Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.O>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CN2CCCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(CN2CCCC2)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of methyl 6-(pyrrolidin-1-ylmethyl)picolinate 73 (36 g) and NaOH (40 g, 1.0 mol) in ethanol/H2O (320 mL) was stirred at 75° C. for 16 h. The pH was adjusted to 7 with 3N HCl and extracted with EtOAc. The aqueous layer was concentrated to dryness and extracted with dichloromethane/methanol (v:v=3:1), The organic layer was dried to give 74 (27 g, 55% yield).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([OH:43])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41](=[O:43])[N:2]([CH3:1])[C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Reactant: CN[C@H](CN1CCCC1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Cc1ccccc1CNC(=O)OC(C)(C)C)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl-[1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl]-amine in acetonitrile (0.3 M) at 0° C. under nitrogen was added diisopropylethylamine (2.2 eq), 6a (1.1 eq) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.1 eq). The reaction was stirred at room temperature overnight. The acetonitrile was removed under reduced pressure. The remaining oil was partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (2×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (1-15% gradient methanol/dichloromethane) to afford the product. (65%) 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 9H), 6.21 (m, 1H), 5.62 (m, 1H), 4.31 (m, 2H), 3.95 (m, 1H), 3.71 (m, 1H), 3.05 (m, 1H), 2.82 (m, 5H), 2.55 (m, 2H), 1.85 (m, 5H), 1.46 (s, 9H). Mass Spectral Analysis m/z=452.3 (M+H)+ tR=4.92 min (96%)
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[OH:9].C(N(CC)CC)C.C(O)(=O)C.C(OC([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH:36]=O)[C:30](=[O:38])[CH:29]1[CH3:39])=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[ClH:1].[OH:9][C@H:4]1[C@@H:3]([CH3:2])[CH2:8][CH2:7][N:6]([CH2:36][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][NH:28][CH:29]([CH3:39])[C:30]2=[O:38])[CH2:5]1
Reactant: C[C@H]1CCNC[C@H]1O
Reactant: CC1C(=O)N(CCC=O)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Reaction time: 2 h
Yield: 194.8 %

Procedure:
To a suspension of (3S,4S)-4-methyl-piperidin-3-ol hydrochloride (intermediate 26; 0.04 g, 0.3 mmol) in dichloromethane (1 ml) was added triethylamine (0.04 ml, 0.3 mmol) and acetic acid (0.03 ml, 0.5 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.08 g, 0.3 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.07 g, 0.4 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=468.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CN(C)[CH:9]=[O:10].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=O>ClCCl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([C:18]([C:2]2[CH:1]=[CH:17][C:21]([O:10][CH3:9])=[CH:13][CH:14]=2)=[O:20])[CH:21]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: -5 °C
Reaction time: 14 h

Procedure:
38.3 mL oxalyl chloride and 0.8 mL dimethylformamide are added to a mixture of 100 g 5-bromo-2-chloro-benzoic acid in 500 mL dichloromethane. The reaction mixture is stirred for 14 h, then filtered and separated from all volatile constituents in a rotary evaporator. The residue is dissolved in 150 mL dichloromethane, the resultant solution is cooled to −5° C., and 46.5 g anisole are added. Then 51.5 g aluminum trichloride are added batchwise so that the temperature does not exceed 5° C. The solution is stirred for 1 h at 1 to 5° C. and then poured onto crushed ice. The organic phase is separated off, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with 1 M hydrochloric acid, twice with 1 M sodium hydroxide solution and with brine. Then the organic phase is dried over sodium sulfate, the solvent is removed and the residue is recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[CH:25]1([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(COC)OC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[CH:32]1([NH2+:31][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: COCCOC
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (3.0 g, 0.0083 mole) is dissolved in glyme (20 ml) and dicyclohexylamine (1.64 g, 0.0091 mole) is added at room temperature while stirring. The solvent is removed in vacuo, the residue triturated with petroleum ether (bp 30°-60° C.) and dried tp give 2.7 g of product, mp 197°-9° C. Anal. Calcd. for C26H30ClF3N2O5 : C, 57.51; H, 5.56; N, 5.15; Cl, 6.53; F, 10.49. Found C, 57,25; H, 5.71; N, 5.55, Cl, 6.40; F, 10.24.
Reaction SMILES: [F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](OCC)=[O:4].[NH2:16][NH2:17].O>CCO>[F:1][C:2]([F:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([NH:16][NH2:17])=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)Cc1ccccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(F)(F)Cc1ccccn1
Reaction time: 1 h

Procedure:
The product of Example 66 (0.18 g, 0.84 mmol) was dissolved in 5 mL of EtOH. To the solution was added NH2NH2.H2O (0.084 g, 1.7 mmol). The reaction was complete in 1 hour. The solvent was removed under vacuum. The structure was confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>>[C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
L-aspartic acid, 13.3. parts, was added to 100 parts by volume of 2N aqueous sodium hydroxide and the resulting solution was cooled to 0°-10° C. in an ice bath. Diketene, 8.4 parts, was added and the resulting two phase mixture was stirred for 2.5 hours at 0°-10° C. The homogeneous solution was washed twice with 100 parts by volume of ether and the aqueous layer was acidified with 16.6 parts by volume of concentrated hydrochloric acid. This solution was extracted three times with 100 parts by volume of ethyl acetate, the combined extracts were dried over sodium sulfate, filtered and the solvent evaporated under vacuum at 25°-30° C. to give 2.3 parts of N-aceto-acetyl-L-aspartic acid, mp 127°-129.5° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.O1CCCC1.[CH3:31][NH2:32].[Cl-].[Na+]>C(OCC)(=O)C.CO>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:24][CH3:25])[N:3]=[C:2]([NH:32][CH3:31])[N:11]=[C:10]2[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CN
Reactant: COc1cc2nc(Cl)nc(-c3cccc(NC(C)=O)c3)c2cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(-c2cccc(NC(C)=O)c2)c2cc(OC)c(OC)cc2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To 353 mg (0.96 mmol) of N-[3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]acetamide, tetrahydrofuran (2.06 mL), and methanol (1.03 mL) was added a methanol solution (2.06 mL) of 40% methylamine, and the mixture was reacted at 90° C. for 9 hours. The mixture was allowed to cool and then poured into a mixed solution of ethyl acetate (30 mL) and 5% w/w sodium chloride solution (30 mL) while washing with tetrahydrofuran (30 mL) to extract the organic layer. The organic layer was washed with 5% w/w sodium chloride solution (30 mL) and then concentrated under reduced pressure. To the concentration residue was added t-butyl methyl ether (3 mL), and the mixture was crystallized with a spatula and then suspended by stirring at 50° C. for 2 hours. The mixture was allowed to cool gradually, and then the precipitated crystals were collected by filtration and dried to give 318 mg of a target product (yield: 91.1%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]1.C[C@H]1COCCN1C1C=C(CS(C)(=O)=O)N=C(N2CCC(N)CC2)N=1>>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:21])[CH3:16])[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(N)CC2)n1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(N2CCC(N)CC2)n1

Procedure:
1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]piperidin-4-amine was prepared from (3S)-4-{2-Chloro-6-[1-methyl-1-(methylsulfonyl)ethyl]pyrimidin-4-yl}-3-methylmorpholine and tert-butyl N-(4-piperidyl)carbamate in an analogous two step procedure to 1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]piperidin-4-amine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:23][CH3:24])=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=2)[CH:11]=[C:10]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:9]=1>>[CH3:24][O:23][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[C:8]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[N:9][C:10]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:11]2
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Reactant: OC1CCOC1
Product: COCCOc1cc2c(OC3CCOC3)nc(Nc3cc(C)[nH]n3)cc2cc1OC

Procedure:
Similar procedure as described in example 400 was used, starting from 3-hydroxy-tetrahydrofuran and [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-Methoxy-7-(2-methoxy-ethoxy)-1-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 415(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9]OS(C)(=O)=O)=[O:4].[C-:23]#[N:24].[Na+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9][C:23]#[N:24])=[O:4]
Reactant: [C-]#N
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCC#N
Temperature: 80 °C
Yield: 93 %

Procedure:
To 1-tert-butoxycarbonylamino-2 (2-methanesulfonyloxy-1-ethyl)-cyclopropanecarboxylic acid methyl ester (400 mg, 1.19 mmol) from example 109 in DMF (6 mL) was added NaCN (350 mg, 7.14 mmol) and NaI (178 mg, 1.19 mmol). The reaction mixture was heated at 80° C. for 2 h then diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica (20→50% EtOAc/Hexanes) to afford 1-tert-butoxycarbonylamino-2-(2-cyano-ethyl)-cyclopropanecarboxylic acid methyl ester (297 mg, 93%). 1H NMR (300 MHz, CDCl3): δ 5.13 (br s, 1H), 2.44 (m, 2H), 2.05 (m, 2H), 1.70-1.53 (m, 1H), 1.53-1.37 (m, 4H) 1.45 (s, 9H). LCMS found 290.9 [M+Na]+. To this intermediate (297 mg, 1.10 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxanes (2 mL). Ater stirring at room temperature for 2 h the reaction was concentrated to afford 225 mg (100%) of the HCl salt of 1-amino-2-(2-cyano-ethyl)-cyclopropanecarboxylic acid methyl ester, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with (S)-2-fluoro-2-methyl-malonic acid monoethyl ester in analogy to the description in example 73 to yield (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid ethyl ester as colourless oil.
Reaction SMILES: COC1N=CC(N2CCC([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)CC2)=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][CH:47]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)[CH2:16]3)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reactant: O=C1CCN(c2cccc(Cl)c2)CC1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3cccc(Cl)c3)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 1-(3-chlorophenyl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.87-2.10 (m, 5H), 2.37-2.44 (m, 1H), 2.66-2.74 (m, 2H), 2.86-2.95 (m, 2H), 3.03-3.09 (m, 1H), 3.55 (d, J=11.7 Hz, 1H), 3.64-3.76 (m, 3H), 4.06-4.23 (m, 2M), 4.79-4.83 (m, 1H), 6.74-6.78 (m, 1H), 6.83-6.85 (m, 2H), 7.13-7.18 (m, 1H), 7.53-7.57 (m, 1H), 7.66-7.75 (m, 2H), 8.09 (m, J=7.5 Hz, 1H), 8.20 (s, 1H), 8.28 (s, 1H), 9.09 (d, J=7.8 Hz, 1H). MS m/z: 509 (M+1).
Reaction SMILES: [CH:1]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([O:17][NH:18][C:19](=[O:25])OC(C)(C)C)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:50]=N/C(OCC)=O)=O>C1COCC1>[OH:17][N:18]([CH2:8][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[C:19]([NH2:50])=[O:25]
Reactant: OCC1CCCCCC1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)N(O)CC1CCCCCC1
Reaction time: 3 h

Procedure:
To a stirred solution of cycloheptanemethanol (11.2 g, 100 mmol), tert-butyl N-(tert-butoxycarbonyloxy)carbamate (7.2 g, 104 mmol) and triphenylphosphine (7.2 g, 104 mmol) in THF (150 mL) was added diethylazodicarboxylate dropwise. The mildly exothermic reaction was stirred 3 hours, then concentrated in vacuo. The concentrate was treated with hexane, and the crystalline by-product was vacuum filtered. The filtrate was concentrated in vacuo and the resulting residue was chromatographed (silica gel, ethyl acetate:hexanes, 2:8) to afford the protected hydroxylamine derivative.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.Cl[CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][C:12]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:11]1=2>CN(C)C=O.O>[CH3:2][O:4][CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][C:12]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:11]1=2
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Mix 0.415 gm of potassium tert-butoxide, 5 ml of methanol and 5 ml of dimethylformamide and add the mixture to a solution of 1.07 gm of methyl 6,11-dihydro-11-chlorodibenz[b,e]oxepin-2-carboxylate in 40 ml of dimethylformamide. Stir at room temperature for 3 days. Dilute with water and extract with ether. Evaporate to dryness and chromatograph over silica gel with benzene as the eluting solvent to obtain the title product.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:8][N:7]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1c(O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(C)(C)C
Yield: 64.3 %

Procedure:
4-(tert-Butyl)-3-hydroxy-5-phenylisoxazole (0.15 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.12 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.16 g, 64%) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:23]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>CN(C=O)C.CCOC(C)=O>[C:14]([CH:10]1[S:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:23]
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCSC(C(N)=O)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (2.47 g, 10 mmol) and HOBt (1.62 g, 12 mmol) were dissolved in DMF (20 mL), and EDCl (2.11 g, 11 mmol) was added. The reaction mixture was stirred for 1 hour, and 25% aqueous ammonia (5 mL) was added, and the reaction was stirred for another 2 hours. The reaction was then diluted with EtOAc (200 mL) and partitioned with water (100 mL). The organic layer was washed with saturated aq. NaHCO3 (2×100 mL), and then dried with Na2SO4. The solvent was removed in vacuo to afford title compound as white solid 2.46 g. MS (m/z): 147 (M+H-Boc)+
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O.CCOCC>[CH3:27][C:26]([Si:23]([O:21][CH2:20][C:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:22])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5.0 g of 2-[(hexadecyloxy)methyl]-2-propen-1-ol in 50 ml of dry N,N-dimethylformamide is added 6.05 g of tert-butyldimethylsilyl chloride followed by 8 g of imidazole. This mixture is stirred overnight, then diluted with ether, washed with saturated aqueous sodium bicarbonate, water and brine, dried and evaporated, to give 6.49 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][CH:16]=2)=[CH:6][C:3]=1[C:4]#[N:5].[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].N1C=CC=CC=1.CN(C)C=O>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)[CH:16]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc(-n2cc(-c3cc(C#N)c(N)nc3-c3ccco3)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (20 mg, 0.071 mmol), 4-cyanophenylboronic acid (35 mg, 0.24 mmol), copper acetate monohydrate (3.0 mg, 0.015 mmol), pyridine (0.015 mL, 0.19 mmol) and N,N-dimethylformamide (1.0 mL) were introduced into a reaction vessel and stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extracting with ethyl acetate. The organic layer was dried, and then dissolved in dimethyl sulfoxide (1.0 mL) and purified by high performance liquid chromatography, to give the title compound as a yellow solid (8.32 mg, 62%).