Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[CH2:12][C:13](=[O:19])[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH:20](OCC)=[O:21].[O-]CC.[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:11]3[CH2:18][CH2:17][CH2:16][CH:15]2[C:14](=[CH:20][OH:21])[C:13](=[O:19])[CH2:12]3)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)s1
Temperature: 60 °C

Procedure:
To a stirring mixture of 9-(5-chloro-thiophene-2-sulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (160 mg, 0.50 mmol) in THF/ethanol (3 mL, 1/1, v/v) was added ethyl formate (500 mg, 6.76 mmol) followed by sodium ethoxide (0.56 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NH4Cl solution (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 9-(5-chloro-thiophene-2-sulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=1.985 min, Method [1], MS (ESI) 348.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([OH:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=[C:27]=[O:28])C=CC=CC=1>C(OCC)(=O)C>[OH:13][C:4]1[C:3]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:27](=[O:28])[NH:1][C:2]=2[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1c(-c2ccccc2)c(O)nn1-c1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(c(O)nn2-c2ccccc2)c2ccccc12
Temperature: 290 °C
Yield: 81 %

Procedure:
2.51 Grams (0.01 mole) of 5-amino-3-hydroxy-1,4-diphenylpyrazole is mixed with 1.62 ml (0.015 mole) of phenylisocyanate and is gradually heated to 290° C. The obtained residue is then ground and boiled with 40 ml of ethyl acetate. 2.7 Grams of crude compound recovered by filtering the hot mixture is taken up with aqueous 4% NaOH. On acidifying the filtered solution with acetic acid, 2.24 g of the title compound precipitates. Yield 81%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:10][N:11]([CH2:33][C:32]#[CH:31])[C:12]=2[C:13]([F:15])([F:16])[F:14])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1nc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 21.1 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole (0.15 g) from step 1 was added to potassium carbonate (0.14 g) and propargyl bromide (0.45 g) in 5 mL of DMF. HPLC purification gave 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1-propargyl-5-(trifluoromethyl)pyrazole (35 mg, 22%) in the first fraction (mp 144.5°-146° C.) and 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1-propargyl-3-(trifluoromethyl)-1H-pyrazole in the second fraction (87 mg, 56%, mp 135.5°-138.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([N+:17]([O-])=O)=[CH:15][C:6]2[O:7][C:8]([CH3:14])([CH3:13])[C:9](=[O:12])[N:10]([CH3:11])[C:5]=2[CH:4]=1.[Sn](Cl)Cl>C(O)C>[NH2:17][C:16]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[C:8]([CH3:14])([CH3:13])[O:7][C:6]=2[CH:15]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C(=O)N2C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1cc2c(cc1N)OC(C)(C)C(=O)N2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
6-Methoxy-2,2,4-trimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (250 mg, 0.94 mmol) was stirred in ethanol (15 mL) then tin (II) chloride was added. The reaction was heated to 80° C. with stirring for 2 h. The volatiles were removed under reduced pressure and the residue was slurried with 2M sodium hydroxide aqueous solution. The aqueous was extracted with ethyl acetate and the combined organic extracts were passed through a phase separation cartridge and evaporated, to afford a brown crystalline solid (220 mg, 99%) which was taken through to the next step with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[N:14]([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)N2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (400 mg, 2.25 mmol, Precursor Chemicals) in trifluoroacetic acid (4 mL, Aldrich) was treated with sodium nitrite (156 mg, 2.26 mmol, added slowly in about 4 portions, Aldrich). The dark brown reaction was stirred for 1 h after which an aliquot was taken out, diluted with water and extracted with ethyl acetate. TLC analysis of the ethyl acetate layer revealed that starting material remained. More sodium nitrite (50 mg, 0.72 mmol) was added and the reaction stirred for another 2 h at which point some precipitation was observed in the reaction. The reaction was poured over ice and then extracted with ethyl acetate. The organic layer, which still had undissolved solids in it, was concentrated to give 6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (372 mg, 70%) as a white powder. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.45-2.49 (m, 2 H), 2.98 (t, J=7.5 Hz, 2 H), 3.88 (s, 3 H), 7.29 (s, 1 H), 7.38 (s, 1 H), 10.18 (bs, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].Cl.[H][H]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][NH:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: [H][H]
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)c(F)c2)C1

Procedure:
A solution of 5.73 g (18.2 mmol) of the compound from Example 91A in 116 ml of ethanol was admixed with 1.11 g (0.27 mmol) of platinum oxide, and hydrogenated with 14.3 ml of concentrated hydrochloric acid solution and at RT overnight in a 3.5 bar hydrogen atmosphere. The catalyst was then filtered off through a filter layer and washed repeatedly with ethanol. The combined filtrates were concentrated under reduced pressure. Yield: 5.95 g (100% of theory)
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:20][CH:21]1[CH2:26][C:25](=O)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>ClCCl>[CH3:20][CH:21]1[CH2:26][C:25]2([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]23)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)Oc1ccccc1-n1cccc12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (443 μL, 5.75 mmol) was added to a solution of 2-pyrrol-1-ylphenol (457 mg, 2.87 mmol) and tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (613 mg, 2.87 mmol) in dichloromethane (19 mL) and the solution was vigorously stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and the organics were extracted with EtOAc (3×200 mL). The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel: 0-10% EtOAc in dichloromethane) to give tert-butyl 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate as a brown oil. The crude residue was dissolved in a solution of HCl in dioxane (1.4 mL of 4.0 M, 5.6 mmol) and stirred for 30 min at room temperature. The volatiles were removed in vacuo and the residue was dissolved in diethylether. The solids were collected by filtration to provide 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride (386 mg, 46%) as a reddish brown solid. ESI-MS m/z calc. 254.1. found 255.5 (M+1)+; Retention time: 1.12 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([O:15]C)=[O:14].[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH:21]=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:21][C:20]1[C:19]([O:18][CH3:17])=[CH:26][C:25]([O:27][CH3:28])=[CH:24][C:23]=1[O:29][CH3:30])[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CC1=C(C)Cc2ccc(O)cc21
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Product: COc1cc(OC)c(C=C2C(C)=C(CC(=O)O)c3cc(O)ccc32)c(OC)c1

Procedure:
The reaction of Example 13(D) is repeated except that the starting materials are methyl 5-hydroxy-2-methyl-3-indenylacetate and 2,4,6-trimethoxybenzaldehyde. With the same reaction conditions and techniques, 5-hydroxy-2-methyl-1-(2,4,6-trimethoxybenzylidene)-3-indenyl acetic acid is obtained. (R and R1 =H, R2 =OH, R3 and R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, R9 =H, R10 and R11 =double bond, m=0, n=0, M=OH)
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>CO>[OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]/[C:4](/[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[N:25]\[OH:26]
Reactant: O=C(CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O/N=C(\CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of 3-hydroxy-3,3-diphenyl-1-pyridin-4-yl-propan-1-one (115 mg) in methanol (4 ml) were added hydroxylamine hydrochloride (63 mg) and sodium acetate (75 mg). The mixture was stirred at room temperature for 6 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1 to 1:3) to give the title compound (60 mg) as a colorless solid, MS (ESI+): m/z=319.1 [M+H]+.
Reaction SMILES: C[NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.[C:12]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16])(=[O:14])[CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:11][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][NH:2][S:23]([C:20]2[CH:19]=[CH:18][C:17]([N:15]([C:12](=[O:14])[CH3:13])[CH3:16])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:10]=[CH:9][CH:8]=1
Reactant: CNCCc1cccc(C)n1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NCCc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]amine (14.66 g, 97.7 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (24.2 g, 97.3 mmol) prepared in Preparative Example 12 and sodium acetate (24.0 g) in ethanol (140 ml). The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-[2-(6-methyl-2-pyridyl)ethyl]-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless oil. This oil was dissolved in 4N aqueous hydrochloric acid. The solution was heated under reflux for 2 hours. The pH of the mixture was adjusted to about 8 by the addition of an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give an oily residue. This residue was purified by flash column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3) to give the title compound as a light brown oil (25.8 g, overall yield of two steps: 83%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:11][S:12]([O:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)(=[O:14])=[O:13]
Reactant: OC1Cc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
2-Indanol (1.34 g) in pyridine (5 ml) was stirred with cooling to 0° C. Methylsulphonyl chloride (1.38 g) was added dropwise while maintaining the temperature at 0°. The mixture was then allowed to warm to room temperature and was stirred for 0.5 hour. The mixture was then poured on to ice and immediately a white precipitate formed; the mixture was allowed to stand overnight. The precipitate was then filtered off, washed with water and air-dried to give 2-methylsulphonyloxyindane (1.9 g), m.p. 75°-77° C.
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][C:6]1=[O:19].O.NN>CCO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:19])[N:5]([CH2:4][CH3:3])[C:11]=2[CH:12]=1
Reactant: COCCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN1C(=O)CCCc2ccc(N)cc21
Yield: 113.1 %

Procedure:
To a solution of 1-(2-methoxy-ethyl)-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.00 g, 3.9 mmol) in EtOH (13 mL) was sequentially added 10% Pd/C (155 mg) and hydrazine-monohydrate (3 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine to afford 8-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (901 mg, 98%) that had the following properties: LC/MS (ESI+): 235 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 6.95 (d, J=7.9, 1H), 6.68 (s, 1H), 6.51 (d, J=7.9, 1H), 3.95 (br s, 2H), 3.67 (br s, 2H), 3.56 (m, 2H), 3.32 (d, 3H, J=2.2), 2.75 (br s, 2H), 2.30 (m, 2H), 2.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:28][C:29]1[C:30](Cl)=[N:31][CH:32]=[CH:33][CH:34]=1>CO>[Br:28][C:29]1[C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)=[O:16])[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1ncccc1Br
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(Nc2ncccc2Br)c1
Temperature: 180 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of 3′-amino-6-methyl-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (150 mg, 0.41 mmol) and 3-bromo-2-chloropyridine (90 mg, 0.47 mmol) was heated neat to 180° C. in an oil bath. The temperature was increased to 200° C., and then heating was discontinued and the reaction mixture was allowed to stir for 72 h. The resulting solid was dissolved in methanol and purified by flash column chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) to afford product (87 mg, 39%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[C:26]([CH:28]=[C:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1)#[N:27].N12CCCN=C1CCCCC2>>[C:26]([CH2:28][C:29]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1)#[N:27]
Reactant: COC(=O)C1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (2.01 g, 0.00637 mol) in acetonitrile (4.0E1 mL, 0.77 mol) was added methyl 3-(cyanomethylene)cyclobutanecarboxylate (1.93 g, 0.0127 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.953 mL, 0.00637 mol). The resulting mixture was stirred at 50° C. overnight. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired Micheal addition product as a mixture of cis- and trans-isomers (2.12 g, 71.3%). LCMS calculated for C23H31N6O3Si(M+H)+: 467.2; Found: 467.4.
Reaction SMILES: [CH2:1]([C:3]([CH:17]([CH3:24])[CH2:18][CH:19]=[C:20]([CH3:23])[CH2:21][CH3:22])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)[CH3:2].C(OO)(=[O:27])C>>[O:27]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:19]1[CH2:18][CH:17]([CH3:24])[C:3]([CH2:1][CH3:2])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)OO
Reactant: CCC(C)=CCC(C)C(=CCOc1ccc2c(c1)OCCC2)CC
Product: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC1OC1(C)CC

Procedure:
Following the procedure of Example 17, 7 -(3-ethyl-4,7-dimethyl-2,6-nonadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-ethyl-4,7-dimethyl-2-nonenyloxy)-chromane, nD20 = 1.5190.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=O.Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>N1C=CC=CC=1>[CH2:27]([O:29][N:30]=[CH:24][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[C:2]=1[CH3:1])[CH3:28]
Reactant: CCON
Reactant: Cc1c(C=O)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Agent: Cl
Solvent: c1ccncc1
Product: CCON=Cc1oc2cccc(OCCCN(C)Cc3cccnc3)c2c1C
Reaction time: 7 h

Procedure:
To a solution of 3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-carbaldehyde (the compound of Example 115-b) (29 mg) in pyridine (5 ml) was added O-ethyl hydroxylamine hydrochloride (84 mg) at room temperature. After stirring for seven hours, the mixture was partitioned between ethyl acetate and NH4Cl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography developed by dichloromethane and methanol to give the title compound as a colorless oil (19 mg). ESI-MS: m/z 382 (MH+); 1H-NMR (CDCl3): δ 1.35 (3H, t, J=6.9 Hz), 2.03 (2H, m), 2.27 (3H, s), 2.29 (3H, s), 2.59 (2H, t, J=6.9 Hz), 3.52 (2H, s), 4.11 (2H, t, J=5.9 Hz), 4.32 (2H, q, J=6.9 Hz), 6.60 (1H, d, J=7.6 Hz), 7.05-7.11 (2H, m), 7.21 (1H, t, J=7.9 Hz), 7.58-7.63 (1H, m), 8.12 (1H, s), 8.42 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.52 (1H, d, J=2.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][O:14]3)=[CH:8][CH:9]=2)[CH2:4][CH:3]1[O:18]C(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:18][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][O:14]3)[CH:6]=2)[C:2]1=[O:1]
Reactant: CC(=O)OC1Cc2cc(OC[C@H]3CCCO3)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1c2ccc(OC[C@H]3CCCO3)cc2CC1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic acid 1-oxo-5-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-indan-2-yl ester (1.02 g) and potassium carbonate (264 mg) in methanol (1 mL) was stirred at room temperature for 1 h. After adding water it was extracted with dichloromethane, dried over magnesium sulfate and concentrated. In this way the product was obtained with molecular weight 248.28 (C14H16O4); MS (ESI): 249 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].[C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:18][CH:17]=2)[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: BrCCCCCCOc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1O
Yield: 55.5 %

Procedure:
A mixture of 1.0 g (6 mmol) of 2,5-dihydroxybenzoic acid methyl ester, 2.0 g (6 mmol) of 6-([1,1'-biphenyl]-4-yloxy)hexyl bromide and 1.24 g (9 mmol) of potassium carbonate in 50 ml of acetone and 5 ml of DMF was stirred at reflux for 27 hours. The solvents were removed at reduced pressure, water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by chromatography on 40 g of silica gel using 50% toluene-hexane to give 1.4 g (56% yield, mp 91°-92°) of 5-[[6-([1,1'-biphenyl]4-yloxy)hexyl]oxy]-2-hydroxybenzoic acid methyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:27]3[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:29][CH:28]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 86A and 2-[4-(methylsulfonyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.95-8.02 (m, 2H), 7.90-7.94 (m, 2H), 7.72-7.75 (m, 1H), 7.65-7.68 (m, 2H), 7.61-7.66 (m, 4H), 3.86 (s, 2H), 3.20 (s, 3H); MS (ESI−) M/Z 466 (M−H)−.
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.[CH3:13]OC(OC)N(C)C>C1C=CC=CC=1>[N:1]12[CH:13]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:3][CH2:2]2
Reactant: COC(OC)N(C)C
Reactant: C1CNCCNCCNCCN1
Solvent: c1ccccc1
Product: C1CN2CCN3CCN(CCN1)C23

Procedure:
In a manner similar to that of Example 2 (A), 5.00 g (29.1 mmol) of 1,4,7,10-tetraazacyclododecane, 3.46 g of dimethylformamide dimethyl acetal and 50 ml of dry benzene gave 5.00 g of colorless liquid, bp 88.5°-90° (0.30 mm). Analytically pure 1,4,7,10-tetraazatricyclo[5.5.1.04,13 ]tridecane was obtained by distillation of this material through a spinning band column, bp 82°-83° (two fractions) (0.25 mm) One fraction had nD25 = 1.5331. The other fraction was analyzed.