Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19](O)C.CI>O>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11]([S:15][CH3:19])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Temperature: 60 °C

Procedure:
5-Benzyl-6-methylthiouracil (6.0 gms) and sodium hydroxide (1.06 gms) were dissolved in water (30 mls). The solution was cooled and ethanol (60 mls) and methyl iodide (3.67 gms) added with stirring. The mixture was heated at 60° C. for 1/2 hour, cooled and the resulting solid collected and water-washed. A second crop of solid was obtained by acidification of the filtrate to pH=4 with acetic acid. Recrystallisation from ethanol produced 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (5.53 gms) m.p. =220°-221.5° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[N:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:1]1([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:19]2[N:24]3[N:25]=[CH:26][N:27]=[C:23]3[N:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(OC[C@H]3CCCN3)cccc2c1
Reactant: Clc1ccnc2ncnn12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(OC[C@H]3CCCN3c3ccnc4ncnn34)cccc2c1

Procedure:
400 mg of (R)-2-(naphthalen-1-yloxymethyl)pyrrolidine, 500 mg of the 7-chloro-[1,2,4]triazolo[1,5-a]pyrimidine prepared above and 650 mg of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 40 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 640 mg of “A1”; m.p. 74-75°;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1.[C:13]1(C)C=CC=C[C:14]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:13]=[CH2:14])=[CH:7][N:6]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: COC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(NC(=O)OC)nc1
Temperature: 85 °C
Yield: 439.1 %

Procedure:
A solution of (5-bromo-pyridin-2-yl)-carbamic acid methyl ester (1.68 g, 7.2 mmol) in acetonitrile (15 ml) and triethylamine (1.84 ml) was treated with palladium acetate (65 mg, 0.29 mmol) and tri-o-tolylphosphine (295 mg, 0.97 mmol). The mixture was placed in a pressure reactor under 130 psig of ethylene pressure and heated at 85° C. for 18 hours. The reaction mixture was cooled, vented and diluted with ethyl acetate and filtered. The ethyl acetate solution was washed sequentially with 1M aqueous citric acid, water, brine and was dried over sodium sulfate and filtered. The filtrate was evaporated. The residue was recrystallized from dichloromethane-hexane to afford 0.759 g (58%) of the title product as colorless crystals. mp 146-148° C. 1H NMR (CDCl3): δ=9.04 (br, 1 H): 8.28 (d, 1 H); 7.97 (d, 1 H); 7.77 (d of d, 1 H); 6.64 (d of d, 1 H); 5.71 (d, 1 H); 5.26 (d, 1 H); 3.81 (s, 3H). MS (Cl): m/z =179 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:14])=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.[CH2:15]([O:17][C:18](=[O:34])[CH2:19][C@H:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][C@H:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][O:14][C:9]3[CH:8]=[CH:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[C:10]=3[CH2:11][CH2:12][CH3:13])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:16]
Reactant: CCCc1c(O)ccc2c(C)noc12
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)OCC)ccc2c(C)noc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a mixture of 3-methyl-7-propyl-1,2-benzisoxazol-6-l (269 mg, 1.01 mmol) (Example 67) and ethyl[(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (331 mg, 1.01 mmol) (Example 45) in DMF (8 mL, containing 1 vol % water) was added Cs2CO3 (661 mg, 2.03 mmol). The mixture was stirred for 16 h at rt, and then the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a small plug of silica to give 204 mg (39%) of the title compound as a white solid that was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21]CC)=[O:20])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O.C1COCC1.CO>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([OH:21])=[O:20])[N:10]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
Ethyl 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoate (870 mg, 2.37 mmol) was dissolved in the mixture of water (3.0 mL), THF (3.0 mL) and methanol (3.0 mL) followed by the addition of lithium hydroxide monohydrate (497 mg, 11.85 mmol). The reaction mixture was stirred at room temperature for 16 h and was neutralized with 1N aqueous HCl until pH=6 (monitored with pH paper). Upon removal of the organic solvent in vacuo the resulting brown solid was collected and dried to give 620 mg (87% yield) of 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[O:21]1.I([O-])(=O)(=O)=[O:30].[Na+]>O1CCOCC1.O.C(OCC)C>[CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:30])[CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[O:21]1
Reactant: COC1C(OC(=O)N2CCSCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: COC1C(OC(=O)N2CCS(=O)CC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
To a solution of 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(thiomorpholin-4-ylcarbonyloxy)-1-oxaspiro[2,5]octane (41 mg) in 1,4-dioxane (2 ml) and water (0.2 ml) was added sodium periodate (21 mg) at ambient temperature. After stirring at the same temperature for 18 hours, the reaction mixture was diluted with diethyl ether. The precipitates were filtered off by celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by ethyl acetate) to yield 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(l-oxothiomorpholin-4-ylcarbonyloxy)-1-oxaspiro[2,5]octane (25 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([OH:22])[C@:20]([CH3:24])([OH:23])[C@@H:19]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:42])[C@:20]([CH3:24])([OH:23])[C@@H:19]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](O)[C@]1(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](OC(=O)Oc2ccccc2)[C@]1(C)O
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Compound 5.09 (4.0 g, 8.0 mmol) was dissolved in CH2Cl2 (80 mL) and pyridine (2.6 mL, 32 mmol) then chilled to 0° C. Phenyl chloroformate (1.1 mL, 8.8 mmol) was added and the reaction was stirred for 20 min then quenched with 20 mL MeOH and concentrated in vacuo. The residue was dissolved in CH2Cl2 then washed with H2O and brine. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford the title compound (5.0 g, 8.0 mmol, 100%). 1H NMR (500 MHz, CDCl3): δ ppm 7.36-7.25 (m, 7H, PhH), 7.22 (t, J=7.3 Hz, 1H, PhH), 7.10 (d, J=8.8 Hz, 2H, PhH), 4.97 (d, J=10.3 Hz, 1H, H-3), 4.95, 4.67 (ABq, J=11.2 Hz, OCH2Ph1H each,), 4.53 (d, J=7.8 Hz, 1H, H-1), 4.04-3.96 (m, 1H, OCHHCH2SiMe3), 3.89 (d, J=7.3 Hz, 2H, H-6), 3.64 (s, 1H, OH), 3.63-3.58 (m, 1H, OCHHCH2SiMe3), 3.54 (t, J=7.1 Hz, 1H, H-5), 3.38 (dd, J=10.3, 7.8 Hz, 1H, H-2), 1.36 (s, 3H, Me), 1.04 (t, J=8.8 Hz, 2H, OCH2CH2SiMe3), 0.91 (s, 9H, SiCMe3), 0.13, 0.12 (s, 3H each, SiMe2), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 153.72, 151.34, 138.51, 129.43, 128.44, 127.66, 127.64, 125.97, 121.18, 103.63, 83.26, 79.14, 75.22, 74.80, 73.57, 68.06, 62.56, 25.94, 18.69, 18.26, 16.13, −1.29, −5.38, −5.55; HRMS calcd for C32H54NO8Si2 [M+NH4]+: 618.3044. found 618.9056.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:13].Cl.Cl.Cl.N1CCCCCCC[CH2:21]NNN1.C([O-])([O-])([O-])OCC>C(O)C>[Cl-:13].[CH2:2]1[CH2:3][N:4]2[C:21]3=[N+:7]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][N:1]13)[CH2:6][CH2:5]2
Reactant: C1CCCCNNNNCCC1
Reactant: C1CNCCNCCNCCN1
Reactant: Cl
Agent: CCOC([O-])([O-])[O-]
Solvent: CCO
Product: C1CN2CCN3CC[N+](=C23)CCN1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of 0.52 g of 1,4,7,10-tetraazacyclododecane, 0.32 g of tetraazacyclododecane tetrahydrochloride, 0.77 g of ethyl orthocarbonate, and 5 ml of absolute ethyl alcohol was heated with stirring on a steam bath (ca. 100°C) for 8 hours. The nmr spectrum of a small sample of the mixture indicated that the desired reaction was about 75-80% complete. The mixture was heated with stirring on a steam bath for 19 hours more. Volatile materials were evaporated under reduced pressure, and the residue was recrystallized from acetonitrile to give 0.20 g of 1,2,3,4,6,7,8,9-octahydro-5H-4a-azonia-2a,7,9a-triazacycloocta[cd]pentalene chloride (II) as needle-like crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: Nc1cc(F)ccc1F
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
2,5-Difluoroaniline (0.19 mL, 1.85 mmol), ethyl 2-bromo-2-phenylacetate (0.22 mL, 1.23 mmol), and DIPEA (0.32 mL, 1.85 mmol) are dissolved in acetonitrile (3 mL) and heated under MW irradiation at 100° C. for 6 hours and then at 110° C. for 4 hours. Acetonitrile is evaporated and the crude is purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I104 as a white solid (240 mg, 67% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1([CH3:16])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])O1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC>[CH3:8][C:9]1([CH3:16])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:5]2[CH:6]=[C:1]([OH:7])[CH:2]=[CH:3][C:4]1=2
Reactant: CC1(C)CCC(C)(C)O1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 13.2 g (0.1403 mol) of phenol and 12.8 g (0.0998 mol) of 2,2,5,5-tetramethyltetrahydrofuran in 50 ml of heptane was added 13.1 g (0.0982 mol) of aluminum chloride in small portions. After the addition was complete the mixture was stirred at room temperature for 2.5 hours, at reflux for 2 hours and then at room temperature for a further 16 hours. The reaction mixture was then treated with 100 ml of 3N HCl and stirred for 0.5 hours. The mixture was filtered and the residue washed with water and dried in-vacuo to give crude product. The organic layer was separated from the filtrate and the aqueous layer extracted with 3×75 ml of ether. The organic layers were combined and washed with saturated NaCl solution, dried (MgSO4) and then concentrated in-vacuo to give further crude product. The crude product was recrystallized from hexanes to give the title compound as pale brown crystals.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]4[CH:23]=[CH:22][N:21]=[N:20]4)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:27].[Na+]>CO.C(OCC)(=O)C.O>[F:25][C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:11]=[CH:12][C:7]=1[C:4]1[CH2:5][CH2:6][S:1](=[O:27])[CH2:2][CH:3]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCSCC2)c(F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCS(=O)CC2)c(F)c1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (Example 83; 1.25 g, 3.5 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 50 ml) at ambient temperature. Sodium periodate (0.93 g, 4.3 mmol) in water (10 ml) was added dropwise, and it was stirred for 18 hours. Precipitated salts were removed by filtration and solvents were removed under vacuum. The residue was chromatographed on silica gel, washing with 25% acetone in dichloromethane, then eluting with 5 to 7% methanol in dichloromethane to give the title product (1.152 g).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: CSCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CSCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 89 %

Procedure:
Prepared as in Example 197c from 4-(methylthio)butan-1-ol and 2,6-dinitrobenzonitrile in 89% yield. MS 267 (MH+).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]3[CH2:25][C@H:24]3[N:26]([CH2:34][CH:35]3[CH2:37][CH2:36]3)C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40].COC1CCCC1>>[ClH:40].[C:1]([NH:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]3[CH2:25][C@H:24]3[NH:26][CH2:34][CH:35]3[CH2:36][CH2:37]3)=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(NC(=O)c3ccccc3)cc2)cc1
Agent: Cl
Solvent: COC1CCCC1
Product: O=C(Nc1ccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NCC3CC3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [trans-2-(4-{[4-(benzoylamino)benzoyl]amino}phenyl)cyclopropyl]-(cyclopropylmethyl)carbamate (98.0 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (44.6 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][CH:31]=[CH2:32])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][CH2:31][CH3:32])=[O:22])=[CH:34][CH:35]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C=CCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-allylphenyl)benzamide (100 g) and 10% palladium on carbon (20 mg) in methanol (15 ml) was stirred under an atmospheric pressure of hydrogen at ambient temperature. After 3 hours, the reaction mixture was filtered through a bed of Celite, concentrated and then triturated from diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-propylphenyl)benzamide (70 mg).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[NH:5]1[CH:9]=[N:8][C:7]([C:10](=[O:12])[CH3:11])=[N:6]1>C1COCC1>[NH:5]1[CH:9]=[N:8][C:7]([C:10]([OH:12])([C:1]#[CH:2])[CH3:11])=[N:6]1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1nc[nH]n1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1nc[nH]n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethynylmagnesium bromide (45 mL, 2.50 equiv). This was followed by the addition of a solution of 1-(1H-1,2,4-triazol-3-yl)ethan-1-one (1000 mg, 9.00 mmol, 1.00 equiv) in THF (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 10 min at 0° C. The resulting solution was allowed to react with stiffing for an additional 6 h at room temperature. The reaction was then quenched by the addition of 10 mL of sat. aq. NH4Cl. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with petroleum ether:ethyl acetate (1:1). This resulted in 0.4 g (32%) of 2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol as a white solid.
Reaction SMILES: [S:1](S([O-])=O)([O-:3])=[O:2].[Na+].[Na+].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.O.CN(C)[CH:22]=[O:23]>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][S:1]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:23][CH3:22])=[CH:12][CH:13]=2)(=[O:3])=[O:2])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=S([O-])S(=O)[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: COc1ccc(CS(=O)(=O)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a well-stirred suspension of 6.93 grams (40 mmol) of sodium hydrosulfite (Na2S2O4) in 70 ml N, N-dimethylformamide (DMF) was added 4.85 grams (31 mmol) of 4-methoxy benzyl chloride. The mixture was stirred for five hours at room temperature, then brought to 85° C. for 24 hours. The mixture was poured onto 250 ml of crushed ice, and the total volume brought to 700 ml with water. The hygroscopic solid product was isolated by filtration and recrystallized from toluene to give 2.9 grams (9.5 mmol, 61% yield) of bis(4-methoxy benzyl) sulfone as white plates (mp 182° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:15]([CH:18]=O)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]C(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].C(=O)([O-])[O-].[K+].[K+].O>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:15]([C:18]#[CH:28])=[CH:16][N:17]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(C=O)n1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cnc(C2CCCN2C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Reaction time: 3.33 h
Yield: 76.7 %

Procedure:
2-[5-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.625 g, 4.11 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (1.056 g, 5.50 mmol) were dissolved in 1:1 MeOH/THF (10 mL) and potassium carbonate (1.14 g, 8.25 mmol) was added. After stirring for 200 min, more potassium carbonate (1.14 g, 8.25 mmol) was added. 45 min later, the reaction mixture was poured into 100 mL 1:1 water/saturated aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with diethyl ether. The combined organic phases were dried with magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (20% to 45% EtOAc/hexanes) to afford 2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.234 g, 77%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:25]3=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]3[CH2:23][CH2:22][O:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:25]5=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]5[CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=CCC2CCOC3(CCNCC3)C2=C1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CC1)OCCC1CC=CC=C12

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1,5-dihydrospiro[4H-2-benzopyran-1,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 58% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-23.56 (c=0.51, methanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][C@H:39]([OH:41])[CH3:40])[CH:37]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:33]4[CH:34]=[N:35][N:36]([CH2:38][C@H:39]([OH:41])[CH3:40])[CH:37]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: C[C@@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3cnn(C[C@@H](C)O)c3)cc1-2
Yield: 9.6 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (418 mg, 1.02 mmol) and (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazol-1-yl)propan-2-ol (307.4 mg, 1.22 mmol) were reacted to give 369 (44.8 mg, 10% yield, M+1 457.1).