Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCCCCBr)CC1
Temperature: 0 °C
Yield: 15 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (6 g) in N,N-dimethylformamide (30 ml) was portion wise added sodium hydride (60%, 1.6 g) at 5° C. with stirring. The mixture was stirred at room temperature for 0.5 hour and at 60° C. for an hour. To the reaction mixture was added dropwise 1,4-dibromobutane (19 g) at 5° C. with stirring. The mixture was stirred at room temperature for 4 hours and at 50° C. for 2 hours. The reaction mixture was poured into ice-water and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1). The organic layer was washed with saturated sodium chloride aqueous solution and dried over magnesium sulfate. The magnesium sulfate was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give oil. The oil was subjected to column chromatography on silica gel (silica gel 60 F254, Merck) and eluted with a mixture of ethyl acetate and n-hexane (1:10-1:3). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-4-[(4-bromo)butoxy]piperidine (1.5 g).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CCOC(=O)CCCN1CCC(c2ccc(F)c(Cl)c2)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:20]([OH:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(C)=O.C(OC(=O)C)(=O)C.C(OCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:20](=[O:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COc1ccc(CO[C@H]2C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
Compound 5.06 (10.5 g, 17.4 mmol) in DMSO (80 mL) and acetic anhydride (60 mL) was heated to 65° C. for 3 h then cooled to room temperature. The reaction mixture was poured into a separatory funnel, diluted with ethyl ether, and washed with H2O. The aqueous layer was back-extracted with additional ethyl ether (5×). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by silica gel column chromatography (8% EtOAc/petroleum ether) to afford the title compound (10.4 g, 17.4 mmol, 100%). 1H NMR (500 MHz, CDCl3): δ ppm 7.40-7.34 (m, 6H), 7.32 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 4.88 (d, J=7.8 Hz, 1H), 4.86 (d, J=7.8 Hz, 1H), 4.79-4.74 (m, 2H), 4.58 (d, J=11.2 Hz, 1H), 4.15-4.08 (m, 3H), 4.05 (t, J=8.5 Hz, 1H), 3.98 (dd, J=7.1, 3.7 Hz, 1H), 3.85-3.81 (m, 1H), 3.80 (s, 3H), 3.74-3.61 (m, 2H), 1.09-1.02 (m, 2H), 0.93 (s, 9H), 0.11 (s, 6H), 0.06 (s, 9H); 13C NMR (125 MHz, CDCl3): δ ppm 202.00, 159.50, 138.34, 129.89, 129.72, 128.41, 128.12, 127.81, 113.86, 102.52, 83.74, 83.10, 74.75, 73.50, 67.53, 61.74, 55.31, 25.97, 18.46, 18.42, −1.29, −5.17, −5.25; HRMS calcd for C32H54NO7Si2 [M+NH4]+: 620.3439. found 620.3423.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24](=[O:26])[NH2:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-]>C1COCC1.O>[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:27])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1)(=[O:26])[NH2:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(N)=O)cn3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cnc(C(N)=O)cn2)cc2c1C(CC(=O)O)OB2O
Yield: 52.7 %

Procedure:
A solution of [6-(5-carbamoyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (77 mg, 0.21 mmol) in THF (4 mL) was treated with LiOH (35 mg, 0.84 mmol) in water (4 mL) at room temperature for 1 h. The reaction was concentrated to dryness. The residue was diluted with water and adjusted to pH 3. The mixture was purified by preparative HPLC to give the title compound (38 mg). 1H NMR (300 MHz, CD3OD) δ 8.76 (s, 1H), 8.46 (s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 5.73-5.69 (m, 1H), 3.33-3.18 (m, 1H), 2.42 (s, 3H), 2.38-2.33 (m, 1H). MS found: (M+H)+: 344.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=[CH2:18])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6])C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:20][C:15]1([CH3:19])[CH2:16][CH:17]=[CH:18][CH2:1][N:4]([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)(=[O:6])=[O:7])[CH2:14]1
Reactant: C=CCN(CC(C)(C)CC=C)S(=O)(=O)c1ccccn1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC1(C)CC=CCN(S(=O)(=O)c2ccccn2)C1
Yield: 88.2 %

Procedure:
Pyridine-2-sulfonic acid allyl-(2,2-dimethyl-pent-4-enyl)-amide (0.6 g, 2 mmol) was diluted in CH2Cl2 (50 ml) After carefully degass by Ar, Grubbs catalyst (0.17 g, 0.2 mmol) was added under Ar protection. The mixture was then refluxed for 2 h before the solvent was removed on rotavapor. The crude product was purified by column chromatography (5%-20% E/H) to give 0.47 g of the title compound in 87% yield. MS (M+H+): 267.0; 1H-NMR (400 MHz, CDCl3): •8.70-8.69(d, 1H), 7.96-7.88(m, 2H), 7.49-7.46(m, 1H), 5.81-5.70(m, 2H), 3.93-3.92(d, 2H), 3.26(s, 2H), 2.13-2.12(d, 2H), 1.00(s, 6H)
Reaction SMILES: [CH2:1]([NH:14][CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH3:21]>>[CH2:1]([NH:14][CH2:15][CH2:16][C:17]([NH2:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCNCCC(=O)OC
Reactant: N
Product: CCCCCCCCCCCCCNCCC(N)=O
Reaction time: 168 h

Procedure:
A solution of methyl 3-(tridecylamino)propionate (0.77 g) in 10N-methanolic ammonia (7 ml) was allowed to stand at room temperature for 7 days. The resultant crystal was collected by filtration and washed with a small portion of methanol to give 3-(tridecylamino)propionamide (0.16 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:17][CH3:18])[C:11](=[O:19])[CH2:10][CH2:9]2)=[O:5])C.[OH-].[Na+]>CO>[CH2:17]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:15]([CH3:16])[CH:14]=2)[CH2:9][CH2:10][C:11]1=[O:19])[CH3:18]
Reactant: CCOC(=O)c1cc2c(cc1C)N(CC)C(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1C(=O)CCc2cc(C(=O)O)c(C)cc21
Yield: 96 %

Procedure:
The compound (9.54 g, 36.5 mmol) obtained in step C was dissolved in methanol (100 ml), 1N sodium hydroxide (100 ml) was added at room temperature with stirring, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (160 ml) was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with a diisopropyl ether-isopropanol mixed solvent, and dried under reduced pressure to give the title compound (8.17 g, yield 96%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][N:11](Cl)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:27]#[N:28])(C)C.O1CCOCC1>[I-].[Zn+2].[I-].O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][CH:10]1[C:27]#[N:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Product: N#CC1NC[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the toluene solution was added zinc iodide (0.5 g) and trimethylsilyl cyanide (20 ml, 160 mmol). The mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Dioxan (5 ml) and water (5 ml) were added and stirring was continued for 11/2 hour at room temperature. Water (150 ml) was added, the organic phase isolated and washed with water (200 ml), dried with magnesium sulphate and evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: ethyl acetate) afforded (3R,4R)-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (13.5 g, yield: 82% overall) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16](N1C=CN=C1)([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)=[O:17].CN(C1C=CC=CN=1)C>CC#N>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:16]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[O:17])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: O=C1CN(C(=O)n2ccnc2)CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-fluorobenzyl)piperazin-2-one (2.17 grams, 10.4 mmol) in 50 ml MeCN was added 1,1′-carbonyldiimidazole (2.03 g, 12.5 mmol) and dimethylaminopyridine (64 mg, 0.52 mmol). The solution was stirred at room temperature for 1 hour, concentrated under vacuum, and then dissolved in a mixture of CH2Cl2/CHCl3. The organic solution was washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and filtered to provide the title product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.27 (t, J=6.9 Hz, 2H), 7.21 (t, J=1.4 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J=8.6 Hz, 2H), 4.60 (s, 2H), 4.34 (s, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.40 (t, J=5.4 Hz, 2H); ES MS (M+1)=303.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:10][C:11]1[CH:49]=[CH:48][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:37]([O:39]CC3C=CC=CC=3)=[O:38])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[O:26])=[C:20]([Cl:47])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.Cl.[C].[Pd]>[C:54]([O:53][C:51]([NH:50][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:37]([OH:39])=[O:38])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[O:26])=[C:20]([Cl:47])[CH:19]=2)=[O:16])=[CH:48][CH:49]=1)=[O:52])([CH3:56])([CH3:57])[CH3:55]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3cccc(F)c3)C(=O)OCc3ccccc3)c(Cl)c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3cccc(F)c3)C(=O)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of benzyl N-{[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]acetyl}-3-fluoro-L-phenylalaninate (260 mg) in tetrahydrofuran (4.00 mL) was added one drop of 1 M hydrochloric acid, and 10% palladium-carbon (20.5 mg) was added under an argon atmosphere, followed by stirring at room temperature for 1 hour at normal pressure under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain N-{[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]acetyl}-3-fluoro-L-phenylalanine (187 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:20][C@@H:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][C@@H:4]2[O:3]1.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[C@@H:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:8][CH2:9][C@@H:4]2[O:3]1
Reactant: O=C1N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@@H]2O1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (3aR,7aS)-benzyl 2-oxohexahydrooxazolo[4,5-c]pyridine-5(6H)-carboxylate (1.0 equiv.) in dichloromethane (0.09 M) was added BOC2O (1.1 equiv.), triethylamine (1.1 equiv.), and a catalytic amount of DMAP. The reaction was stirred at room temperature for one hour at which point it was concentrated under vacuo and filtered through a plug of silica gel eluting with ethylacetate. The product was dried under vacuo to give a white solid in 75% yield. LCMS (m/z): 277.2 (MH+), LC Rt=3.43 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([CH3:28])([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1([C:54]#[CH:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CCN(CC)CC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:20]([CH3:28])([CH2:19][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:2]=1[C:55]#[C:54][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1C#Cc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Ethyl 4-{2-bromo-4-[3-(pyridin-2-ylamino)propoxy]phenyl}-3,3-dimethylbutanoate (500 mg) was dissolved in Et3N (5 ml) followed by the addition of phenylylacetylene (250 μL), Cul (11 mg), triphenylphosphine (85 mg), and Pd(Ph3P)2Cl2 (42 mg). The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 24 hours. Further phenylacetylene (125 μL) and triethylamine (5 mL) were added and heating was continued for a further 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered through a pad of celite. The solvent was evaporated and the residue was chromatographed on silica gel eluting with hexane/ethyl acetate (3:2). This gave the product (516 mg) as an oil. The NMR spectrum was consistent for the proposed structure.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=1[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:18])=[O:7]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCCC(=O)O
Product: CON=C1C[C@@H](C(=O)NCCCC(=O)O)N(C(=O)c2ccccc2-c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-aminobutanoic acid, the title compound was obtained in 57% purity by HPLC. MS(ESI+): m/z=424.
Reaction SMILES: C([O-])=O.[NH4+].C(O)C.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24]([O:35][CH:36]([CH3:38])[CH3:37])[CH:23]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1>O.O1CCCC1.[Pd]>[CH:36]([O:35][C:24]1[CH:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)[N:26]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:25]=1)([CH3:38])[CH3:37]
Reactant: COc1ccc(-n2nc(OC(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(OC(C)C)cc2-c2ccc(O)cc2)cc1

Procedure:
To a solution of ammonium formate (954 mg) in water (2 ml) were added ethanol (10 ml), a solution of 5-[4-(benzyl-oxy)phenyl]-3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazole obtained by Example 36 (2.09 g) in tetrahydrofuran (10 ml), and 10% palladium on carbon 50% wet (200 mg) successively. The mixture was refluxed for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[C:5]2[N:6]([C:8]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.C(O)C.NN>CC(=O)OCC>[NH2:23][CH2:22][C:4]1[C:5]2[N:6]([C:8]([C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[O:21])=[C:9]([CH3:11])[N:10]=2)[N:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1nc2c(CN3C(=O)c4ccccc4C3=O)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc2c(CN)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine 2-((6-chloro-3-(4-chloro-2-fluorobenzoyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)isoindoline-1,3-dione (7.30 g, 15.1 mmol), ethanol (200 mL), and hydrazine (1.45 mL, 3 equiv.) in a round bottom flask and place under nitrogen. Stir for 2 days at RT. Heat for 2 h at 50° C. then concentrate the reaction in vacuo. Dilute with EA. Wash the organics with 1 N HCl (aq) to pull product into the aqueous layer. Make the aqueous layer basic with 1 N NaOH (aq) and extract with EA. Wash the EA layer with aqueous saturated sodium chloride, and dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo to give the title compound crude (1.2 g, 23%) as a light green solid. MS=355.0, 353.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3[C:13]4[CH2:14][NH:15][CH2:16][CH2:17][C:12]=4[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>>[CH:21]([NH:24][C:25]([N:15]1[CH2:16][CH2:17][C:12]2[NH:11][N:10]=[C:9]([C:7]3[NH:6][C:5]4[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]=4[N:8]=3)[C:13]=2[CH2:14]1)=[O:26])([CH3:23])[CH3:22]
Reactant: Cc1cc2nc(-c3n[nH]c4c3CNCC4)[nH]c2cc1C
Reactant: CC(C)N=C=O
Product: Cc1cc2nc(-c3n[nH]c4c3CN(C(=O)NC(C)C)CC4)[nH]c2cc1C

Procedure:
By proceeding in a manner similar to Example 255(a) above but using 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [Example 251(a)] and isopropylisocyanate, and subjecting the reaction product to flash column chromatography eluting with ethyl acetate/methanol (19:1, v/v), there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide (93.3 mg) as an off-white solid. LC-MS (METHOD M): RT=10.15 minutes, 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)O)=[CH:4][CH:3]=1.[BrH:20]>C(O)(=O)C>[BrH:20].[Br:20][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[N:16][N:15]([CH3:18])[C:14]=2[CH:19]=1
Reactant: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3)cc21
Agent: Br
Solvent: CC(=O)O
Product: Cn1nnc2ccc(C(Br)c3ccc(Cl)cc3)cc21
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A mixture of 245 parts of α-(4-chlorophenyl)-1-methyl-1H-benzotriazole-6-methanol and 1500 parts of a hydrobromic acid solution in acetic acid was stirred for 2.5 hours at 40° C. The reaction mixture was evaporated at 60° C. and the residue was stirred in dichloromethane. After cooling to 10° C., the precipitated product was filtered off and dried, yielding 285 parts (76.6%) of 6-[bromo(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole monohydrobromide (int. 130).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH3:16]>>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CN1CCC(NC(=O)OC(C)(C)C)CC1
Yield: 79.4 %

Procedure:
The procedure of Preparation Example (1-iii-1) was repeated except for using t-butyl-piperidin-4-ylcarbamate (1.67 g, 8.4 mmol) obtained in Preparation Example 1-ii and iodomethane as the starting materials, to obtain 1.43 g of the title compound as pale yellow oil (yield 79.4%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC#N>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:31][C:46]([C:44]3[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:34]4[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])[N:45]=3)=[O:47])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
3-Amino-4-{(3R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (153 mg, 0.352 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (107 mg, 0.422 mmol), HATU (330 mg, 0.88 mmol), and DIPEA (180 μL, 1.0 mmol) were dissolved in DMF (4.9 mL) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with MeCN and purified by RP-HPLC (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% TFA, at flow rate of 30 mL/min.) to give the sub-title compound as a white solid (118 mg, 50%). LCMS calc. for C34H39F3N5O6 (M+H)+ m/z=670.3. found 670.3.