1,2,4-oxadiazol-5-yl]piperidine (34c) (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 69%; 1H NMR (CD2Cl2) δ 8.32 (d, J=8.7 Hz, 2H), 8.08 (d, J=8.7 Hz, 2H), 4.52-4.57 (m, 1H), 3.92-3.96 (m, 1H), 3.23-3.39 (m, 2H), 3.11 (s, 3H), 2.92-3.01 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.16-2.32 (m, 4H), 1.82-2.01 (m, 4H). tR LCMS 5.7 min. Purity >99%; MS [M+H]+ m/z 446.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1>>[OH:8][C:9]1[CH:10]=[C:11]([S:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(S)c1
Product: CCOC(=O)CSc1cccc(O)c1
Yield: 41 %

Procedure:
Ethyl [(3-hydroxyphenyl) sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromoacetate (7.95 g, 47.6 mmol) and 3-hydroxythiophenol (7.95 g, 47.6 mmol); 4.21 g yellow oil. Yield 41%; MS: 211.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[CH3:8][N:7]([CH3:9])[CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCCN(C)C
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CO[Si](CCCOCCN(C)C)(OC)OC
Reaction time: 24 h
Yield: 85.9 %

Procedure:
After adding toluene (200 mL) to a round-bottom flask containing 2-(allyloxy)-N,N-dimethylethanamine (0.398 mol) and dissolving trimethoxysilane (0.398 mol), a commercially available platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane solution was added and the mixture was stirred for 24 hours under reflux. Upon completion of reaction, after removing the solvent through distillation under reduced pressure, 0.342 mol (yield: 86%) of the target compound was obtained by extracting with water and diethyl ether. 1H and 13C NMR spectroscopic data of the purified N,N-dimethyl-2-(3-(trimethoxymethylsilyl)propoxy)ethanamine are as follows.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH2:8]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH:8][C:3]([NH:2][CH3:1])=[O:4]
Reactant: Nc1ccc(F)cc1F
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(F)cc1F
Reaction time: 1 h

Procedure:
Methyl isocyanate (9.6 g, 10 mL, 0.174 mol) is added to a solution of 2,4-difluoroaniline (15 g, 0.116 mol) in toluene. The reaction mixture is stirred for 1 hour and filtered to obtain a solid. The solid is washed with hexanes and air-dried to give the title product as an off-white solid, mp 182°-1830° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[O:6][CH2:5][CH2:4][O:3]1.[CH3:12][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:10][C:9]([OH:11])([CH2:8][CH2:7][C:2]1([CH3:1])[O:3][CH2:4][CH2:5][O:6]1)[CH3:12]
Reactant: CC(=O)CCC1(C)OCCO1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCC1(C)OCCO1
Reaction time: 0.67 h

Procedure:
The obtained 4-(2-methyl[1,3]dioxolan-2-yl)butan-2-one (27.60 g) was dissolved in tetrahydrofuran (220 ml), and thereafter, methylmagnesium bromide (3 M tetrahydrofuran solution; 85 ml) was added to the solution at a room temperature. The obtained mixture was stirred for 40 minutes, and an aqueous saturated ammonium chloride solution (300 ml) was then added thereto, followed by extraction with ethyl acetate (300 ml×3). The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate-hexane (1:1)) to obtain 2-methyl-4-(2-methyl[1,3]dioxolan-2-yl)butan-2-ol (21.18 g).