Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[CH:21]=3)[CH:17]=1)[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (47 mg, 0.124 mmol) in pyridine (2.0 mL) was added cyclopropanecarbonyl chloride (25 μL, 0.273 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (1.0 mL)/water (1.0 mL). 1N Aqueous sodium hydroxide solution (1.0 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (40 mg, 64%) as a colorless powder.
Reaction SMILES: [C:1](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:7][C@H:6]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[C@H:5]([CH2:30][CH3:31])[CH2:4]1.[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.[OH-].[Na+]>O1CCOCC1>[CH:43]1([NH:47][C:1](=[O:32])[O:2][C@@H:3]2[CH2:7][C@H:6]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:5]([CH2:30][CH3:31])[CH2:4]2)[CH2:46][CH2:45][CH2:44]1
Reactant: CC[C@@H]1C[C@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: NC1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](OC(=O)NC2CCC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of a scalemic mixture enriched in (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.150 g, 0.254 mmol) in 1,4-dioxane (1 mL) was added to a solution of cyclobutanamine (0.090 g, 1.27 mmol) in 1,4-dioxane (0.2 mL). After about 1 h, aqueous NaOH (1 N, 1.5 mL, 1.50 mmol) was added and the reaction mixture was heated at about 60° C. for about 2 h before cooling to rt. The organic solvent was removed under reduced pressure. The resulting aqueous layer mixture was acidified with AcOH to pH about 5 and extracted with DCM (3×5 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by preparative HPLC (Table 1 method d) to give (1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl cyclobutylcarbamate (0.0468 g, 50%): LC/MS (Table 1, Method c) Rt=1.17 min; MS m/z: 369 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10](O)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:45]([SH:47])[CH3:46].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([S:47][CH2:45][CH3:46])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCS
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(O)c2c1[nH]c1ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(SCC)c2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-1-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (60 mg, 0.3 mmol) in DCM (2 mL) was added trifluoromethanesulfonic anhydride (50 mL, 0.6 mmol) at 0° C. and the mixture was stirred for 1 hour at 0° C. Ethanethiol (34 mL, 0.9 mmol) was added and the reaction mixture was stirred overnight at 20° C. Water was added and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was then washed with water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:19) to give the title compound (2 mg); 1NMR (CDCl3): δ 8.59 (1H, s), 8.77 (1H, d), 7.54 (2H, m), 7.36 (1H,), 7.19 (1H, m), 7.06 (2H, m), 6.73 (1H, s), 4.41 (2H, m), 4.21-4.30 (3H, m), 2.59-2.69 (2H, m), 1.28 (3H, t), 1.19 (3H, t). MS (ES): 439 (MH+).
Reaction SMILES: NN.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4]>CCO.[Pd]>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC(C)N1CCC(c2ccc(N)cc2)CC1
Yield: 72.2 %

Procedure:
Hydrazine (35% by weight in water, 0.67 mL, 7.2 nnol) and 10% Pd/C (38 mg, 0.03 mmol) are added to a solution of 1-isopropyl-4-(4-nitrophenyl)piperidine (180 mg, 0.72 mmol) in EtOH (10 mL) and the mixture is heated at reflux for 3 h. After cooling, the mixture is filtered through celite and the solvent evaporated. The residue is redissolved in DCM (25 mL), dried over MgSO4 and the solvent evaporated to afford the desired compound as a pale yellow solid (113 mg, 0.52 mmol) which was used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][C:15]=1[O:23][CH3:24].[Cl-].[NH4+]>C1COCC1>[CH3:24][O:23][C:15]1[CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[CH:18]=[N:19][C:14]=1[O:10][CH2:9][C:8]([F:12])([F:11])[F:7]
Reactant: COc1cc(C(C)=O)cnc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of potassium tert-butoxide (0.22 g, 1.97 mmol) in THF (7 mL) is added 2,2,2-trifluoroethanol (0.09 mL, 1.28 mmol), and the mixture is stirred at rt for 20 minutes. A solution of 1-(6-chloro-5-methoxypyridin-3-yl)ethanone (0.18 g, 0.99 mmol, Step-2) in THF (8 mL) is added dropwise to the mixture, and the resulting mixture is stirred at rt for 3.5 hours. The reaction mixture is poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (30 mL). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1) to give 0.25 g (>99% yield) of the title compound as white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([NH:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[CH:7]1([NH:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CCCNC1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: NCCCNC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.9 %

Procedure:
To a cooled (0° C.) suspension of lithium aluminum hydride (3.295 g, 86.8 mmol) in anhydrous diethyl ether (150 mL) was added a solution of 3-(cyclopentylamino)propanenitrile (6.000 g, 43.4 mmol) in anhydrous diethyl ether (40 mL), dropwise over 45 mins. The reaction mixture was stirred at room temperature for 15 mins and at reflux for 4 hrs, cooled to room temperature and stirred for 1 hr. The mixture was cooled to 0° C. and vigorously stirred while water (3.4 mL) was added dropwise, followed by 15% aqueous sodium hydroxide (3.4 mL), and finally water (10.2 mL). The resultant slurry was warmed to room temperature, stirred for 15 mins, and anhydrous magnesium sulfate was added, stirring for an additional 15 mins. Solid materials were removed by filtration, washing multiple times with warm methylene chloride, and the filtrate concentrated under reduced pressure to give the desired product as a clear oil (4.5 g, 73%). 1H NMR (CDCl3, 300 MHz) δ 3.05-2.96 (quint, 1H, J=6.6 Hz), 2.74-2.71 (t, 2H, J=6.6 Hz), 2.68-2.58 (t, 2H, J=6.9 Hz), 1.85-1.68 (m, 2H), 1.62-1.42 (m, 6H), 1.34 (br s, 3H), 1.30-1.21 (m, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][C:28]#[CH:29])[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: C#CCCCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(-c2ccccc2)no1
Temperature: 50 °C

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of Example 2, 2.61 g, 16.8 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6, 2.90 g, 8.39 mmol) and triethylamine (3.50 mL, 25.2 mmol) in dichloromethane at 6° C. The solution was heated at 50° C. under a nitrogen atmosphere for 4 hours. The solution was diluted with dichloromethane, transferred to a separatory funnel, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was triturated with hexanes and the solvent was decanted. The oil was triturated with diethyl ether and a solid formed that was isolated by filtration to provide 4-chloro-2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.98 g). The filtrate was purified by flash chromatography (silica gel, gradient elution from 7:3 to 1:1 hexanes/ethyl acetate) to provide an additional 0.24 g of product. The total amount of 4-chloro-2-(ethoxymethyl)-1-[3-(3-phenylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline isolated was 2.22 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[C:32]([Cu])#[N:33]>N1C=CC=CC=1>[C:32]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)#[N:33]
Reactant: N#C[Cu]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: c1ccncc1
Product: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 160 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl) methyl-3H-imidazo[4,5-b]pyridine (41 mg), CuCN (80 mg), and pyridine (0.2 mL) was heated with stirring to 160° C. for 4 hours. The pyridine distilled off during the course of the heating. The cooled dark mass was dissolved in 2 mL of 20% aqueous KCN by heating to 50° C. for 15 minutes. Acetic acid (2 mL) (Caution HCN is evolved.) was added and the mixture was extracted (2×EtOAc). The organic layers were dried (Na2SO4), concentrated, and purified (SiO2, 80/20/1 CH2Cl2 --MeOH--NH4OH) to give 26 mg of the title compound as a solid. 1H NMR (250 MHz, CD3OD) δ 7.66-7.45 (m, containing a singlet at 7.57, 5H), 7.15-7.04 (m, 4H), 5.53 (s, 2H), 2.91 (q, 2H, J=7.5 Hz), 2.66 (s, 3H), 1.27 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:38])[N:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[NH:20][C:19]4[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=4[CH:13]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCOC)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 94 °C
Reaction time: 72 h
Yield: 26.6 %

Procedure:
9a (25 mg) was suspended in THF (2 ml) in a pressure tube, 4-fluorophenyl isocyanate (200 mg) was added and the mixture was stirred at 94° C. for 3 days. After cooling to room temperature, the mixture was evaporated to almost dry and the solid was filtered and washed with ether (two peaks shown in HPLC, rt=8.0 min, rt=1.6 min). The solid was stirred with DCM, the solid (rt=8.0 min) was removed and the mother liquid was collected. After removal of the solvent, the residue was purified by column (14 g silica gel, RT Scientific) (CH2Cl2: MeOH=100:0 to 98:2) to give the product (11a) (9 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=11.60 min. 1H NMR (DMSO, d6): 0.83-0.95 (m, 6H), 1.53-1.75 (m, 4H), 3.26 (s, 3H), 3.60 (t, 2H), 3.87 (t, 2H), 4.17 (t, 2H), 6.85 (s, 1H), 7.16 (t, 2H, J=8.7 Hz), 7.48 (m, 3H), 8.30 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.95 (d, 1H, J=2.4 Hz), 10.87 (s, 1H), 12.50 (s, 1H). MS: m/z 523 (M+H)+.
Reaction SMILES: [BrH:1].[CH2:2]([C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:5]=1N)[CH3:3].[Br-].[Na+].N(OCCC(C)C)=O>ClC1C=CC=CC=1Cl>[Br:1][C:5]1[C:4]([CH2:2][CH3:3])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[CH2:12][CH3:13]
Reactant: CCc1cc(C)cc(CC)c1N
Reactant: Br
Agent: CC(C)CCON=O
Agent: [Br-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CCc1cc(C)cc(CC)c1Br
Temperature: 50 °C

Procedure:
Gaseous hydrogen bromide (1.05 equiv.) is fed into a mixture of 2,6-diethyl-4-methylaniline (1.00 equiv.) and sodium bromide (0.10 equiv.) in o-dichlorobenzene. The resulting salt suspension is cooled to 50° C. Isoamyl nitrite (1.05 equiv.) and additional gaseous hydrogen bromide (0.3 equiv.) are fed subsurface simultaneously at 50-55° C. over a 2-hour period to afford 1-bromo-2,6-diethyl-4-methylbenzene as a yellow to light brown solution. The reaction mass is neutralized with 25% caustic solution (ca. 0.3 equiv.). The bottom aqueous phase is separated off. Isoamyl alcohol and o-dichlorobenzene are sequentially stripped off to produce the crude 2,6-diethyl-4-methylbromobenzene material with an assay of 90% and an isolated yield of 87-90%. The product can be further purified by vacuum distillation at 95° C./5 mmHg to give an assay of 97-99%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=O)[CH2:3][CH2:2]1.[O:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CN(C)C=O.O1CCCC1>[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH2:9])[CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: O=C(O)C1CCOCC1
Reactant: NC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a stirred mixture of piperidine-4-carboxamide (1.28 g, 10 mmol), tetrahydro-2H-pyran-4-carboxylic acid (1.43 g, 11 mmol) and diisopropylethylamine (2.09 mL, 11 mmol) in N,N-dimethylformamide was added HBTU (N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate, 4.14 g, 11 mmol) at 0° C. After being stirred for 0.5 h at 0° C., the mixture was stirred for 3 h at ambient temperature. Then, the mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic extract was washed with brine, dried over magnesium sulfate and concentrated. This crude material was dissolved in tetrahydrofuran (50 mL) and added to the mixture of lithium aluminum hydride (1.90 g, 50 mmol) in tetrahydrofuran (50 mL) at 0° C. Then, the mixture was heated at 40° C. and stirred for 5 h. The mixture was cooled to 0° C. and quenched with sodium sulfate decahydrate (3.8 g) and potassium fluoride (9.0 g). After vigorous stirring for 0.5 h, the insoluble materials were filtered off. The filtrate was concentrated to give 2.19 g (99%) of the title compound as a colorless viscous oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:32]([C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>>[C:32]([C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:31][CH:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=2)[CH2:17][CH2:18]1)(=[O:34])[CH3:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc3c(c2)CCC3)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:34]#[N:35])([NH:14][C:15](=[O:33])[CH:16]([NH:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[C:34]([C:11]1([NH:14][C:15]([CH:16]([NH:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:33])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reaction time: 1 h

Procedure:
4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylic acid t-butyl ester (1000 mg, 2.03 mmol) was dissolved in 20 mL of 4 M HCl in dioxane and stirred for 1 hour at which time the volatiles were remove in vacuo. The resulting residue was triturated with 100 mL of diethyl ether and the resulting solid was collected by filtration under inert atmosphere (the solid is very hygroscopic) and washed 2×50 mL of diethyl ether and dried in vacuo to yield the title compound as a bright white powder (802 mg); MS, m/z 392, M−35).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:19])[C:10]2=[O:29])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.N[C@H](C(OC)=O)C(C)(C)C.O[NH:42][C:43](=[NH:45])[CH3:44].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH2:45][C:43](=[N:42][O:27][C:26]([C@@H:21]([NH:20][C:18]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:10]1=[O:29])=[O:19])[C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28])[CH3:44]
Reactant: CC(C)(C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)O
Reactant: CC(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(N)=NOC(=O)[C@@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(C)(C)C
Reaction time: 9 h
Yield: 57 %

Procedure:
To a solution of N-({3-[2-(4-morpholinyl)ethyl]-oxo-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-tert-leucine (prepared according to the procedure described in step 1 of example 3 from methyl L-tert-leucinate hydrochloride) (0.18 g, 0.45 mmol) in DMF (1 mL) were added a solution of N-hydroxyethanimidamide (37 mg, 0.50 mmol, Hamze, A.; Hernandez, J.-F.; Fulcrand, P.; Martinez, J. J. Org. Chem. 2003, 68, 7316-7321.) in DMF (1 mL), triethylamine (0.26 mL, 1.8 mmol), HOBt (83 mg, 0.54 mmol) and WSC (0.10 g, 0.54 mmol) at rt. After 9 h, to this mixture were added N-hydroxyethanimidamide (20 mg, 0.26 mmol), triethylamine (0.10 mL, 0.70 mmol), HOBt (10 mg, 0.06 mmol) and WSC (20 mg, 0.10 mmol). After 13 h, the reaction was quenched by addition of sat. aq. sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2), brine (20 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (10/1) to afford 0.12 g (57%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](OCC)=[O:26]>>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:24][CH:25]=[O:26])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: CCOC=O
Product: O=CNCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 67.5 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
A mixture of 2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethylamine (0.0714 g, 0.226 mmol) and ethyl formate (3 mL) is stirred at 65-70° C. for 45 min. After cooling, excess ethyl formate is removed in vacuo and the residue is partitioned between CH2Cl2 and aq. sodium sulfate. The organic layers are dried over sodium sulfate and concentrated; the residue is crystallized from CH2Cl2-EtOAc-hexane to give 0.0585 g (75%) of the title compound as a white, crystalline solid; mp 161-162° C.; MS (ESI+) for m/z 345 (M+H)+, 367 (M+Na); 1H NMR (CDCl3) δ3.95, 4.38, 5.52, 6.13, 6.68, 7.03, 7.10, 7.2-7.4, 8.27, 8.29; IR (drift) 3297, 1659, 1459, 1385, 1341, 1332, 1269, 1255, 1145, 1116, 780, 747, 737, 717, 700 cm−1. Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C, 76.53; H, 5.99; N, 8.09.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1.CN1CCOCC1>CO>[CH:21]1([CH2:24][NH:25][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[CH2:23][CH2:22]1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCC1CC1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCC3CC3)cc2s1
Yield: 24.8 %

Procedure:
the title compound (27 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), C-cyclopropylmethylamine (53 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 364.5 (M+1, 100%). Yield=21%.