Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].I[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:15])[CH2:10]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CCOC(=O)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidin-3-yl-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) and ethyl iodoacetate (0.99 g, 4.6 mmol) in acetonitrile (30 mL) is added K2CO3 (1.5 g, 10.5 mmol) and the mixture stirred overnight at room temperature. Volatiles are evaporated under reduced pressure and the residue taken up with water and extracted twice with ethyl acetate. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The resulting material is purified via chromatography over silica gel eluting with a mixture of EtOAc/MeOH (95:5 v/v). Yield: 0.8 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:13]([O-:25])[C:14]([O:23][CH3:24])=[C:15]([CH2:17]OS(C)(=O)=O)[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>C1(C)C=CC=CC=1>[CH2:3]([O:10][C:11]1[C:12]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:13]([O-:25])[C:14]([O:23][CH3:24])=[C:15]([CH2:17][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1c(COS(C)(=O)=O)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1c(Cc2c[nH]c3ccccc23)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
300 Microliters of toluene and 3.7 mg of 60% sodium hydride were added to a mixture of 8.8 mg of 3-benzyloxy-5-mesyloxymethyl-2-isobutyl-6-methoxypyrazine 1-oxide and 8.2 mg of indole. The mixture was stirred for 16 hours at room temperature, and the reaction mixture was subjected to the same post-treatment as in Example B-1 to obtain 5.8 mg of 3-benzyloxy-5-(indol-3-yl)methyl-2-isobutyl-6-methoxypyrazine 1-oxide (Compound B-41) as colorless prismatic crystals having a melting point of 139.6°-141.9° C.
Reaction SMILES: [CH3:1][C@H:2]([C:9]([OH:11])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].Cl.O>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[OH:13][C:12]1[CH:14]=[C:15]([OH:16])[CH:17]=[CH:18][C:19]=1[C:9](=[O:11])[CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:1]
Reactant: Oc1cccc(O)c1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 110 °C
Yield: 41.3 %

Procedure:
3.0 g (20 millimols) of S-(+)-2-phenylpropionic acid was mixed with 3.3 g (24 millimols) of anhydrous zinc chloride and heated to 110° C. to dissolve the latter in the former. 2.64 g (24 millimols) of resorcinol was added to the solution and further heated to 150° C. over a period of 20 minutes while stirring the reaction mixture. The reaction mixture was then cooled to the room temperature. 10 ml of concentrated hydrochloric acid solution and 50 ml of water was added to the reaction mixture, and the reaction product was extracted for 3 times while using 50 ml of ethyl ether in each extraction operation. The extract in ethyl ether was rinsed with an aqueous solution of NaHCO3 for two times, and then rinsed with water for three times. The extract in ethyl ether was then dried by adding anhydrous Na2SO4. The drying agent was removed by filtration and ethyl ether was removed by distillation to obtain 3.6 g of a crude product. The crude product was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 2.0 g of 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenol was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([F:8])[C:3]=1[OH:9]
Reactant: Oc1c(F)cccc1F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2,6-difluorophenol (2.00 g) in acetic acid (20 ml) was added dropwise 60% nitric acid (1.20 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. After pouring into iced water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1→2/1 as an eluant to give the desired compound (1.37 g, yield 51%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)(F)F)C1
Yield: 47.3 %

Procedure:
The title compound was prepared as described in Example 103C using (S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at 40° C. for 3 hours, which was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)urea as solid (0.108 g, 47%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.39 (t, 1H), 7.32 (m, 1H), 7.20 (s, 1H), 7.01 (d, 1H), 5.89 (s, 1H), 5.06 (m, 1H), 4.03 (s, 3H), 3.41 (m, 1H), 3.18 (q, 2H), 2.9-3.08 (m, 3H), 2.44 (m, 1H), 2.2 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1ccc(-c2cc(OC)nc(-n3ccc(C(F)(F)F)n3)n2)cc1
Yield: 55 %

Procedure:
4-Methoxy-6-(4-methoxy-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307d was synthesized from compound 305 (1 g, 3.59 mmol) and (4-methoxy-phenyl)-boronic acid 306d (819 mg, 5.39 mmol), according to the procedure as described for compound 307b, as a beige solid in 55% yield. MS (ESI, EI+): m/z=351 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(OCCCC)(=O)C.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>CCCCCCC>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[O:28])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])#[N:13]
Reactant: O=C1C=CC(=O)O1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCCCOC(C)=O
Solvent: CCCCCCC
Product: N#Cc1ccc(NC(=O)C=CC(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Yield: 100.2 %

Procedure:
5-amino-2-cyanobenzotrifluoride (210.6 mmoles; 40.00 g) and butyl acetate (80 mL) were added to a 250 mL round bottom flask, followed by the addition of maleic anhydride (231.9 mmoles, 23.20 g). The resulting suspension was heated to 60° C. for 3.5 h. The reaction mixture was cooled to 25° C. and then heptane (160 mL) was added dropwise over a period of 25 minutes. The resulting suspension was filtered and washed with a mixture of 4:1, hepatane:butyl acetate (30 mL) and heptane (45 mL). The cake was dried in vacuo to give 60 g (95% yield) of compound 516A.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C@@H:11]([O:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]=1[O:20][CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>C(O)C>[CH3:21][O:20][C:6]1[C:7]([C@@H:11]([O:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:22]=[C:23]([NH2:25])[S:24][CH:2]=1
Reactant: CCCCCC[C@H](OC)c1cccc(C(=O)CCl)c1OC
Reactant: NC(N)=S
Solvent: CCO
Product: CCCCCC[C@H](OC)c1cccc(-c2csc(N)n2)c1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
(S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11) obtained in the third step was dissolved in ethanol (30 ml,), thiourea (1.4 g) was added, and the mixture was stirred at 100° C. for 3 hours. Extraction with toluene and purification by silica gel chromatography afforded (S)-4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazole-2-amine (12, 4.22 g, yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[Br:19]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Oc2ccccc2)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 22.68 g of methyl[p-(phenoxy)phenyl]acetate, 17.195 g of N-bromosuccinimide and 20 drops of carbon tetrachloride saturated with HBr in 300 ml of carbon tetrachloride is heated at reflux for 28 hours. After cooling, the mixture is filtered through aluminum oxide, concentrated and distilled at 0.15 mm to give the product as a colorless oil (bp 162.5°-165° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CO.[N+](=[CH:17][Si](C)(C)C)=[N-]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(I)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(4-iodophenyl)propanoic acid (commercially available) in toluene and methanol (9:1, 0.2 M) 0° C. was added (diazomethyl)trimethylsilane (1 N solution in Et2O, 2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford methyl 3-(4-iodophenyl)propanoate.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:32][CH2:33][CH:34]1[O:36][CH2:35]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>O.C(O)(C)C>[ClH:1].[OH:36][CH:34]([CH2:33][O:32][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:35][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CNCCCC[C@H](N)C(=O)O
Yield: 23.6 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 12.0 g of Nε-(2-hydroxy-3-octadecyloxypropyl)-L-lysine hydrochloride (yield 23.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl)([O-])=O.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)C>C(O)(=O)C>[N+:10]([C:6]1[C:5]2[C:4](=[N:1][N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: NNc1ccccc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nn(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 17.7 %

Procedure:
A solution of 40.6 grams of 2,6-dinitrochlorobenzene, 21.6 grams phenylhydrazine and 350 milliliters of 95% ethanol is heated at the reflux temperature for 22 hours. Then the solvent is evaporated to yield a dark oil. To the oil is added 70 milliliters of acetic acid and the mixture is heated to reflux for 6 hours. After cooling to room temperature, the crude product is collected by filtration, washed with petroleum ether and then washed with hot methanol to yield 8.5 grams (18%) of product m.p. 155°-156° C. The analytical sample is recrystallized from methanol, m.p. 155°-156° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1.O>C1COCC1>[C:1]([NH:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncnc2cc(NC(C)=O)ncc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Acetyl chloride (0.70 mL, 9.84 mmol) is added to a solution of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.20 g, 1.04 mmol) (described in a previous experimental) and Eton (1.51 mL, 10.8 mmol) in THF at 0° C., and then the mixture is stirred at 20° C. for 4 h. Water (50 mL) was added, then the solution was extracted with EtOAc (3×50 mL). Evaporation and chromatography on alumina (1% EtOH/CHCl3) yields 7-acetylamino-4-methylthiopyrido[4,3-d]pyrimidine (0.12 g, 49%) as a yellow solid. 1H NMR (DMSO) δ 11.05 (1H, s), 9.30 (1H, s), 9.02 (1H, s), 8.38 (1H, s), 2.71 (3H, s), 2.18 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16](OC)=[CH:15][C:14]=3OC)[C:10](=[O:23])[C@@H:9](CC(O)=O)[O:8][C@H:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Cl)[C:6]=2[CH:35]=1.[OH-:36].[Na+].Cl>CO>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:35][C:6]=2[C@H:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:8][C@H:9]([CH2:5][CH2:6][C:7]([OH:8])=[O:36])[C:10]1=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](CC(=O)O)O[C@H](c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC[C@H]1O[C@@H](c2ccccc2)c2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 0.5 g of ethyl ester of cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid obtained in Example 8. To the solution was added 7 ml of 1N sodium hydroxide, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was acidified with 100 ml of 1N hydrochloric acid, which was subjected to extraction with 150 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure to leave 0.46 g of cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid as plates, m.p. 112°-114° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ncccn2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl (2-pyrimidinyl)tin 54 were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 429 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc(OCc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
A mixture of 4-(pyridin-2-ylmethoxy)-benzaldehyde (29 g, 136 mmol) described in Manufacturing Example 203-1-1, nitromethane (36.6 mL, 680 mmol), ammonium acetate (21 g, 272 mmol), and acetic acid (300 mL) was stirred for 21 hours at 100° C. This mixture was cooled to room temperature and concentrated under a reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (33.9 g, 97%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([NH:28][NH2:29])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C1COCC1>[Br:13][C:14]1[C:15]2[N:16]([C:5](=[O:11])[NH:29][N:28]=2)[CH:17]=[CH:18][C:19]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(-c2ccnc(NN)c2Br)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
To a solution of triphosgene (1.50 g, 5.20 mmol) in anhydrous THF (10 mL) at 60° C. was added 4-(3-bromo-2-hydrazinylpyridin-4-yl)benzonitrile (500 mg) in small portions over 5 min. The resulting yellow suspension was then refluxed for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the THF. Water (5 mL) was added carefully to the remaining solution to destroy the excess triphosgene, then the resulting aqueous suspension was stirred at room temperature for 30 min. The suspension was filtered, and the collected solid was washed with water (10 mL×2), then dried in a 45° C. vacuum oven for 16 h to afford 575 mg of the title compound as a yellow solid. HPLC/MS: retention time=2.44 min, [M+H]+=315.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:15]1([S:21]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>[Fe].C(Cl)(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2cccs2)cc1
Reactant: ClSc1ccccc1
Agent: [Fe]
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1ccc(-c2ccc(Sc3ccccc3)s2)cc1

Procedure:
Into 150 ml of reagent carbon tetrachloride were added 29 g (0.143 mole) 2-(p-isopropylphenyl)thiophene, 17 ml (21 g, 0.145 mole) of benzenesulfenyl chloride and 0.05 g of iron powder. At the end of four days a vapor phase chromatogram of the reaction mixture showed the presence of diphenyl disulfide, unreacted 2-(p-isopropylphenyl)thiophene and the desired product. An additional 4 ml (5 g, 0.035 mole) of benzenesulfenyl chloride and 0.05 g of iron powder was added and the mixture allowed to stand another four days at room temperature. Evaporation of the carbon tetrachloride gave a residue which was twice recrystallized from 250-ml portions of petroleum ether. There was obtained 16 g (36%) of 2-(p-isopropylphenyl)-5-(phenylthio)thiophene, m.p. 61°-63° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][N:21]=1)#[N:19].CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:26][C:25]2[C:20]([C:18]#[N:19])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: N#Cc1ncccc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1cccnc1C#N)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine in CH3CN with 2-cyano-3-bromomethyl-pyridine, KI and DIPEA gave 3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridine-2-carbonitrile as a dark red oil. 1H NMR (CDCl3) δ 2.04 (s, 6H), 3.86 (s, 4H), 3.99 (s, 2H), 7.07 (m, 2H), 7.38 (m, 3H), 7.84 (d, 1H, J=9.0 Hz), 8.37 (m, 2H), 8.53 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:8])([O-])=O.O=NC1C=CC=CC=1.CO.C(Cl)(Cl)Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:8]
Reactant: O=C1Cc2cc(C(=O)c3cccc([N+](=O)[O-])c3)ccc2N1
Agent: [Pd]
Agent: O=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reaction time: 0.08 h

Procedure:
5-(3-Nitro-benzoyl)-1,3-dihydro-indol-2-one (2.0 g, 7.09 mmol) was dissolved in MeOH (600 mL). 10% Pd/C (0.20 g) was added to the flask and then placed under vacuum to remove any O2(g). The reaction mixture was kept under reduced pressure for ˜5 min and was then charged with H2(g) at atmospheric pressure. This evacuation/H2(g) fill procedure was repeated twice. The reaction mixture was stirred for 2 h at which point the starting material had been completely consumed. As the desired ketone product was prone to over-reduction to the alcohol, stopping the reaction immediately upon complete consumption of the starting material limited the amount over-reduction that occurred. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo resulting in a solid that contained the desired keto-aniline product plus ˜5% of the overreduced alcohol-aniline. Flash silica gel chromatography (5% MeOH/CHCl3) of the crude solid provided pure 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one in 72% (0.957 g, 3.80 mmol) yield.