Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CN(C)C(=O)C>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Temperature: 130 °C

Procedure:
4-chloronitrobenzene (31.5 g, 200 mmol) was dissolved in N,N-dimethylacetamide (80 ml), and potassium carbonate (35.9 g, 260 mmol) and 4-hydroxypiperidine (22.3 g, 220 mmol) were added thereto, followed by stirring under heat at 130° C. for 3 hours. After cooling to room temperature, water was added to the mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-hydroxy-N-(4-nitrophenyl)piperidine (41.3 g, 93%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)([O-:16])=[O:15].CN(C)C=O>O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:20]1[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CNCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 72 h

Procedure:
A mixture of N,N,N′-trimethylethane-1,2-diamine (2.17 g), potassium carbonate (3.0 g), 4-nitrofluorobenzene and dimethylformamide (30 ml) was stirred for 72 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried and concentrated. The product with the molecular weight of 223.28 (C11H17N3O2); MS (ESI): 224 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].N1C=CC=CC=1.[CH:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl-]C([O-])=O)[CH:18]=1.[OH2:30].[O:31]1[CH2:35]CCC1>>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:35](=[O:31])[O:30][C:19]2[CH:18]=[CH:17][C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: O
Reactant: C1CCOC1
Reactant: CC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Product: CC(=O)c1cccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
To a solution of 3-aminoacetophenone (2.049 g) and pyridine (1.286 g) in tetrahydrofuran (35 ml) was added dropwise a solution of 4-nitrophenylchloroformate (3.288 g) in tetrahydrofuran (10 ml) under cooling in an ice bath. After completion of the addition, the mixture was allowed to stand to ambient temperature and stirred over night. Water was added to the mixture. The resultant precipitate was collected by suction filtration, washed with water and dried in vacuo at 80° C. to afford 4-nitrophenyl N-(3-acetylphenyl)carbamate (3.31 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3cc(Cl)ccc3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 2,5-dichlorophenylboronic acid (191 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 47%). 1H NMR (CDCl3, 300 MHz) δ 7.30-7.36 (m, 2H), 7.15-7.19 (m, 1H), 7.01 (s, 1H), 3.82-4.22 (m, 2H), 3.82-3.96 (m, 1H), 2.82-3.52 (m, 7H), 1.82-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:14]([S:17][CH:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:20]([C:36](O)=[O:37])[CH2:19]1)(=[O:16])[CH3:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:14]([S:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([C:36](=[O:37])[NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[C:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:3]=2)[CH2:19]1)(=[O:16])[CH3:15]
Reactant: C=CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)SC1CC(C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The above allyl 3-aminobenzoate (26.6 g, 0.15 M) was condensed with 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (55.2 g, 0.15 M) by suspension in toluene (750 ml) and addition of EEDQ (44.5 g, 0.18 M). The mixture was stirred overnight, diluted with EtOAc (2 l) and washed with dilute HCl, water and brine. The EtOAc phase was dried and evaporated, and the residue recrystallised from ethanol giving (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine (67.7 g). Nmr (DMSO-d6): δ1.93 (quintet, 1H); 2.9 (m, 1H); 3.35 (m, 1H); 3.91-4.14 (m, 2H); 4.49 (quintet, 1H); 4.81 (dd, 2H); 5.22 (dd, 2H); 5.2-5.44 (m, 2H); 5.95-6.10 (m, 1H); 7.47 (d, 2H); 7.66 (t, 2H); 7.8-7.93 (m, 2 H); 8.18-8.3 (m, 2H); 10.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:15]1[CH:14]=[C:13]([Cl:18])[CH:12]=[C:11]([Br:10])[CH:16]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: Oc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1
Temperature: 140 °C

Procedure:
To a solution of 2-chloro-5-fluorophenol (82.3 g, 562 mmol) and 1-bromo-3-chloro-5-fluorobenzene (124 g, 590 mmol) in NMP (200 mL) was added potassium carbonate (155 g, 1.123 mol). The resulting mixture was then heated to 140° C. and maintained at 140° C. for hours, after which the mixture was poured into water (1500 mL) and extracted with EtOAc (2500+1500 mL). The combined extracts were washed with water and brine. This solution was concentrated on the rotary evaporator and the residue was distilled at high vacuum at 135-190° C. to give the title compound as a clear, colorless liquid. 1H NMR (CDCl3) δ 7.45 (dd, 1H, J=9.0 and 4.5 hz), 7.28 (dd, 1H, J=1.7 Hz), 7.26 (s, 1H), 7.00 (dd, 1 h, J=1.95 Hz), 6.92 (ddd, 1H, J=10.5, 7.6 and 2.7 Hz), 6.89 (dd, 1H, J=1.95 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCCCc2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCCCc2ccccc2)c2cccc(N)c2)cc1
Yield: 78.7 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(3-phenylpropyl)amine (2.79 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.52 g) and sodium borohydride (1.12 g) were reacted, to afford the title compound (2.02 g) as a pale yellow oil.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:41]3[CH2:46][CH2:45][C@@H:44]([N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[CH2:43][CH2:42]3)[N:21]=[C:22]([C:23]3[CH:40]=[CH:39][C:26]([NH:27][C:28]4[O:29][C:30]5[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:31]=5[N:32]=4)=[CH:25][CH:24]=3)[C:15]=12.[OH-].[Na+].O.OO>O1CCOCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:41]3[CH2:42][CH2:43][C@@H:44]([N:47]4[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]4)[CH2:45][CH2:46]3)[N:21]=[C:22]([C:23]3[CH:40]=[CH:39][C:26]([NH:27][C:28]4[O:29][C:30]5[CH:36]=[CH:35][C:34]([C:37]([NH2:38])=[O:3])=[CH:33][C:31]=5[N:32]=4)=[CH:25][CH:24]=3)[C:15]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(C#N)ccc6o5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(C(N)=O)ccc6o5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 120 %

Procedure:
To a mixture of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1,3-benzoxazole-5-carbonitrile triacetate (0.18 g, 0.00025 mol) in dioxane (2 mL) were added a 2N aqueous solution of sodium hydroxide (1.25 mL, 0.0025 mol) and water (0.75 mL). The mixture was stirred at room temperature for 2 minutes under the atmosphere of nitrogen before adding 30% hydrogen peroxide solution (0.2 mL). The mixture was refluxed for 5 hours, then stirred at room temperature for 18 hours. More 30% hydrogen peroxide solution (0.2 mL) was added to the mixture before refluxing for additional 6 hours, then stirred at room temperature for 2 days. The organic solvent was removed under reduced pressure, and 5% citric acid solution was added to maintain pH 7. The aqueous layer was removed under reduced pressure, and the crude was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to give cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1,3-benzoxazole-5-carboxamide triacetate (0.11 g, 0.00015 mol).
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[IH:23]>O>[I-:23].[NH2:1][N+:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: c1ccc2cnccc2c1
Reactant: I
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N[n+]1ccc2ccccc2c1
Product: [I-]

Procedure:
A solution of hydroxylamine-O-sulfonic acid (2) (2 g, 1 equiv), water (10 mL) and isoquinoline (1) (6.3 mL, 3 equiv) was heated at 90° C. for 2-3 h. Potassium carbonate (2.44 g, 1 equiv) was added, and the water was evaporated. Ethanol (20-30 mL) was added to the solid residue, and insoluble potassium sulfate was filtered out. Hydroiodic acid (57%-67%, 1.34 mL, 1 equiv) was added to the filtrate, and the resulting solution was placed in a freezer. The precipitate was filtered out, washed with ethanol, and dried in vacuo. Isolated products were used as such in further reactions. Yield of the product was 1.78 g.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[CH:4]([NH2:20])[C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:30][C:31]1[S:35][C:34]([S:36]([NH:20][CH:4]([C:5]2[N:9]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:21][CH3:22])(=[O:38])=[O:37])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Yield: 32.9 %

Procedure:
To (2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)amine (0.200 g, 0.630 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.18 mL, 1.3 mmol) and 5-chlorothiophene-2-sulfonyl chloride (0.14, 0.76 mmol). After 1 day the reaction mixture was diluted with chloroform (30 mL), washed with H2O (2×30 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexane, 3:7) provided 5-chloro-N-(2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide (0.104 g, 33%) as a white solid (mp=146-148° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34]>>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]([NH:34][CH2:33][C:32]([O:31][CH3:30])=[O:35])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CCC(=O)CN(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(CCN1CCN(C)CC1)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl-4-fluorobenzyl[4-(4-methylpiperazin-1-yl)-2-oxobutyl]carbamate and glycine methyl ester hydrochloride using a procedure essentially the same as that in Example 6, Step 6. 1H NMR (400 MHz, CDCl3) δ 7.19 (br s, 2H), 7.00 (t, J=8.4 Hz, 2H), 4.50-4.46 (m, 1H), 4.39 (d, J=15.6 Hz, 1H), 4.05 (d, J=4.8 Hz, 1H), 3.77 (s, 1H), 3.72 (s, 3H), 3.56-3.38 (m, 2H), 3.27-3.05 (m, 2H), 2.82-2.77 (m, 2H), 2.55-2.43 (m, 8H), 2.29 (s, 3H), 2.05 (s, 2H), 1.45 (d, J=13.2 Hz, 9H). ES MS (M+1)=467.4.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2].[NH:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To a stirring suspension of EtSO2—D—Phe—OH (257 g, 100 mmol), Pro—OBn.HCl (26.6 g, 110 mmol), HOBT (13.5 g, 100 mmol) and N,N-diisopropylethylamine (43.5 mL, 250 mL) in THF (1 L) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 g, 120 mL). After stirring for 20 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1 N citric acid. The organic phase was washed twice with 1 N KHCO3, twice with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 29 g (65%) of a clear, thick oil.
Reaction SMILES: O(C)[Na].[CH3:4][O:5][CH:6]([C:12]([O:14]C)=O)[C:7]([O:9]CC)=O.Cl.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](=[NH:26])[NH2:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CCO>[OH:14][C:12]1[N:25]=[C:24]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[NH:26][C:7](=[O:9])[C:6]=1[O:5][CH3:4]
Reactant: CCOC(=O)C(OC)C(=O)OC
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Agent: CO[Na]
Agent: Cl
Solvent: CCO
Product: COc1c(O)nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The NaOCH3 (7.8 g, 3 eq) was added to a stirred solution of 1-ethyl 3-methyl 2-methoxymalonate (11 g, 1.3 eq), 4-nitrobenzimidamide hydrochloride (9.6 g, 1 eq) and EtOH (240 ml) and the mixture was refluxed for 8 hrs. After 8 hrs, the solvent was evaporated and water (10˜15 ml) was added to the mixture then the mixture was cooled to 0° C. and carefully acidified with conc. HCl. After overnight cooling, it led to the formation of brown precipitates. The mixture was filtered and the precipitates was dried in vacuo to give a brown solid (65%) as a product.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]1
Reactant: COC(=O)C1CC(O)CN(C(=O)OC(C)(C)C)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
To a solution of dimethylsulfoxide (2.2 mL, 41.46 mmol) in dry dichloromethane (50 mL) at −78° C. was added dropwise at oxalyl chloride (1.57 mL, 18.2 mmol). After 10 min, a solution of 1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (4.3 g, 16.59 mmol) in dichloromethane was added dropwise. After 15 min, triethylamine (6.92 mL, 49.7 mmol) was added dropwise and the reaction mixture was then allowed to warm to room temperature. After 3 h, the mixture was diluted with dichloromethane and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (4.2 g) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH:21][C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([NH:21][C:22](=[CH:27][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:17])[CH:11]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(C)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere a mixture of 40.0 g (137 mmol) 2-benzyloxy-5-bromo-1,3-dimethylbenzene and 24.1 g (165 mmol) methyl 2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrile was combined with 3.5 g (11.2 mmol) tri-o-tolyl-phosphane and 2.5 g (11.1 mmol) Pd(OAc)2 and the mixture was stirred for 18 h at 80° C. The precipitate was suction filtered, the filtrate was evaporated down i. vac. and combined with 800 mL DCM and 800 mL water. The organic phase was separated off, suction filtered through Na2SO4, the solvent was removed i.vac., the residue was stirred with EtOAc, suction filtered and dried i. vac.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ncccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccnc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 64.5 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.20 g, 0.48 mmol) obtained in Example 19, step 4 and 3-amino-2-methylpyridine (0.105 g, 0.97 mmol), the title compound (0.150 g, 64%) was obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.C(=O)=O.CO.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([B:28]([OH:33])[OH:29])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: COc1cc(I)cc(OC)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(OC)cc(B(O)O)c1
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
Under argon, to anhydrous tetrahydrofuran (9.0 mL) stirred in a dry ice-methanol bath was gradually added a 1.57 M solution of n-butyllithium in hexane (3.9 mL, 5.9 mmol), followed by the dropwise addition of a solution of 3,5-dimethoxyiodobenzene (713.0 mg, 2.70 mmol) in anhydrous tetrahydrofuran (5.0 mL). After the mixture was stirred for 20 minutes in the dry ice-methanol bath, triisopropyl borate (0.75 mL, 3.2 mmol) was added and the mixture was additionally stirred for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure, then a 1.0 M aqueous sodium hydroxide (7.0 mL) was added to the residue. The resulting aqueous solution was washed with chloroform, acidified by adding concentrated hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as a colorless crystalline powder (melting point: 159.0-161.0° C.)(367.0 mg, yield: 91%).
Reaction SMILES: [CH2:1]([C@@:3]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:7][CH2:6][C@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4]1)[CH3:2].[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([C@@:3]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
tert-Butyl [(1S,3R)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (0.39 g, 0.83 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (3.1 mL) and the solution was stirred at room temperature overnight. The reaction solution was evaporated to give the desired product as a yellow powder (0.36 g, 96%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:35][CH3:36])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:3]=1.C[N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=O.CN(C)C=[O:47]>>[CH3:34][O:33][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:35][CH3:36])[N:3]=[C:2]([N:38]1[CH2:42][CH2:41][O:47][CH2:40][CH2:39]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[N+:29]([O-:31])=[O:30])[CH2:14][CH2:13]1
Reactant: COc1cc2nc(Cl)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Reactant: CN(C)C=O
Reactant: CN1CCCC1=O
Product: COc1cc2nc(N3CCOCC3)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Yield: 83 %

Procedure:
The same procedure as in Example 1 was repeated, except that 2.5 g (4.87 mmol) of Compound m obtained in Reference Example 10 was used, and N-methylpyrrolidinone was used as the solvent in place of dimethylformamide, to give 2.29 g (yield: 83%) of Compound n as white crystals.