Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:18][C:19]#[N:20]
Reactant: N#CCCl
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of 14.99 g of 2-chloro-4-(3-chlorophenoxy)phenol, 4.44 g of chloro acetonitrile and 8.94 g of potassium carbonate in 150 ml dimethylformamide was stirred at a temperature of 70° to 80° C. in an oil bath for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with 100 ml of ethyl acetate. The extracts were conbined together, washed twice with 200 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 14.0 g of [2-Chloro-4-(3-chlorophenoxy)phenoxy] acetonitrile as a crude product.
Reaction SMILES: [O-]CC.[Na+].[H-].[Na+].[CH3:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([CH:9]([C:8](=[O:13])[CH3:7])[C:10](=[O:12])[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C(Cc1ccccc1)C(C)=O
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of sodium ethoxide (freshly prepared from sodium hydride (0.474 g, 19.8 mmol) and anhydrous ethanol (50 mL)) was added pentane-2,4-dione (6.00 g, 60.0 mmol). The resulting mixture was heated to 50° C. while a solution of benzyl bromide (3.42 g, 20 mmol) in ethanol (20 mL) was added over 30 minutes. The reaction was then heated to reflux. After 2 hours, the mixture was concentrated, and the residue was dissolved in ethyl acetate, washed three times with water, once with brine, dried (magnesium sulfate) and concentrated to afford an oil. Flash chromatography over silica (ethyl acetate/dichloromethane) afforded 3.13 g (82%) of a colorless oil. The proton spectrum showed the product exists as equal parts of the keto and enol tautomers: 1H NMR (CDCl3) δ 16.81 (s, 0.5H), 7.13-7.32 (m, 5H), 4.00 (t, J=7.6 Hz, 0.5H), 3.65 (s, 1H), 3.14 (d, J=7.6 Hz, 0.5H), 2.06-2.13 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH3:29])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[OH:28])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:41][CH2:42][F:43])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH3:29])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[O:28][CH2:41][CH2:42][F:43])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2O)nc2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2OCCF)nc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
7-Bromo-2-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-3-methylquinazolin-4(3H)-one (9.5 mg, 0.020 mmol) and potassium carbonate (8.3 mg, 0.06 mmol) were stirred in DMF (0.5 mL) at room temperature, and 2-fluoroethyl tosylate (6.6 mg, 0.03 mmol) was dropwise added thereto and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (4.5 mg, 47%) as a milky white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[F:27][C:21]1[CH:20]=[C:19]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH2:17]2)[CH:24]=[C:23]([F:25])[C:22]=1[F:26]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 15 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.1 g) in tetrahydrofuran (100 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether; 55 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. for five hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 4.8 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl(R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 15 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen stream at 1 atm for six hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.91 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:15]=1[CH3:32].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=4)[C:15]=3[CH3:32])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: Cc1ncccc1-c1nc2cc(F)ccc2c(Cl)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1ncccc1-c1nc2cc(F)ccc2c(N2CC(C)(C)c3ncc(Br)cc32)c1C
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.44 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (126 mg, 0.44 mmol) and hydrochloric acid in 1,4-dioxane (0.11 mL, 0.44 mmol) in NMP (2.0 mL) and heating in the microwave at 150° C. for 2 h. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline was obtained as a yellow film. Mass Spectrum (ESI) m/e=477 [(M+1) (79Br)] and 479 [(M+1) (81Br)].
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: CNC(=O)c1cc(F)cc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C

Procedure:
To a solution of 2-Amino-3,5-difluoro-N-methyl-benzamide (1.099 g, 0.006 mol) and NMP (6 mL, 0.06 mol) was added DIEA (1.23 mL, 7.8 mmol) followed by 2,4,5-Trichloro-pyrimidine (0.812 mL, 7.1 mmol) and the reaction mixture was heated at 100° C. for 16 h. Title compound isolated as an off-white solid (1.10 g, 56%), MP=220-221, HPLC purity=95%, LCMS=333.38 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.94 (s, 1H), 8.22 (s, 1H), 7.12-7.06 (m, 2H), 6.17 (s, 1H), 2.99 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH3:14][O:15][CH2:16]Cl.O>CN(C=O)C>[CH3:14][O:15][CH2:16][O:13][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:10][CH2:9][CH2:8]2
Reactant: COCCl
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCC2
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
1.04 g of 55% sodium hydride/paraffin oil was suspended in 40.0 mL of DMF, and a solution of 3.90 g of 6-nitroindan-5-ol in DMF (10.0 mL) was added dropwise thereto at 5° C. over 15 minutes, followed by stirring at 5° C. for 30 minutes. To the reaction liquid was added dropwise 2.15 mL of methoxymethyl chloride over 5 minutes, followed by stirring at room temperature for 1 hour. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20) to obtain 4.20 g of 5-(methoxymethoxy)-6-nitroindane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]([OH:32])CO)=[CH:23][CH:22]=5)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[O:32])=[CH:23][CH:22]=5)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCC(O)c1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=Cc1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Reaction time: 0.67 h

Procedure:
To a solution of 1-(3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethane-1,2-diol (Preparation 26B, 0.097 g, 0.223 mmol) in methanol (2 mL) at 0° C. was added a solution of sodium periodate (0.057 g, 0.268 mmol) in water (2 mL) dropwise. The white heterogeneous reaction mixture was stirred for 40 mins. at 0° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, concentrated, dried in vacuo to yield 3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde. LC/MS M+1=402.23.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][C:3]=1[CH3:12].Cl.[C:14](=[NH:19])(OCC)[CH3:15].C(N(CC)CC)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:19]=[C:14]([CH3:15])[NH:9][N:8]=2)=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(C(=O)NN)ccc1Br
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(Br)c(C)c2)n[nH]1
Yield: 59.5 %

Procedure:
4-Bromo-3-methylbenzoic hydrazide (D30, 3.06 g, 13 mmol), ethyl acetimidate hydrochloride (2.48 g, 20 mmol) and triethylamine (5.6 ml, 40 mmol) were stirred at reflux under Ar for 24 h, and then evaporated to dryness. The residue was chromatographed on silica gel, eluting with dichloromethane/ethanol/ammonia (300:8:1). This gave the title compound (1.95 g, 58%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>[Ag]=O.O>[F:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[C:6]([OH:1])=[O:7]
Reactant: [OH-]
Reactant: Cc1cc(F)c(C=O)c(F)c1
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Silver oxide (43.8 g, 0.189 mol) was placed in a flask along with water (200 mL) and sodium hydroxide (33.7 g, 0.842 mol). To it was added 2,6-difluoro-4-methylbenzaldehyde (29.23 g, 0.187 mol) in small portions over a 30 min period. After a vigorous exothermic reaction, the color of the reaction mixture changed from black to gray. Resulting thick suspension was stirred for 1 hr, filtered through a Buchner funnel. The filtrate was acidified to pH 2 with concentrated HCl to give a suspension. The precipitate was collected by suction filtration, dissolved in ether and dried over anhydrous Na2SO4, filtered and concentrated to give white solid (17.0 g, 53%). 1H-NMR (500 MHz, d6-DMSO): δ13.7 (br.s, 1H), 7.02 (d, 2H, J=9.3 Hz), 2.32 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:44][C:45]([O:47][CH3:48])=[O:46].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[N:18]=[N:19][N:20]=3)[CH2:15][C@@:9]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([O:21][CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 2 g, 3.4 mmol), methyl bromoacetate (0.5 ml, 5.1 mmol) and potassium carbonate (0.75 g, 0.51 mmol) were stirred in acetonitrile (20 ml) at 45° C. for 90 minutes. After this time the mixture was concentrated in vacuo and the residue partitioned between brine and ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated. The residual clear oil was chromatographed on silica gel eluting with 10, 20 and 50% ethyl acetate/iso-hexanes to yield the title compounds: isomer A (1.2 g, 54%) and isomer B (0.9 g, 40%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([NH:27]C(OC(C)(C)C)=O)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([NH2:27])[CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:17][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester (0.488 g, 1.0 mmol) in DCM (8 ml) is treated with trifluoroacetic acid (2 ml). The reaction mixture is stirred at ambient temperature for 1 hour. The solvent is evaporated and the residue taken up in DCM and washed with saturated aqueous NaHCO3. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-amino-4-[4-(4-fluorophenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 387.1
Reaction SMILES: C(NC(/[N:6]=[C:7]1/[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH3:22])[C:9](=[O:14])[N:10]([CH2:12][CH3:13])[S:11]/1)=O)C.[OH-].[Na+]>CO>[CH2:12]([N:10]1[C:9](=[O:14])[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH3:22])[C:7](=[NH:6])[S:11]1)[CH3:13]
Reactant: CCNC(=O)/N=c1\sn(CC)c(=O)n1-c1ccccc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccccc1-n1c(=N)sn(CC)c1=O
Temperature: 25 °C
Yield: 66.1 %

Procedure:
(Z)-1-Ethyl-3-(2-ethyl-4-(2-ethylphenyl)-3-oxo-1,2,4-thiadiazolidin-5-ylidene)urea (CB42) (0.484 g, 1.51 mmol) was dissolved in methanol (150 mL). Sodium hydroxide (3.36 g, 84.0 mmol) was slowly added and the reaction was stirred at room temperature. After 4 hours the solution was concentrated to ½ volume, poured onto water, and extracted with ethyl acetate. The organics were dried and concentrated to give the title compound as an orange solid (0.249 g, 65%): 1H NMR (400 MHz, CDCl3) δ 7.35-7.32 (m, 2H), 7.30 (dd, J=5.4, 1.5 Hz, 1H), 7.25-7.20 (m, 1H), 3.65 (q, J=7.2 Hz, 2H), 3.39-3.19 (m, 1H), 2.73 (q, J=7.6 Hz, 2H), 1.26-1.13 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.32, 165.49, 141.20, 135.74, 130.42, 129.31, 127.67, 126.01, 39.50, 24.79, 15.22, 14.93; ESIMS m/z 250 ([M]+).
Reaction SMILES: C([O:8][C:9]([N:11]1[C@@H:16]([C@@H:17](O)[C@@H:18]([NH:27][C:28](=[O:30])[CH3:29])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH2:15][O:14][C@@H:13]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@@H:12]1[CH3:38])=[O:10])C1C=CC=CC=1.[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH:39]1([CH2:42][O:26][C:22]2[CH:21]=[C:20]([CH2:19][C@H:18]([NH:27][C:28](=[O:30])[CH3:29])[C@H:17]3[C@H:16]4[CH2:15][O:14][C@@H:13]([O:32][CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@H:12]([CH3:38])[N:11]4[C:9](=[O:8])[O:10]3)[CH:25]=[CH:24][CH:23]=2)[CH2:41][CH2:40]1
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OCc1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cccc(OCC2CC2)c1)[C@@H]1OC(=O)N2[C@@H]1CO[C@@H](OCC(C)(C)C)[C@@H]2C
Yield: 85.9 %

Procedure:
Heat a mixture of (2R,3S,5R)-5-[(1S,2S)-2-Acetylamino-1-hydroxy-3-(3-hydroxy-phenyl)-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid benzyl ester (69 mg, 0.13 mmol), cyclopropylmethyl bromide (0.019 ml, 0.195 mmol), cesium carbonate (127 mg, 0.39 mmol) and N,N-dimethylformamide (2 mL) to 60° C. for 18 hours. Cool and dilute with ethyl acetate and wash with saturated sodium chloride, dry with magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound (53 mg). MS(ESI): m/z=475 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: COc1ccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
To the mixture of 3-(3-piperidinomethylphenoxy)propylamine (3.1 g) in ethanol (31 ml) was added 4-methoxyphenylisocyanate (1.9 g) dropwise slowly under cooling on an ice-water bath. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (50 ml), washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the crude product (3.3 g) was obtained (yield 66.0%). This crude product was recrystallized from ethanol to give the title compound (2.1 g), mp 111-112° C.
Reaction SMILES: [N+]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-])=O.[C:11]1(=[O:17])CCCC[CH2:12]1>>[C:11]([O:10][C:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1)(=[O:17])[CH3:12]
Reactant: O=C1CCCCC1
Reactant: O=C1CCCCC1[N+](=O)[O-]
Product: CC(=O)OC1=CCCCC1

Procedure:
nitrocyclohexanone process in which cyclohexanone is acetylated to obtain cyclohexenyl acetate, the obtained cyclohexenyl acetate is nitrated to obtain 2-nitrocyclohexanone, the obtained 2-nitrocyclohexanone is subjected to hydrolysis, thereby causing ring cleavage of the 2-nitrocyclohexanone to obtain nitrocapronic acid, the obtained nitrocapronic acid is hydrogenated to obtain ε-aminocapronic acid, and the obtained ε-aminocapronic acid is converted into ε-caprolactam.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]2[N:43]=[CH:44][N:45]=[C:39]2[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]4[N:43]=[CH:44][N:45]=[C:39]4[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1ccn2ncnc2c1
Product: C[C@@H](c1ccc(-c2ccn3ncnc3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 68 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine following a procedure analogous to that described in EXAMPLE 7. Yield: 68% of theory; Mass spectrum (ESI+): m/z=471 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.82 (s, 3H), 1.19 (s, 3H), 1.49 (d, J=7.1 Hz, 3H), 2.03 (s, 2H), 2.14-2.23 (m, 1H), 2.39-ca. 2.55 (m, 2H) superimposed on DMSO-d5, 3.01-3.09 (m, 1H), 4.23 (s, 1H), 5.46 (q, J=7.1 Hz, 1H), 7.02 (dm, J=8.3 Hz, 2H), 7.27-7.41 (m, 5H), 7.46 (dm, J=7.2, 1.8 Hz, 1H), 7.62 (dm, J=8.3 Hz, 2H), 8.06 (hardly resolved d, 1H), 8.52 (s, 1H), 8.98 (d, J=7.2 Hz, 1H).