Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]1[CH:35]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:36][CH:37]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28]>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[CH2:31][CH:32]([OH:34])[CH2:33][N:29]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Yield: 98 %

Procedure:
Using the above described procedure, oleic acid 101f (2.83 g, 10 mmol) was coupled with the amine 100 and after work-up and column purification the pure amide was isolated as aa oil (7.7 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 7.71-7.67 (m, 1H), 7.34-7.10 (m, 9H), 6.90-6.79 (m, 4H), 5.33-5.26 (m, 2H), 4.98 (d, J=3.90 Hz, 0.7H), 4.88 (d, J=3.90 Hz, 0.3H), 4.40-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.20 (m, 2H), 3.18-3.10 (m, 1H), 3.02-2.92 (m, 3H), 2.20-1.80 (m, 6H), 1.50-1.04 (m, 39H), 0.83 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.81, 170.92, 170.83, 158.09, 157.96, 145.08, 144.74, 135.87, 135.72, 135.42, 129.61, 129.54, 127.86, 127.74, 127.57, 126.56, 113.18, 113.09, 85.78, 85.10, 68.57, 67.44, 65.19, 63.32, 54.97, 54.92, 48.59, 45.71, 40.12, 38.21, 38.02, 36.29, 35.41, 34.16, 32.53, 31.28, 29.09, 28.84, 28.69, 28.66, 28.59, 28.55, 26.58, 26.56, 26.19, 25.32, 24.54, 24.14, 22.10, 13.94.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]([C:18]1[C:19]([NH2:31])=[N:20][CH:21]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([C:18]1[C:19]([NH:31][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:20][CH:21]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: Nc1ncc(Sc2ccncc2)cc1Oc1ccccc1
Product: c1ccc(Oc2cc(Sc3ccncc3)cnc2Nc2nc3cccnc3s2)cc1

Procedure:
Prepared according to the method of Example 292 from 2-chloro-3-isothiocyanatopyridine (0.116 g, 0.677 mmol) and 3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-amine. 1H NMR (d6-DMSO) δ 7.10 (d, 2H), 7.17-7.23 (m, 3H), 7.40-7.47 (m, 4H), 7.97 (bs, 1H), 8.36-8.41 (m, 4H), 11.88 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:16]O.[OH-].[Na+].O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[O:11][N:16]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CC(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(O)on2)cc1

Procedure:
According to method of U.S. Pat. No. 3,781,438, 2 g of methyl 3-(4-methylphenyl)-3-oxopropanoate was dissolved in methanol, slightly excessive hydroxylamine hydrochloride and equivalent amount of sodium hydroxide were added, the mixture was heated to reflux. 3 hr later, the reaction was traced by Thin-Layer Chromatography, after the reaction, water was added to the reaction mixture, extracted with ethyl acetate, The combined organic extracts were dried and concentrated to obtain 3-(4-methylphenyl)isoxazol-5-ol as solid (compound III-3).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:12][CH:11]([OH:13])[CH:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH:11]([OH:13])[CH2:12][N:8]([C:6](=[O:7])[C:5]4[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9]3)[C:15](=[O:20])[CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)C(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 1-[1-(4-Chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-piperazin-2-one (50 mg, 0.15 mmol) in CH2Cl2 (1 mL) at 0° C., was added DIPEA (27 uL, 0.154 mmol) and 4-Chloro-benzoyl chloride (20 uL, 0.154 mmol). The mixture was stirred at RT for 4 h. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Methanol:Et3N:10.1:0.1) to give the desired product (36 mg, 50% yield) as a white solid. MS: (ESI), M/Z, 462 (M+1). Retention time: 2.25 min (FA-polar).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:7](=[O:35])[N:8]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[O:19][CH3:20])[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:7](=[O:35])[N:8]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]3)=[O:23])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[O:19][CH3:20])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)CN2CC(c3cccc(OC)c3OC)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(C2CN(CC(=O)N3CCC(C(=O)O)CC3)C(=O)C(CC(C)C)c3ccc(Cl)cc32)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg of the compound from Example 20 (0.11 mol) are dissolved in 3.3 ml of dioxane/water (2:1), mixed with 165 μl of 1 N sodium hydroxide solution and stirred at room temperature overnight. The reaction solution is acidified (pH 2) with 1 N hydrochloric acid and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 61 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=1)[CH2:8]2.Br[CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:24]3)[N:14]=1)[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCNCC2)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCN(CCO)CC2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
After N-(adamantan-2-yl)-6-(piperazin-1-yl)picolinamide (34 mg, 0.100 mmol) was dissolved in DMF (2 ml), 2-bromoethanol (19 mg, 0.150 mmol) and potassium carbonate (41 mg, 0.300 mmol) were added thereto, and then the resulting mixture was stirred at 100° C. under nitrogen stream for 18 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 37 mg of colorless oil (96%). MS (ESI): 385 [M+H]+
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[CH2:22]([C:24]([C:49]1[CH:54]=[CH:53][C:52](O)=[C:51]([CH3:56])[CH:50]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:44][CH2:45][O:46][CH3:47])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:49]1[CH:54]=[CH:53][C:52]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[C:51]([CH3:56])[CH:50]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:44][CH2:45][O:46][CH3:47])([C:40]([F:42])([F:43])[F:41])[C:36]([F:38])([F:39])[F:37])=[C:29]([CH3:48])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Pyridine (0.513 mL, 6.36 mmol) and trifluoromethanesulfonic anhydride (0.835 mL, 5.09 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenol (Example 26-(2); 2.14 g, 4.24 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target product as a colorless oil (2.41 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](C)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CC[C@@H](C(=O)O)Cc2onc(-c3ccc(Cl)cc3)c21
Yield: 80.5 %

Procedure:
0.36 g (1.13 mmol) of methyl trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylate in 35 ml of dioxane was stirred at room temperature for 1 hour with 15 ml of 1N aqueous sodium hydroxide solution. Water was added and the solution was partially evaporated. Additional water was added to give a solution which was then acidified with 1N hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 0.278 g of trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:49])=[CH:4][C:5]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30](CC3C=CC(OC)=CC=3OC)[C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:29])=[O:28])=[CH:23][C:22]=2[C:47]#[N:48])=[C:6]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:49])=[CH:4][C:5]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:28])=[O:29])=[CH:23][C:22]=2[C:47]#[N:48])=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(F)c(Cl)cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(C#N)c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1cc(F)c(Cl)cc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-4-fluorophenyl]-1H-pyrazole-1-carboxylate (Preparation 728, 190 mg, 0.26 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.3 mL, 3.65 mmol) and the reaction mixture was left to stir at room temperature for 16 hours. The reaction was quenched by addition of water (10 mL) and the resulting mixture left to stir for 20 minutes. Then the layers were separated, the organic phase was washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude oil was purified using ISCO™ (5 g cartridge) 1-20% v/v gradient of methanol in dichloromethane as the eluent. The title compound was obtained as a white solid (61 mg. 50%).
Reaction SMILES: CO[C:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[N:15][C:5]=2[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:8]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:30]([NH2:31])=[CH:29][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[H-].[Na+].O>CN(C)C=O>[N:22]1([C:25]2[C:30]([NH:31][C:3]3[C:4]4[CH:18]=[CH:17][CH:16]=[N:15][C:5]=4[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:8]=3)=[CH:29][C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:27][N:26]=2)[CH2:21][CH2:20][O:19][CH2:24][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: COc1nc(-c2ccccn2)nc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c3cccnc3n2)nc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-methoxy-2-(pyridin-2-yl)pyrido[2,3-d]pyrimidine (0.050 g, 0.21 mmol) and 2,5-dimorpholinopyridin-3-amine (0.061 g, 0.23 mmol) in N,N-dimethylformamide (2.0 mL) was added 60% sodium hydride (9.23 mg, 0.23 mmol). The reaction was heated to 60° C. Stirring continued overnight. The reaction was cooled to rt and water was added to quench. The reaction was extracted with EtOAc (3×10 mL). The combined organic layer were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0 to 30% MeOH in DCM) to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-2-(2-pyridinyl)pyrido[2,3-d]pyrimidin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 9.75 (1H, d, J=2.7 Hz), 9.36 (1H, br. s.), 9.23 (1H, dd, J=4.4, 1.7 Hz), 8.87 (1H, d, J=8.0 Hz), 8.70 (1H, m), 8.30 (1H, dd, J=8.2, 1.8 Hz), 7.91 (1H, m), 7.84 (1H, d, J=2.7 Hz), 7.62 (1H, dd, J=8.2, 4.3 Hz), 7.42-7.49 (1H, m), 3.94-4.04 (8H, m), 3.43-3.55 (4H, br m), 3.09 (4H, br. m.). Mass Spectrum (ESI) m/e=471.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C1COCC1>[OH:32][C@H:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c([C@H](C)O)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of (S)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (70 mg, 0.16 mmol) in THF (2 mL) was added DIPEA (30 μL, 0.17 mmol) and isobutyryl chloride (17 μL, 0.16 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) then (Si—PCC, MeOH:DCM, 0-8%) affording 859 (22 mg, 27%). LCMS (method I): RT 3.46 min, [M+H]+ 519.3. 1H NMR (DMSO, 400 MHz): δ 7.95-7.95 (1 H, m), 7.70-7.69 (1 H, m), 7.30-7.26 (2 H, m), 5.59-5.57 (1 H, m), 5.39 (1 H, d, J=6.33 Hz), 4.39-4.10 (4 H, brd s), 4.34 (1 H, t, J=8.25 Hz), 4.02 (1 H, t, J=8.79 Hz), 3.95 (1 H, dd, J=8.47, 5.27 Hz), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.67-3.65 (1 H, m), 3.27-3.21 (3 H, m), 2.48-2.39 (1 H, m), 1.60 (3 H, d, J=6.48 Hz), 0.98 (3 H, d, J=1.76 Hz), 0.96 (3 H, d, J=1.78 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22](O)=[O:23])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1COCC1.[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([NH:59][CH2:58][C:57]3[CH:60]=[CH:61][C:54]([F:53])=[CH:55][CH:56]=3)=[O:23])=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc2c(o1)c(C(=O)NCc1ccc(F)cc1)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 19.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.060 g, 0.159 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.102 g, 0.318 mmol), TEA (0.032 g, 0.318 mmol), THF (5.0 mL), DMF (1.0 mL), 4-fluoro benzyl amine (0.035 g, 0.318 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 2.49 (s, 3H), 4.55 (d, J=5.4 Hz, 2H), 6.22 (s, 1H), 7.13-7.16 (m, 2H), 7.41 (m, 3H), 8.44 (s, 2H), 8.61 (s, 1H), 11.22 (s, 1H), 11.76 (s, 1H); MS [M+H]+: 484.24.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6]
Reactant: CNOC
Reactant: CC(=O)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of levulinic acid (30 g, 0.258 mol) in 850 mL CHCl3 at 0° C. was added triethylamine (43.2 mL, 0.310 mol), followed by isobutyl chloroformate (37 mL, 0.284 mol) over 15 minutes. After 30 minutes, triethylamine (57.6 mL, 0.413 mol) was added, followed by N,O-dimethylhydroxylamine hydrochloride (37.8 g, 0.387 mol) in 5 portions over 5 minutes. Vigorous bubbling ensued, and the mixture was allowed to warm to RT and stir for 1 h. The mixture was reduced to a moist solid by rotary evaporation under reduced pressure, slurried in 500 mL EtOAc, washed with 10% K2CO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-1 as a yellow oil.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:19][CH2:18]1.C1(C)C(C)=CC=CC=1>O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:6](=[O:8])[CH:3]3[CH2:2][CH:1]([CH2:5][CH2:4]3)[C:9]2=[O:11])[CH2:22][CH2:21]1
Reactant: NCCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: O=C(O)C1CCC(C(=O)O)C1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2ccc3ccccc3n2)CC1

Procedure:
1,3-Cyclopentane dicarboxylic acid (1.6 g., 10 mmole) and 1-(4-aminobutyl)-4-(2-quinolyl)piperazine (2.8 g., 10 mmole) were combined in 200 ml. of xylene and refluxed for 24 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuum and the residue redissolved in chloroform and filtered through 75 g. of silica gel. The column was rinsed with 5% ethanol/chloroform and the product-containing fractions were combined and evaporated. The residue was recrystallized from isopropanol with the addition of 4N isopropanolic HCl to give 820 mg. of the title compound as the dihydrochloride hemihydrate; m.p. 240°-242° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)=[CH2:5])C.C1C(=O)N([Br:23])C(=O)C1>C1COCC1.O>[Br:23][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc(C(=O)OC)nc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of step 1 product (780 mg, 3.76 mmol) in THF (37.5 ml) and H2O (2.5 ml) was added NBS (670 mg, 3.76 mmol) in one portion. The solution was stirred at rt for 10 min, solvent was removed and purified on silica gel column eluting a gradient of 8-75% EtOAc in hexane to afford methyl 5-(bromoacetyl)pyridine-2-carboxylate (0.92 g) LCMS: [M+H]+=258.1, 260.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[C:47]([CH2:53]CO)=[CH:46][C:34]=1[NH:35][C:36]([C:42]([F:45])([F:44])[F:43])=[CH:37][C:38]([O:40][CH3:41])=[O:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[C:47]([CH2:53][CH2:20][Cl:24])=[CH:46][C:34]=1[NH:35][C:36]([C:42]([F:43])([F:44])[F:45])=[CH:37][C:38]([O:40][CH3:41])=[O:39])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)C=C(Nc1cc(CCO)c([N+](=O)[O-])cc1OCc1ccccc1)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C=C(Nc1cc(CCCl)c([N+](=O)[O-])cc1OCc1ccccc1)C(F)(F)F
Reaction time: 8 h

Procedure:
Triphenylphosphine (2.57 g, 9.77 mmol), CCl4 (2.83 mL, 29.3 mmol), and dry CH2Cl2 (55 mL) were added to methyl 3-[2-benzyloxy-5-(2-hydroxyethyl)-4-nitroanilino]4,4,4-trifluoro-2-butenoate (2.10 g, 4.89 mmol) in a round bottom flask. The yellow solution was flushed with N2 and stirred overnight. The solution was checked by TLC (20% ethyl acetate/petroleum ether) and then concentrated under reduced pressure. The residue was purified on a silica gel column run in 10% ethyl acetate/petroleum ether solvent system to give methyl 3-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino]-4,4,4-trifluoro-2-butenoate. Total yield: 1.25 g (2.71 mmol, 57%). M.p.=105-110° C. TLC (20% ethyl acetate /petroleum ether) Rf320.69.500 MHz 1H-NMR (CDCl3) 10.04 (s, 1H), 7.72 (s, 1H), 7.48 (d, 7.5, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 7.14 (s, 1H), 5.63 (s, 1H), 5.23 (s, 2H), 3.80 (t, 6.5, 2H), 3.75 (s, 3H), 3.33 (t, 6.5, 2H). IR (neat) 2415, 3050, 2956, 1730, 1687, 1640, 1615, 1585, 1530, 1334, 1296, 1215, 1143, 1024, 815, 739, 696. EI-MS (relative intensity) 458 (M+, 6). Accurate mass for C20H18O5N235ClF3: calcd. 458.0856, obsd. 458.0853.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.[OH-].[Li+]>CO.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-n2cccn2)cc1
Yield: 97.2 %

Procedure:
To a solution of methyl 4-(1H-pyrazol-1-yl)benzoate of Step A (0.529 g, 2.62 mmol) in methanol (20 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.220 g, 5.23 mmol) and the reaction mixture heated to reflux for 2 hours. The cooled reaction mixture was concentrated in vacuo to remove methanol and then diluted with water (40 mL). The resulting aqueous solution was washed with diethyl ether (40 mL), then acidified to pH 3 by the addition of concentrated hydrochloric acid. The solid product was filtered and dried in vacuo at 50° C. overnight to afford the title compound (0.479 g, 97%) as a white solid, m.p. 270-272° C.