Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:20]I.[H-].[Na+]>CN(C=O)C>[CH3:20][O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution of methyl 2-hydroxy-4-benzyloxybenzoate (50 g, 194 mmol) in dry DMF (500 mL) was added methyl iodide (30 mL, 2.5 eq) and the solution was cooled to 0° C. under argon. The solution was stirred at 0° C. and sodium hydride (60% dispersion in mineral oil, 12 g, 1.5 eq) was added in several portions over 15 minutes. The reaction was allowed to warm to ambient temperature with stirring over 18 hours. The reacton was quenched with 12 mL of acetic acid and the solvent was removed under reduced pressure. The residue was partitioned between methylene chloride (700 mL) and saturated sodium bicarbonate (700 mL) and the organic layer was washed with water (2×700 mL), brine, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to give methyl 2-methoxy-4-benzyloxybenzoate as a crystalline solid in 90% yield.
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([CH3:26])[C:23]([O:25][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:24])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(C)C(=O)O
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(C)C(=O)OCC(O)CO
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 2-(4-tetradecenylamino)phenylpropionic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([Cl:19])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClSCl
Reactant: COc1ccc(C(=O)O)cc1OC1CCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reaction time: 5 h
Yield: 98 %

Procedure:
54 g of 3-cyclopentyloxy-4-methoxybenzoic acid was added to 30 ml of thiochloride and was stirred for 5 hours. 50 ml of toluene was added to the reaction solution and was concentrated under reduced pressure to obtain 58 g of the dense brown title compound (yield: 98%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[NH2:6].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:37](O)=[O:38])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[CH3:2][O:3][C:4](=[O:13])[CH:5]([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[NH:6][C:37](=[O:38])[C@H:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[NH:24][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: COC(=O)C(N)Cc1cccs1
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 73.6 %

Procedure:
A mixed solution of 1.11 g (5 mmole) of 3-(2-thienyl)-DL-alanine methyl ester hydrochloride and 1.75 g (5 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine in 15 ml of dimethylformamide was cooled with ice water, and then 1.11 g (11 mmole) of triethylamine was added with stirring. After that, 0.83 g (5 mmole) of diethyl phosphorocyanidate was added, and the mixture was stirred for 3 hours at room temperature. Subsequently, the reaction product was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water, then dried, and finally purified by thin layer chromatography, yielding 1.9 g (73.6%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine methyl ester melting at 140°-141° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1Br)(=[O:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:24]=[CH:23][N:22]=[CH:21]1.C1(C)C=CC=CC=1>[Cl-].[Zn+2].[Cl-].[O-2].[Zn+2].C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:31][C:28]1[CH:27]=[CH:26][C:25]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:30][CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Br
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [Cl-]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-n2ccnc2)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture of 3 g (22 mmol) of zinc chloride, 5 g of 4 Å molecular sieve, 6.5 g of zinc oxide, 9 g (25 mmol) of 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranosyl bromide, 3.2 g (20 mmol) of 4-(1H-imidazol-1-yl)phenol, 70 ml of toluene and 70 ml of acetonitrile is prepared. The mixture is kept stirred at 55° C. for 24 hours and then cooled and filtered. The residual solid is rinsed on the filter with ethyl acetate and the combined filtrates are successively washed with water, with an N sodium hydroxide solution and again with water to neutral pH. The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel, elution being carried out using an ethyl acetate/ethyl ether mixture (8/5; v/v). The expected compound is thus obtained in the form of a pulverulent solid which is reacted further in order to obtain the nonacetylated xyloside.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]OS(C)(=O)=O)=[CH:7][CH:6]=2)#[N:2].[CH3:25][NH2:26]>>[CH3:25][NH:26][CH2:13][CH:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:1]#[N:2])=[CH:11]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1
Reactant: CN
Product: CNCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1

Procedure:
A mixture of methanesulfonic acid 2-(2-cyano-1H-indol-5-yl)-2-phenyl-ethyl ester CCLXXI (0.24 g) and a solution of methylamine (33% in EtOH, 15 mL) was heated at reflux for 2 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/(DCM+MeOH+NH4OH 60/10/1), 70/30 to 50/50) to give 80 mg of 5-(2-methylamino-1-phenyl-ethyl)-1H-indole-2-carbonitrile CCLXXII as a light yellow foam. MS=290 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:12])[NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CN(C=O)C.[C:18]1([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:11]1[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH:9]=[C:10]1[CH3:12]
Reactant: COc1nccc2[nH]c(C)cc12
Reactant: BrCc1ccccc1-c1ccccc1
Solvent: CN(C)C=O
Product: COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of intermediate (3) (0.70 g, 4.69 mmole) in anhydrous DMF (40 mL) sodium hydride (60% in mineral oil, 0.28 g, 7.04 mmole) was added, the mixture was stirred for 1 h. To the mixture 2-phenylbenzyl bromide (0.95 mL, 5.16 mmole) was added dropwise. The mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated ammonium chloride solution (200 mL), the mixture was extracted with ethyl acetate (3×200 mL). The organic layer was separated and washed with water, dried over magnesium sulphate and concentrated. The residue was purified by column chromatography (3:1 Hex:EtOAc) to afford intermediate (4) as a yellow solid. Yield: 1.1 g 71%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([I:13])[CH:4]=1.O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([I:13])[CH:4]=1)=[O:1]
Reactant: CC(=O)Nc1ccc(CO)cc1I
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of IBX (0.93 g, 3.3 mmol) in dimethylsulfoxide (3.5 mL) was added N-(4-hydroxymethyl-2-iodo-phenyl)-acetamide (0.87 g, 3.0 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added and the solid was separated by filtration, and washed with ethyl acetate (20 mL). The filtrate was collected and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave N-(4-formyl-2-iodo-phenyl)-acetamide as a light brown solid. Yield: 0.82 g (95%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:34]O)[C:22]1[C:31]([F:32])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:33])[CH:23]=1>>[Cl:33][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:34]=2)[C:31]([F:32])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc(F)c(C(N)=NO)cc1Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cc(Cl)c(C(=O)OC)cc3F)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (230.67 mg; 0.90 mmol) and Intermediate 55 (184.97 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1). The white solid was washed with MeOH affording the title compound as a white powder. 1H NMR (CDCl3, 300 MHz) δ 8.44-8.43 (m, 1H), 8.35 (d, J=6.1 Hz, 1H), 8.18 (dd, J=7.9, 1.8 Hz, 1H), 7.77 (d, J=10.1 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.32-7.24 (m, 3H), 7.13 (d, J=7.2 Hz, 1H), 4.27-4.18 (m, 2H), 3.99 (s, 3H), 3.34 (s, 3H), 2.08 (s, 3H). LC/MS (Method B): 467.1 (M+H)+. HPLC (Method A) Rt 6.09 min (Purity: 98.8%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:17])=[O:16]
Reactant: c1c[nH]cn1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Imidazole (5.00 g, 73.6 mmol) was dissolved in toluene (80 ml), and thereto were added triethylamine (9.52 ml, 68.4 mmol) and dimethylsulfamoyl chloride (6.77 ml, 63.3 mmol), and the mixture was stirred at room temperature for 8 hours. The precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to azeotropic distillation with hexane to give the title compound (10.9 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][CH:9]=1.[Br:14]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][N:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(-c2ccccc2Cl)s1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccccc1-c1cnc(CBr)s1
Temperature: 25 °C

Procedure:
180 mg (0.86 mmol) of the compound from Example 75A together with 229 mg (1.29 mmol) of N-bromosuccinimide and 14 mg (0.09 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride were heated under reflux for 8 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 66 mg (27% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[C:9]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1.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.[NH2:60][C:61]1[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=3)=[O:14])[CH:10]=[C:9]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1
Reactant: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 2-(methoxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylic acid (130 mg, 0.345 mmol) in DMF (5 mL) was added HATU (263 mg, 0.691 mmol) and DIEA (89.3 mg, 0.691 mmol). After stirring the solution at 0° C. for 15 minutes, 2-amino-5-methylpyridine (74.7 mg, 0.691 mmol) was added. The solution was warmed gradually to room temperature and stirred for 14 h. The reaction was concentrated under high vacuum, and the product was purified by reverse phase HPLC to give the title compound (88 mg, 55%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.36 (s, 3 H) 3.07 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.59 (s, 1 H) 7.07-7.18 (m, 2 H) 7.53 (d, J=1.32 Hz, 1 H) 7.74 (dd, J=8.67, 1.32 Hz, 1 H) 7.85-7.95 (m, 2 H) 8.00 (s, 1 H) 8.09 (s, 1 H) 8.22 (d, J=8.67 Hz, 1 H) 9.10 (s, 1 H). LCMS m/z 467.20 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[CH:43][C:42]=1[C:50]1[CH:51]=[N:52][C:53]([N:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65](O)=[O:66])[CH:63]=3)[C:58]([S:68][CH3:69])=[CH:57]2)=[N:54][CH:55]=1>CN(C=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[CH:43][C:42]=1[C:50]1[CH:51]=[N:52][C:53]([N:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:66])[CH:63]=3)[C:58]([S:68][CH3:69])=[CH:57]2)=[N:54][CH:55]=1
Reactant: C1COCCN1
Reactant: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1cn(-c2ncc(-c3cc(C(C)O)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HATU (0.38 g, 0.99 mmol), diisopropylethylamine (0.41 mL, 2.48 mmol) and morpholine (0.08 mL, 0.99 mmol) were added at 0° C. to a solution of 300b) (0.35, 0.83 mmol) in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 6 h and then quenched with ice-cold water. The mixture was extracted with dichloromethane (2×50 mL), the combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The remnant was purified by flash column chromatography [silica, dichloromethane with 1.5% methanol]. White solid. Yield: 0.32 g (80% of theory)
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[O:5].[CH3:15][Mg]Br.CO.[NH4+].[Cl-]>C1COCC1>[OH:5][CH:4]([C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]([CH3:14])[CH3:1])[CH3:15]
Reactant: CC(C)[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(C)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (2.5 g, 12.42 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Methyl magnesium bromide (17.0 mL, 51.0 mmol, 3.0 M in diethyl ether) was carefully added via syringe. The reaction was allowed to warm to ambient temperature and left stirring overnight. The cloudy mixture was chilled to 0° C., quenched with methanol (3.0 mL, 74.0 mmol), followed by the addition of 200 mL saturated NH4Cl solution, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL brine, dried over Na2SO4, filtered, and concentrated to provide the title compound (2.484 g, 11.43 mmol, 92% yield) as a yellow oil. MS (DCI+) m/z 218.1 (M+H).
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[NH:11][C:12]2=[O:18])=[CH:7][CH:6]=1)(=O)C.OS(O)(=O)=O>>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[NH:11][C:12]2=[O:18])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Agent: O=S(=O)(O)O
Product: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Temperature: 70 °C
Yield: 99 %

Procedure:
7-Acetamido-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione (4.0 g, 13.7 mmol) was added to 90% H2SO4 and heated at 70° C. for 8 h. The cooled mixture was poured onto ice. The precipitate was collected, dissolved in ethyl acetate, washed with water, dried and evaporated to give 7-amino-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione (3.38 g, 99%), mp 259-263° C.; MS (CI) 250 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 83 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.47 (m, 3H), 3.63-3.73 (m, 7H), 4.13 (s, 4H), 6.67 (d, J=8.4 Hz, 2H), 7.01-7.12 (m, 1H), 7.30-7.33 (m, 1H), 7.48-7.62 (m, 3H), 8.21 (dd, J=4.8 and 1.5 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13]>>[CH2:1]([C:4]1[C:5]([OH:10])=[CH:6][C:7]2[C:12]([CH3:20])([CH3:13])[CH2:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:8]=2[CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccccc1O
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Product: CCCc1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a), by the reaction of 13.6 g (0.1 mol) of 2-n-propylphenol with 18.3 g (0.1 mol) of 2,5-dichloro-2,5-dimethylhexane, 11.6 g (65%) of the expected phenolic derivative of melting point 96-7° C. were obtained after chromatography on a silica column eluted with dichloromethane.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:16]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
The title compound was prepared by a similar method to example 5 from tert-butyl trans-4-aminocyclohexylcarbamate (1.0 g, 4.7 mmol) (J. Org. Chem. 8811, 61, 1996), benzaldehyde (530 mg, 5 mmol) and sodium triacetoxyborohydride (2.0 g, 9.4 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (0.73 g) as a solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH:10][CH:11]([CH2:13][CH3:14])[CH3:12])[N:7]=[C:6]([O:15]CC2C=CC=CC=2)[CH:5]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH:11]([NH:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([OH:15])[N:7]=1)[C:3]([OH:23])=[O:2])([CH2:13][CH3:14])[CH3:12]
Reactant: [H][H]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)Nc1cc(C(=O)O)cc(O)n1

Procedure:
Treat a solution of 2-benzyloxy-6-sec-butylamino-isonicotinic acid methyl ester (340 mg, 1.036 mmol) in methanol (15 mL) and ethyl acetate (5 mL) with 10% Pd/C (150 mg). Stir the mixture under a balloon containing hydrogen gas for 2.5 h. Filter through a filtering agent, wash with ethyl acetate and concentrate to give the title compound which is used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9][CH2:8]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9][CH2:8]1)=[O:48]
Reactant: Cn1ncc(N)c1N1CCC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](N)CC1
Yield: 25 %

Procedure:
Following the procedures as described in Example 140, (S)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 139 as a white solid (42 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 7.62-7.44 (m, 4H), 7.28 (t, J=8.7, 2H), 3.66 (d, J=17.1, 3H), 3.21-2.93 (m, 5H), 1.93-1.73 (m, 3H), 1.69-1.40 (m, 3H). ESIMS m/z=448.1 (M+1)