Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl.[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH2:71].O>C(Cl)Cl>[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH:71][C:27](=[O:28])[C:26]([C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:22][CH:23]=1)=[N:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC1C(=O)NC1CCl
Reactant: O=C(O)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: O=C(NC1C(=O)NC1CCl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 1.527 g of the syn isomer of sodium 2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetic acid, 419 mg of tosyl chloride and 15 ml of methylene chloride was stirred for 40 minutes and then a solution of 342 mg of 4-chloromethyl-3-amino-2-oxo-azetidine hydrochloride in 15 ml of methylene chloride and 0.6 ml of triethylaime was added thereto. The mixture was stirred for 2 hours and water was added thereto with stirring. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with ether to obtain 736 mg of syn isomer of 4-chloromethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetamido]-2-oxo-azetidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.O1CCOCC1>[O-2].[O-2].[Mn+4].C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (1.68 g, 3.53 mmol, Intermediate 8: step a) was added 1,4-dioxane (75 mL) and THF (10 mL) which produced a suspension at room temperature. Warming to 45° C. formed a homogeneous solution. Then, manganese dioxide (1.5 g, 17.25 mmol) was introduced and the mixture was heated to 80° C. After 60 minutes, the contents were filtered through a Celite® pad, rinsing with THF, and then the solution was concentrated. Trituration with Et2O provided the title compound as a white powder.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[O:19][C@@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(OCC)(=O)C>CC(=O)CC>[O:19]1[CH2:17][C@H:18]1[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Yield: 57.4 %

Procedure:
A mixture of sesamol (2.49 g, 18.02 mmol), potassium carbonate (2.74 g, 19.83 mmol) and (2S)-(+)-glycidyl-3-nitrobenzenesulfonate (4.67 g, 18.02 mmol) in 2-butanone (50 mL) was heated to reflux for 18 h. To the cooled reaction mixture was added 35 mL of ethyl acetate and the solids were remove by vacuum filtration. The filtrate was evaporated in vacuo and the residue was taken up into ethyl acetate (65 mL). The solution was washed with aqueous sodium bicarbonate (2×), and water (2×), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 50% diethyl ether/hexane) to leave 2.01 g of the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].N1[C:62]([CH3:63])=[CH:61]C=CC=1C.FC(F)(F)S(O[Si:71]([CH:78]([CH3:80])[CH3:79])([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:74])[CH3:73])(=O)=O>CCCCCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:71]([CH:78]([CH3:80])[CH3:79])([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:74])[CH3:73])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:71]([CH:62]([CH3:61])[CH3:63])([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:74])[CH3:73])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: Cc1cccc(C)n1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCCCCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C(C)C)(C(C)C)C(C)C)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (7.0 g, 8.84 mmol) containing 2,6 lutidine (3.7 g, 34.6 mmol) was cooled to 0° C. and treated with triisopropylsilyl trifluoromethanesulfonate (11.06 g, 36.0 mmol). After stirring at RT for 16 hr, the reaction mixture was diluted with n-hexane (400 ml). The suspension was filtered and the filtrate passed over SiO2 (760 g). Elution with n-hexane/ethyl acetate (3:1) yielded 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (9.18 g, 94%) as a foam. Mass Spec (C61H109NO12Si2)(1104.72) FAB+Li:1110 (M+Li), 745, 720, 695, 266.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)c(F)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(Br)c(F)c1

Procedure:
To 1-bromo-2-fluoro-4-hydroxybenzene (100 g, 0.52 mol) and K2CO3 (179.4 g, 1.3 mol) in 1300 mL acetone was added dimethyl sulfate (98.38 g, 0.78 mol). After refluxing overnight, the reaction mixture was cooled, filtered and dried over Na2SO4, and the filtrate was concentrated to afford 1-bromo-2-fluoro-4-methoxybenzene as a brown oil.
Reaction SMILES: O1C(C)C1.[H-].[Na+].[CH2:7]1[O:9][CH:8]1[CH2:10][OH:11].C(S([C:17]1[S:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[O:23])=[CH:20][N:21]=1)(=O)=O)C>O1CCCC1>[O:9]1[CH:8]([CH2:10][O:11][C:17]2[S:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)=[O:23])=[CH:20][N:21]=2)[CH2:7]1
Reactant: CCS(=O)(=O)c1ncc(C(=O)NCCC23CC4CC(CC(C4)C2)C3)s1
Reactant: OCC1CO1
Agent: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cnc(OCC2CO2)s1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
This example illustrates further processes of the invention for preparing the 1,2-epoxypropane compounds of formula B. In this example 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfonyl-5-[2-(adamant-1-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained at 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under dryness affording oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate- 60% hexane, by vol., affording 1,2-epoxy-3-[5-(2-[adamant-1-yl]ethylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]1([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1
Yield: 69.3 %

Procedure:
4-Chloro-3-nitropyridine (1.50 g, 9.46 mmol) and aniline (2.0 ml, 21.9 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto, followed by reaction at 80° to 90° C. for 2 hours. Then, the solvent was removed by distillation under reduced pressure, and 10 ml of hexane was added to the residue to wash it. The solvent was removed by decantation. The residue was further similarly treated with 10 ml of ether. The residue was purified by silica gel column chromatography [eluent: hexane:ethyl acetate=2:1 (v/v)] to obtain 1.41 g of a yellow solid (yield: 68.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].O>C(O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)cn1
Yield: 95.1 %

Procedure:
To a solution of 5-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was added sodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45 minutes 0.5 mL water was added and the mixture and evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridin-2-yl)-methanol (4.81 g, 86%) as pale-yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[NH2:1]
Reactant: CCC(=O)Nc1ccc(OC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: CCC(=O)Nc1ccc(OC)c(N)c1
Reaction time: 1 h

Procedure:
114 parts of 2-nitro-4-propionamidoanisole, 160 parts of methanol, 2.5 parts of a 30% aqueous solution of ammonia and 1 part of a 50% suspension of palladium on activated charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 18 bar and a temperature of 80° C., hydrogenation is carried out for 1 hour. 2-Methoxy-5-propionamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.O1CCOCC1>C(O)(=O)C.O1CCCC1.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(C=CC(=O)O)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 272.6 %

Procedure:
Cyclobranyl ester of p-nitrocinnamic acid (165.0 g, 0.268 mole) prepared according to the procedure of Example 103 was suspended in a mixture of acetic acid (1.5 l) and tetrahydrofuran (2 l). To the suspension were added 6N-HCl-dioxane (125 ml) and zinc powder (165 g) and the mixture was stirred at 20° C. for 2 hours. Then the reaction mixture was filtered to remove zinc powder. The filtrate was concentrated under reduced pressure, and the residue was extracted with chloroform. The extracts were washed successively with water and saturated aqueous NaHCO3, then dried, and concentrated in vacuo. The residual crystals were recrystallized from chloroform-ethanol (1:3, v/v), giving cyclobranyl ester of p-aminocinnamic acid (119.2 g), in a 75.9% yield. m.p. 206°-207° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][C:7](=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>O.C(O)(=O)C.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[Cl:5][CH2:6][C:7](=[O:16])/[C:8](=[N:1]/[OH:3])/[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=N\O)C(=O)CCl
Yield: 91 %

Procedure:
A solution of 35.6 g of sodium nitrite in 100 ml of water was added to a cold solution of t-butyl 4-chloro-3-oxobutanoate (100.9 g, 0.439 moles of 84% material*) in 400 ml of acetic acid containing 50 ml of water over a 0.5 hour period with stirring. The mixture was stirred in the cold for an additional hour, then stored in the cold overnight. The mixture was diluted with 500 ml portions of water, 500 ml of saturated sodium bicarbonate, 500 ml of water and 500 ml of brine, then dried over magnesium sulfate and evaporated to give an amber oil; yield 88.6 g (91% yield). This material was used in the next step without further purification. *This compound was obtained from Lonza Chemical Co., Fair Lawn, N.J.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CO)c(C)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cnc(C=O)c(C)c1

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-yl)-methanol (2.12 g, 15.45 mmol) (Weidmann, K. et al. J. Med. Chem. 1992, 35, 438-450) in CH2Cl2 (50 mL) was added MnO2 (9.41 g, 108.18 mmol) and the reaction mixture was refluxed overnight. Then it was cooled and the mixture was filtered through a layer of celite. The filtrate was concentrated to afford a brown/yellow oil. Purification by flash column chromatography on silica gel using 30% EtOAc/hexane afforded 3,5-dimethyl-pyridine-2-carbaldehyde as a yellow oil (960 mg, 31% over 3 steps). 1H NMR (CDCl3) δ 2.39 (s, 3H), 2.62 (s, 3H), 7.41 (s, 1H), 8.47 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClC(Cl)C>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1

Procedure:
Using similar reaction conditions as described in step-iii of example-133, tert-butyl 4-oxopiperidine-1-carboxylate (3 gm, 15.0 mmol) and 4-bromoaniline (2.59 gm, 15.0 mmol) were reacted using Na(OAc)3BH (105 mg, 0.494 mmol) and 3 drops of acetic acid in dichloroethane (80 mL) to afford 6.7 gm (crude) of the titled compound. MS: m/z=256.8 (M-Boc+1).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[Sn:15](C)C.C[Sn](C)C>>[CH3:11][C:9]1([CH3:12])[C:8](=[O:13])[C:7]2[C:2]([Sn:15])=[CH:3][CH:4]=[CH:5][C:6]=2[O:10]1
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
Reactant: C[Sn](C)C
Product: CC1(C)Oc2cccc([Sn])c2C1=O

Procedure:
In a slight variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridines described above, using a method taught by A. Pidcock et al (J. Organometallic Chem. 1981, 215, 49-58), 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone is reacted with hexamethylditin in the presence of tetrakis(triphenylphosphine)palladium(0)in toluene, yielding (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)tin. The organometallic derivative is then reacted with 2-amino-3-cyano-5-iodo-4-methylpyridine, again in the presence of tetrakis(triphenylphosphine)palladium(0) in toluene, affording the corresponding 2-amino-3-cyano-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-4-methylipyridine. This compound is then cyclized with guanidine in ethanol, as previously described, yielding the corresponding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-5-deazapteridine. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([O:11][CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1>CS(C)=O.Cl>[F:10][C:8]1[CH:7]=[C:6]([O:11][CH3:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([OH:1])[CH:9]=1
Reactant: [OH-]
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Yield: 50.5 %

Procedure:
In 10N NaOH (13.1 ml, 131 mmol) and DMSO (25 ml), 3,5-difluoro-2-nitroanisole (8.29 g, 43.8 mmol) was stirred at 50° C. for 5 hours. After cooling, the reaction mixture was poured in 1N HCl (200 ml), followed by extraction with ethyl acetate (300 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, the title compound (4.14 g, 51%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (3.00 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (5.41 g; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 17 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH− 479.4
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@H:11]([NH2:13])[CH3:12].ClC1N=C(Cl)C(F)=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH2:13])[CH3:12]
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Agent: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(N)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-(+)-1-(2-napthyl)ethylamine (102.6 mg, 0.599 mmol), 2,4-dichloro-5-fluoro pyrimidine (100 mg, 0.599 mmol) and cesium carbonate (390 mg, 1.2 mmol) was dissolved in 1,4-dioxane (3 ml) and H2O (3 ml) in a 10 ml microwave vial. The mixture was stirred in the microwave reactor at 80° C. for 10 minutes. The residue was dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to get the crude intermediate 2-chloro-5-fluoro-pyrimidin-4-yl)-(1-naphthalen-2-yl-ethyl)-amine.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](O)[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C@@H]1[C@@H](OCC2C=CC=CC=2)[C@@H](OC(F)(F)F)[C@@H](C(=S(=O)=O)OCC2C=CC=CC=2)O[C@@H]1OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:36]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CO[C@H]1O[C@H](C(OCc2ccccc2)=S(=O)=O)[C@H](OC(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OS(=O)(=O)C(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml) cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.87 ml). The mixture is stirred during 15 min at -10° C., then methyl 2,3,6-tri-O-benzyl-α-D-galacto-pyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 ml) is added (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull. Chem. Soc. Jpn., 56, 2849 (1983)). The mixture is washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford an oil which is the expected trillate methyl 2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D-galactopyranoside.