Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[H-].[Na+].[Cl:15][CH2:16][CH2:17][CH2:18]I.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:18][CH2:17][CH2:16][Cl:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: ClCCCI
Reactant: COC(=O)Cc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCl)c1ccccc1Br
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-bromophenylacetate (2.0 g) in DMF (5 mL) was added to a suspension of sodium hydride (containing mineral oil at 40%, 384 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (1.96 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 2-(2-bromophenyl)-5-chloropentanoate. Hydrazine monohydrate (4 mL) was added to a solution of the resulting crude methyl 2-(2-bromophenyl)-5-chloropentanoate (2.895 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature for three hours. Hydrazine monohydrate (8 mL) was further added to the reaction solution, and the reaction solution was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.504 g of the crude purified title compound. The property value of the compound is as follows.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].[OH:22][CH2:23][CH2:24][CH2:25][CH:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C@@H:28]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([O:22][CH2:23][CH2:24][CH2:25][CH:26]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:27][C@@H:28]([C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])[NH:29][C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:19])=[O:20]
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CCCOS(=O)(=O)c1ccc2ccccc2c1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.68 mL, 4.90 mmol) and naphthalene-2-sulfonyl chloride (0.370 g, 1.63 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.457 g, 0.816 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-[(2-naphthylsulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.479 mg, 78%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak IC 5 μm 250×30 mm, ethanol/methanol 1:1, 30 mL/min):
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I:26][CH2:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].CCOCC>CS(C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9](=[O:16])[CH:10]([CH2:30][CH2:29][CH2:28][CH2:27][I:26])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C(CCCCI)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.5 g), 1,4-diiodobutane(0.23 ml) and potassium carbonate(1.0 g) was stirred in dimethylsulphoxide at 20° C. for 12 hours. The mixture was diluted (ether), washed (brine), dried (MgSO4), evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:3) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-(4'-iodobutyl)-4-methyl-3-oxo-pentanoate (Compound 194, 0.3 g), NMR 1.24(3H, t), 1.3-1.4(2H, m), 1.43((3H, s), 1.48(3H, s), 1.7-2.0(7H, m), 3.12(2H, t), 3.8-3.9(1H, m), 4.1-4.2(2H, m), 5.28(2H, d), 7.2-7.4(5H, m).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>CO>[CH2:13]([N:18]1[CH2:2][C:3]2([CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[O:1][C:24]1=[O:25])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1CCCC2(CO2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)CN
Solvent: CO
Product: COC(=O)C1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
To a solution containing racemic methyl 1-oxaspiro[2.5]octane-5-carboxylate (34.2 g, 201 mmol), dissolved in MeOH (540 mL) was added neopentyl amine (18.4 g, 211 mmol). The reaction was heated at reflux for 20 h. The reaction mixture was cooled to rt and concentrated to an oil. The crude material was dissolved in 1,4-dioxane (540 mL) and treated with CDI (42.3 g, 261 mmol). The reaction was again heated at reflux. After 14 h, the reaction was concentrated to a thick oil, taken up in water, and acidified to pH 3. The product was extracted into DCM (5×300 mL). The combined organics were washed with concentrated aqueous H3PO4 solution followed by brine. The organics were then dried over sodium sulfate, filtered, and concentrated to a waxy white solid. This solid was purified on a 330 g silica gel column (0-60% EtOAc/hexanes, 30 min gradient; 100 mL/min elution; 254 nm detection) to provide the title compound (40.8 g, 69.7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.38 (dd, J=8.78, 13.05 Hz, 2H), 3.01 (dd, J=14.05, 25.35 Hz, 2H), 2.17-2.28 (m, 1H), 2.02-2.12 (m, 1H), 1.98 (dd, J=2.13, 13.68 Hz, 1H), 1.71-1.86 (m, 2H), 1.54-1.65 (m, 2H), 1.29-1.47 (m, 2H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC([O-])(C)C.[K+].CN1CCCC1=O.[Cl:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][N:27]=1>CCOC(C)=O>[Cl:25][C:26]1[CH:31]=[C:30]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: Fc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccnc(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
Add 4-methyl-3-nitrophenol (6.95 g, 45.46 mmol) and t-BuOK (5.94 g, 53.03 mmol) to N-methylpyrrolidin-2-one (100 mL), stir for 30 min, then add 2-chloro-4-fluoro-pyridine (5 g, 37.88 mmol) and stir the reaction at 70° C. overnight. TLC (PE:EtOAc=3:1) shows the reaction is complete. Add water (250 mL) to the reaction mixture, extract with EtOAc (100 mL×4), combine the organic layers, wash with water, brine respectively and dry over Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (5.8 g, 58%). MS: (M+1): 265.1.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[F:13])#[N:2].[NH:27]([C:29]([O:31]CC)=O)N.[N:34]1CCCCN2CCCCC=12.[H-].[Na+]>>[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([NH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)=[N:4][C:3]([C:1]1[NH:27][C:29](=[O:31])[NH:34][N:2]=1)=[CH:12]2
Reactant: C1CCN2CCCCC2=NC1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(F)c23)C1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Temperature: 170 °C
Yield: 25.8 %

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (1.0 g, 2.81 mmol), ethyl hydrazinecarboxylate (7.74 g, 74.40 mmol) and 2,3,4,5,7,8,9,10-octahydropyrido[1,2-a][1,3]diazepine (1.13 g, 7.44 mmol) was added a catalytic amount of NaH (10 mg, 0.25 mmol). The reaction mixture was heated to 170° C. for 30 minutes. The crude product was purified by preparative HPLC to give the title compound as pale yellow solid (300 mg, 25.7%). ESI-MS m/z [M+H]+ 415.2.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:19])=[O:18]
Reactant: OCCC1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCCO1
Temperature: 25 °C

Procedure:
To an ice cooled stirring solution of 2-(tetrahydrofuran-2-yl)ethanol (1.9 g) and triethylamine (4.4 ml) in dry dichloromethane (30 ml) was added dropwise over 5 min methanesulphonyl chloride (1.59 ml). The mixture was allowed to warm slowly to ambient temperature over 16 h then washed with saturated sodium hydrogen carbonate. The aqueous layer was further extracted with dichloromethane and the combined extracts washed with brine, dried by passing through a phase separation cartridge and stripped to give the title compound as a light brown oil, yield 3.1 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.CCN(CC)CC.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=1)=[O:33]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=2)=[O:33])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COc1ccc(C(=O)CBr)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)COC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (1.0 g, 5.42 mmol) in acetonitrile (20 mL) were added Et3N (5.54 mL, 43.4 mmol) and 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.07 g, 3.65 mmol) under an inert atmosphere. The reaction mixture was then stirred at RT for 1 h and concentrated in vacuo to obtain the crude product. The crude material was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(3-chloro-4-methoxyphenyl)-2-oxoethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (750 mg, 29%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].Cl.[O:31]1[CH2:36][CH2:35][CH:34]([NH:37][NH2:38])[CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24]1[N:37]([CH:34]2[CH2:35][CH2:36][O:31][CH2:32][CH2:33]2)[N:38]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: NNC1CCOCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 388 d) was reacted with (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (CAS Reg. No. 116312-69-7) to give the title compound as brown solid. MS (ESI): m/z=520.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Nc2ccc(Cl)cc2C1(c1ccccc1)c1ccccc1

Procedure:
This compound is prepared by the method described in Helv. Chim. Acta, 1946, 29, 415-431, by the reaction of benzene with 5-chloroisatin in the presence of aluminum chloride. M.p.=281° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[NH:16][C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br.Br[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: BrCc1ccnc2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (147 mg, 296 μmol) in DMF (740 μl) was added 4-(bromomethyl)quinoline hydrobromide (135 mg, 444 μmol) and cesium carbonate (289 mg, 888 μmol). The reaction was stirred at rt for 18 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (57 mg, 30%) as a white solid. MS m/z 638 (MH)+.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].C(O)(=O)C>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.67 h

Procedure:
To β-D-glucose pentaacetate (5 g, 12.81 mmol) was added 33% HBr in acetic acid (30 mL, 192 mmol) at rt. After stirring for 40 min, the mixture was diluted with CH2Cl2 (150 mL) and washed with ice cold water until the washings were neutral pH. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.13 (s, 3H), 4.15 (d, J=11.1, 1H), 4.31-4.37 (m, 2H), 4.86 (dd, J=9.9, 4.0, 1H), 5.19 (t, J=9.8, 1H), 5.58 (t, J=9.8, 1H), 6.63 (d, J=4.0, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.CC(C)([O-])C.[K+].Cl[CH2:45][CH2:46][CH2:47][N:48]=[C:49]=[O:50]>ClCCCl.C1COCC1.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([N:1]3[CH2:45][CH2:46][CH2:47][NH:48][C:49]3=[O:50])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C=NCCCCl
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N2CCCNC2=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (97 mg) was dissolved in 1,2-dichloroethane (2 ml)-THF (2 ml), chloropropyl isocyanate (25 μl) was added, and the mixture was stirred at room temperature for 1 hr. Potassium tert-butoxide (30 mg) was added and the reaction mixture was stirred at room temperature for 8 hr, and further at 60° C. for 12 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (4 ml), sodium hydride (50% contained, 26 mg) was added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-methanol (100:0-90:10) and concentrated under reduced pressure to give the object compound (103 mg).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>C(#N)C>[F:27][C:28]([F:33])([F:32])[C@@H:29]([OH:30])[CH2:31][N:12]1[CH2:13][CH2:14][O:15][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: FC(F)(F)c1cccc(C2CNCCO2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O[C@@H](CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
In a 50 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine hydrochloride (515 mg, 1.92 mmol) and DIPEA (249 mg, 336 μl, 1.92 mmol) were combined with acetonitrile (10 ml) to give a white suspension. (S)-2-(trifluoromethyl)oxirane (323 mg, 2.89 mmol) was added. The reaction mixture was stirred at room temperature for 3 days and then was concentrated in vacuo. The reaction mixture was taken up in 100 mL dilute aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford 528 mg (80%) of (2S)-1,1,1-trifluoro-3-(2-(3-(trifluoromethyl)phenyl)morpholino)propan-2-ol, which was used as is in the next step. (M+H)+=344 m/e.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:18][NH2:19])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C.CC(O)=O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:18][NH:19][C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:27]([OH:37])=[O:26])=[CH:29][CH:30]=4)=[O:35])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NNC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(=O)NNC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid hydrazide (0.022 g, 0.068 mmol) and methyl-4-chlorocarbonylbenzoate (0.013 g, 0.068 mmol) were stirred in DMF (1 mL) in the presence of DIEA (0.018 g, 0.14 mmol) for 2 h. An aqueous solution of NaOH (2.5 N, 0.22 mL, 0.55 mmol) was then added and the mixture was stirred for 2 h at room temperature. The reaction mixture was acidified by the addition of AcOH and purified by reversed phase C18 preparative HPLC to give the title compound of example 143.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH:16]=O>>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: NCCCO
Product: OCCCNCc1ccc2ccccc2n1

Procedure:
prepared by reaction of 3-amino-propan-1-ol with quinoline-2-carbaldehyde
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)CC(=O)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(=O)CC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of Toluene. to the stirred solvent was added methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (0.2 g, 1.036 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.82 mmol) was added Tributyl phosphine (0.271 g, 1.324 mmol) and 1,1′-(Azodicarbonyl)di-Piperidine portion wise at 0° C. (0.339 g, 1.346 mmol). Then the reaction mixture was stirred at RT for 12 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated and extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.05 g Yield: 14%) MS (ESI, 120 eV): m/z=448.1 (M+H)+.