Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:22][Si:23]([CH3:37])([CH3:36])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.C([O-])(O)=O.[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([C:32]3[N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:37])([CH3:36])[CH3:22])[N:29]=[CH:30][CH:31]=3)[C:3]=2[N:11]=[N:10]1)([O-:21])=[O:20]
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2c1nnn2Cc1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
A solution of 7-chloro-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (306 mg, 1 mmol), 1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-ylboronic acid (2 mmol), Pd(PPh3)4 (100 mg) and saturated NaHCO3 (5 mL) in THF (20 mL) was refluxed for 2 h, diluted with water (20 mL), extracted with EtOAc(2×20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2:EtOAc (6:1)] to give 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 34%) as a pale yellow syrup.
Reaction SMILES: C(O)C.C(Cl)(=O)C.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21]([C@H:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH3:19])=[CH:14][CH:13]=1)=[O:11]>C(OCC)(=O)C>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][C@H:23]([C:21]([NH:20][C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([O:9][CH3:8])=[O:11])=[CH:17][CH:16]=2)[CH3:19])=[O:22])[NH:24]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Cool a mixture of ethyl acetate (214 mL) and ethanol (87.6 mL, 1.51 mol) to 0° C., and then add acetyl chloride (97.4 mL, 1.37 mol) in a dropwise fashion. Stir the mixture for 30 minutes while allowing it to warm to room temperature. Add a solution of tert-butyl (3R)-3-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (60 g, 137 mmol) in ethyl acetate (480 mL), and then stir the resulting mixture at 40° C. overnight. Cool the mixture to room temperature, then isolate the resulting precipitate by filtration, and dry under reduced pressure. Add water (300 mL) to the solid, and then add a 32% aqueous ammonia solution until the pH of the mixture reaches 10. Isolate the suspended solids by filtration, then dry them in a vacuum oven at 45° C. overnight to furnish the title compound as a white solid (44 g, 95% yield). Mass spectrum (m/z): 339 ([M+H]+), 677 ([2M+H]+), 699 ([2M+Na]+).
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10](#[N:13])[CH:11]=[CH2:12].[C:14](OOC1(OOC(C)(C)C)CC(C)CC(C)(C)C1)(C)(C)C.C(OOC(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[CH3:12][C:11](=[CH:14][CH:3]=[CH:2][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]#[N:13]
Reactant: C=C(C)c1ccccc1
Reactant: CC1CC(C)(C)CC(OOC(C)(C)C)(OOC(C)(C)C)C1
Reactant: C=CC#N
Agent: CC(C)(C)OOC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C#N)=CC=Cc1ccccc1

Procedure:
70 parts by weight of alpha-methylstyrene, 30 parts by weight of acrylonitrile, 5 parts by weight of toluene, 0.135 parts by weight of 1,1-bis (tert-butylperoxi)-3,3,5 trimethylcyclohexane and 0.015 parts by weight of di-tert-butyl peroxide were homogenously mixed and continuously introduced to the reactor. The polymerization was carried out as the reaction temperature was kept at 110° C. After completion of the polymerization, the resulting polymer was supplied to a vaporizer equipped with a heat exchanger, kept at a temperature of 250° C. and a pressure of 20 Torr, in which non-reacted monomers and solvents were removed. Then, the polymer was palletized through an extruder equipped with a discharge pump. The alpha-methylstyrene-acrylonitrile copolymer prepared by the above method had an average molecular weight of 9.5×104 and a glass transition temperature (Tg) of 125° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:26][C:27]([NH2:29])=[O:28])=[C:12]([CH3:25])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[OH-].[Na+]>CCO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[N:13]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:12]=1[CH3:25]
Reactant: CCOC(=O)CCCOc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(CC(N)=O)c2c(OCCCC(=O)O)cccc2n1Cc1ccccc1
Yield: 42.9 %

Procedure:
A solution of 100 mg (0.245 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid ethyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 3.0 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and on concentrating at reduced pressure a precipitate formed that was separated and washed with MeOH to give 40 mg (42% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]butanoic acid, mp, 192-193° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:12]#[N:13])#[N:2]
Reactant: CC(C)(C)c1ccccc1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Product: CC(C)(C)c1ccccc1Oc1ccc(C#N)c(C#N)c1
Yield: 79.7 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 3.0 grams of 2-t-butyl-hydroxybenzene, there was obtained 2.2 grams of 1,2-dicyano-4-(2-t-butylphenyloxy)benzene (yield of 80%). Next, as in Synthesis Example 1 but using 1.38 grams of this benzene compound and 0.42 gram of BBr3, there was obtained 0.77 gram of the end product (yield 50%, mp 163°-165° C.).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[O:8][C:7]2[C:2]([N:25]3[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:22][CH2:23][CH2:24]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: Brc1ncccc1OC(c1cccnc1)c1cccnc1
Reactant: c1ccc2c(c1)NCCO2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1cncc(C(Oc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1

Procedure:
To a solution of 2-bromo-3-(dipyridin-3-ylmethoxy)pyridine (150 mg, 0.438 mmol) and 3,4-dihydro-2H-1,4-benzoxazine (59 mg, 0-438 mmol) in dry dioxane (5 mL) was added sodium t-butoxide (63 mg, 0.658 mmol), bis(tri-t-butylphosphine)palladium(0) (22 mg, 0.044 mmol). The mixture was heated to 100 C for 6 h. The reaction was cooled, diluted with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 4-[3-(dipyridin-3-ylmethoxy)pyridin-2-yl]-3,4-dihydro-2H-1,4-benzoxazine (2-3). LRMS m/z (M+H) Calcd: 397.5, found: 397.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2[OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8].C[N:19]=[C:20]=[O:21].[CH3:22]OCCOC>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:17])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]2([O:14][C:20](=[O:21])[NH2:19])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCCOC
Reactant: CN=C=O
Reactant: CC1=C(C)C(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Solvent: CCN(CC)CC
Product: CC1=C(C)C(C)(OC(N)=O)N(c2ccc(Cl)c(Cl)c2)C1=O
Reaction time: 24 h

Procedure:
16.3 g of N-(3',4'-dichlorophenyl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (see Example 3) is put together with 2 drops of triethylamine in 10 ml of glyme (ethylene glycol dimethyl ether), and 3.8 g of methylisocyanate is then added. After 24 hours, the reaction solution is filtered with a filtering auxiliary (Hyflo®) and the filtrate is concentrated by evaporation to leave an oil, which is crystallised in methanol. In this manner is obtained 15 g (76% of theory) of the above product in the form of yellowish crystals, m.p. 141°-142°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(C)O
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of 1-(5-chloro-2-methoxyphenyl)ethanone (7.97 g, 43.1 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. was added a 1M solution of lithium aluminium hydride In THF (14.2 mL, 14.2 mmol). After 3 hours, ethyl acetate (200 mL) was added and the mixture was washed with a 1M aqueous solution of hydrogen chloride (50 mL). The organic phase was concentrated in vacuo to afford the title compound (6.97 g, 86%)
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].OS(O)(=O)=O.CCN(CC)CC.[CH3:30][C:31]([CH3:33])=O>>[CH3:30][C:31]1([CH3:33])[O:3][C@@H:2]2[C@@H:4]([C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]2[N:10]2[C:11](=[O:12])[NH:13][C:14](=[O:15])[CH:16]=[CH:17]2)[O:5]1
Reactant: CC(C)=O
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc(=O)[nH]c1=O

Procedure:
5′-O-(t-Butyldimethylsilyl)-2′,3′-O-isopropylidene uridine. A stirred suspension of uridine (1 g, 4.098 mmol) in dry acetone (50 mL) was treated with H2SO4 (0.5 mL) drop wise at room temperature and the resulting mixture was stirred further 1 h and neutralized with Et3N. Evaporation of the solvent and purification of the crude by column chromatography (5-8% MeOH in CHCl3) gave 2′,3′-O-isopropylidene uridine (1.15 g) in quantitative yield as a white solid 1H NMR (CDCl3) d: 1.36 (s, 3H, —CH3), 1.57 (s, 3H, —CH3), 3.80 (dd, 1H, J=3.3, 12.0 Hz, H-5′), 3.91 (dd, 1H, J=2.7, 12.0 Hz, H-5″), 4.26-4.30 (m, 1H, H-4′), 4.95 (dd, 1H, J=3.3, 6.3 Hz, H-3′), 5.02 (dd, 1H, J=2.7, 6.3 Hz, H-2′) 5.56 (d, 1H, J=2.7 Hz, H-1′), 5.72 (d, 1H, J=8.1 Hz, H-5), 7.36 (d, 1H, J=8.1 Hz, H-6). A stirred solution of 2′,3′-O-isopropylidene uridine (0.2 g, 0.704 mmol) in dry CH2Cl2 (3 mL) was treated with imidazole (0.095 g, 1.408 mmol) and TBDMSCl (0.105 g, 0.704 mmol) at 0° C. The reaction mixture was brought to room temperature and stirred for 1 h. The solvent was evaporated under vacuum and the solid was taken into ethyl acetate (30 mL), washed with water (15 mL), brine (15 mL) and dried (Na2SO4). Evaporation of the solvent and purification of crude by column chromatography (5% MeOH in CHCl3) gave 5′-O-(t-butyldimethylsilyl)-2′,3′-O-isopropylidene uridine (0.268 mg) in 96% yield as a foamy solid. 1H NMR (CDCl3): δ 0.10 (s, 6H, —CH3), 0.90 (s, 9H, —CH3), 1.36 (s, 3H, —CH3) 1.59 (s, 3H, —CH3), 3.79 (dd, 1H, J=2.7, 11.2 Hz, H-5′), 3.92 (dd, 1H, J=2.4, 11.2 Hz, H-5″), 4.30-4.33 (m, 1H, H-4′), 4.67 (dd, 1H, J=2.7, 6.0 Hz, H-3′), 4.75 (dd, 1H, J=3.0, 6.0 Hz, H-2′), 5.66 (d, 1H, J=8.1 Hz, H-5), 5.96 (dd, 1H, J=3.0 Hz, H-1′), 7.68 (d, 1H, J=8.1 Hz, H-6), 8.47 (brs, 1H, —NH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (42.3 uL, 0.30 mmol) and methanesulfonyl chloride (10.4 mg, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([S:20][CH2:21][CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH2:18]([S:20][CH2:21][CH2:22][O:16][C:12]1[CH:11]=[C:10]([CH3:17])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)=[C:14]([CH3:15])[CH:13]=1)[CH3:19]
Reactant: CCSCCCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (1.83 g, 8.00 mmol) and 2-chloroethyl ethyl sulfide (1.07 mL, 12.0 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (1.33 g, 9.60 mmol) and potassium iodide (0.132 g, 0.800 mmol), and the mixture was stirred at 95° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.19 g, yield 47%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C#N)cccc2C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=N)NO)C1
Temperature: 60 °C
Yield: 69 %

Procedure:
A suspension of 1,1-dimethylethyl 9-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 64) (5.1 g, 18.59 mmol), hydroxylamine hydrochloride (2.58 g, 37.2 mmol) and sodium bicarbonate (7.81 g, 93 mmol) in ethanol (50 ml) was heated at 60° C. overnight. A further portion of hydroxylamine hydrochloride (1 g) was added and the reaction was heated at 60° C. overnight. The solid was filtered from the reaction mixture and the filtrate evaporated. The residue from the evaporation was dissolved in EtOAc, washed with water, dried over magnesium sulphate and evaporated. Trituration with ether to gave the title compound (3.94 g) as a white solid. MS (ES): C15H21N3O4 requires 307; found 308 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([O:16][CH2:17][C:18]([CH3:20])=O)(=[O:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C>[C:13]([O:16][CH2:17][C:18]1([CH3:20])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)(=[O:15])[CH3:14].[C:13]([OH:16])(=[O:15])[CH3:14]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)COC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)O
Product: CC(=O)OCC1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A mixture of the starting material, tryptophol (32.2 g., 0.2 mole), acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acid in 500 ml of benzene is refluxed for 11/2 hr. in the presence of a Dean-Stark water trap. The benzene solution is washed with 5% sodium bicarbonate, water, dried and evaporated to afford an oil. The oil is subjected to chromatography on a silica gel column using 10% ethyl acetate in benzene as eluent. The acetate 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol acetate is obtained as an oil, nmr(CDCl3) δ 1.52 (S,3H), 2.08(S,3H), 4.35(2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-tert-Butyl-2-methyl-6-nitro-phenol (209 mg, 1 mmol) was dissolved in 3 mL acetone. 552 mg K2CO3 (4 eq) was added, followed by addition of MeI (0.33 mL, 5 mmol). The reaction mixture was stirred vigorously at 60° C. overnight. After removal of the acetone, the residue was shaken with DCM. Filtration and evaporation of the solution yielded 221 mg product which was used as such.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:34]1[CH:38]=[N:37][N:36]=[N:35]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:35]2[N:36]=[N:37][CH:38]=[N:34]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nnn[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](n1ncnn1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (200 mg) in tetrahydrofuran (5 ml) were added triphenylphosphine (787 mg), tetrazole (210 mg) and diethyl azodicarboxylate (0.47 ml) at 0° C. under argon atmosphere. The mixture was stirred for 16 hours at room temperature. To the reaction mixture were added ethyl acetate (30 ml) and water (15 ml). The separated aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with water and saturated saline, dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4:1→3:1→2:1) to give (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-tetrazol-2-yl) ethyl]oxirane (176 mg).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl-:9].[C:16]([O:8][CH:1]([N+:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Product: O=C(OC(c1ccccc1)[n+]1ccccc1)c1ccccc1
Product: [Cl-]
Reaction time: 96 h

Procedure:
Benzoyl chloride 3.0 g (0.021 mol) and 1.69 g (0.021 mol) pyridine were mixed together under nitrogen and allowed to react at room temperature overnite. Benzaldehyde 2.23 g (0.021 mol) was added and the mixture was allowed to stand at ambient temperature for 4 days. Recrystallization from ethanol:ether gave 4.27 g (0.013 mol), 62%, α-benzoyloxybenzylpyridinium chloride, mp 174.5°-176.5°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[C:8]([Cl:17])[C:9]([Cl:16])=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:18].N12CCCC1=NCCC2.[CH:28]([C:30]([CH3:32])=[O:31])=[CH2:29].O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:29][CH2:28][C:30](=[O:31])[CH3:32])[CH2:13][C:12]2[C:7](=[C:8]([Cl:17])[C:9]([Cl:16])=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:18]
Reactant: C=CC(C)=O
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCl)C2
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCCl)(CCC(C)=O)C2

Procedure:
2-(3-Chloropropyl)-6,7-dichloro-2,3-dihydro-5-methoxy-1H-inden-1-one (59 g, 0.20 mole) was dissolved in tetrahydrofuran (50 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (3 ml) added. The mixture was stirred and methyl vinyl ketone (28.3 g, 0.404 mole) added dropwise over 30 minutes. The temperature rose from 22° C. to 35° C. over the addition period. The mixture was stirred for an additional hour at ambient temperature, then poured into cold water. The solid that separated was removed by filtration, washed with water, dried and recrystallized from a mixture of tetrahydrofuran and ether to give 2-(3-chloropropyl)-6,7-dichloro-2,3-dihydro-5-methoxy-2-(3-oxobutyl)-1H-inden-1-one, 58.5 g, m.p. 120°-122° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-nitrophenol (3.00 g, 21.6 mmol) and K2CO3 (6.00 g, 43.4 mmol) in DMF (50 mL), t-butyl bromoacetate (2.90 mL, 19.6 mmol) was added. The mixture was stirred at room temperature for 5 h. Water and EtOAc were added. The organic phase was separated, washed with water, then with aq. 1N NaOH and brine. It was dried over Na2SO4, concentrated in vacuo to give tert-butyl 2-(4-nitrophenoxy)acetate as a solid.