Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O.[OH-].[NH4+:19]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:8]([OH:9])=[CH:12][CH:11]=[CH:10][N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(=O)c2ccco2)cc1OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ncccc2O)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)furan (764.0 g, 3.28 moles, described in Example 2) is heated at 140° C in an autoclave in the presence of concentrated ammonium hydroxide (7 liters) and methanol (6 liters) for 17 hours. The mixture is cooled and concentrated to 4 liters. Methylene chloride (3 liters) is added and the mixture is extracted with 8N aqueous sodium hydroxide (500 ml). The aqueous extract is washed with methylene chloride. Ice is added to the aqueous phase followed by 6N hydrochloric acid to bring the pH between 7.5-7.0. The brown precipitate is collected, dried and milled to give the title compound, mp 150°-155° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10]([OH:12])=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:37]=3)[NH:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][CH:29]=3.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:26]1[C:25]2[CH:37]=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH:20][C:19]2=[N:35][C:34](=[C:16]([Cl:15])[CH:17]=[N:18]2)[NH:33][C:32]2=[CH:36][C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27]1)(=[O:12])[CH3:9]
Reactant: Clc1cnc2nc1Nc1cccc(c1)CNc1cccc(c1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)N1Cc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of 6-chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (10 mg, 18 μmol) in acetonitrile (0.28 mL) was treated with pyridine (7.3 μL, 91 μmol) followed by acetic anhydride (2.1 μL, 22 μmol) and stirred for 16 h. The reaction mixture was quenched with a few drops of acetic acid and purified by preparative LCMS to give the desired product (5 mg, 58%) as a solid. LCMS for C19H17ClN5O (M+H)+: m/z=366.0. 1H NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 9.24 (s, 1H), 8.16 (s, 1H), 8.06 (dd, J=2.0, 1.8 Hz, 1H), 7.93 (s, 1H), 7.32-7.21 (m, 4H), 7.13 (dd, J=8.2, 1.4 Hz, 1H), 6.97 (dd, J=7.8, 1.2 Hz, 1H), 4.61 (br s, 2H), 1.73 (s, 3H).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=3[F:20])[CH2:6][CH2:5]2)[O:3]C1.C(O)=O>C1(C)C=CC=CC=1>[F:20][C:11]1[C:12]([F:19])=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:10]=1[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: CCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Yield: 100 %

Procedure:
Crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone monoethylene acetal (50.3 mmol) obtained in Step 1 was dissolved in 200 ml of toluene, 87% formic acid (503 mmol) was added, and the solution was heated to reflux for 4 hours. The reaction solution was washed twice with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate, then three times with 100 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to form crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone (50.3 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.Cl.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13]>C1COCC1>[OH:8][C:6]1([CH2:13][C:12]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3](=[O:10])[C:4]([CH3:9])=[CH:5]1
Reactant: CCOC(C)=O
Reactant: CC1=CC(=O)C=C(C)C1=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C(C)=C1
Yield: 80 %

Procedure:
Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,6-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.60 g of the desired product (yield 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:4][C:5](OCC)=[O:6].COCCO[AlH2-]OCCOC.[Na+]>>[CH3:17][N:2]([CH3:1])[CH:3]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH2:4][CH2:5][OH:6]
Reactant: CCOC(=O)CC(c1ccc(F)cc1)N(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: CN(C)C(CCO)c1ccc(F)cc1
Yield: 100.9 %

Procedure:
Ethyl 3-dimethylamino-3-(4-fluorophenyl)propionate (2.8 g) (0.011 mol) was dissolved in a suitable solvent and reduced in the presence of Red-Al (3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene from Aldrich Chemical Company, Milwaukee, Wis.). The reaction mixture was concentrated under vacuum to provide 2.19 g of 3-dimethylamino-3-(4-fluorophenyl)propanol as a solid.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(NC(=O)C3CN4CCC3CC4)cc2)cc1

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 50 mg (0.31 mmol) of 4-(methylsulfanyl)phenylboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 21.6 mg (21% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN2CCOCC2)CC1
Reaction time: 24 h
Yield: 29.6 %

Procedure:
To a solution of 1-Boc-4-(2-formyl-phenyl)-piperazine (500 mg, 1.7 mmol) in methanol (10 mL) was added morpholine (348 mg, 4.0 mmol) and sodium cyanoborohydride (315 mg, 5 mmol) and the mixture was stirred for about 24 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (10 ml), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography (1:1 hexanes/ethyl acetate) afforded the title compound as a colorless oil (182 mg, 30%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21]O)[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:24].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21][Br:24])[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1nc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2nsc(CBr)n2)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
To a solution of (3-(2-(benzyloxy)-4-chlorophenyl)-1,2,4-thiadiazol-5-yl) methanol (0.35 g, 1.05 mmol) in toluene (10 ml) was added PBr3 (0.16 ml, 1.58 mmol) and the resulting reaction mixture was heated at 100° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.33 g, 79% crude yield), that was carried forward as such for the next step. MS: 395.05 (M+H)+.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.C(I)[I:22].CCOC(C)=O>C1COCC1.[Cu]I>[I:22][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Reactant: ICI
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(I)nc1
Temperature: 70 °C

Procedure:
N-(2-Aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide [prepared according to Specific Method 1] (200 mg, 0.732 mmol), CuI (140 mg, 0.732 mmol) and CH2I2 (0.30 mL, 3.73 mmol) were taken up in THF (3.7 mL) in a 16×100 mm resealable pyrex tube. The tube was sealed and the mixture was heated at 70° C. for 2 h. After cooling to rt, the crude reaction mixture was taken up in 1:1 EtOAc:1N HCl and the layers were separated. The organics were washed with saturated NH4Cl then dried over Na2SO4. Purification by MPLC (Isco—100% EtOAc eluent) afforded N-(2-iodopyrimidin-5-yl)-2-methyl-5-nitrobenzamide as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cccc(CCCBr)c1
Yield: 87.9 %

Procedure:
Compound 75-2 (4.45 g) was dissolved in methylene chloride (95 ml), triphenylphosphine (8.13 g) and N-bromosuccinimide (5.51 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.44 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([I:21])[CH:14]=2)=[C:7]([Br:22])[CH:6]=1.B(Br)(Br)Br.O>ClCCl>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]=[C:7]([Br:22])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:21])[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(I)c2)c(Br)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Temperature: -78 °C
Reaction time: 30 h
Yield: 89.8 %

Procedure:
Methyl[3,5-dibromo-4-(4-methoxy-3-iodophenoxy)phenyl]acetate (0.82 g, 1.5 mmol) was dissolved in dichloromethane (25 mL) and cooled down to −78° C. Boron tribromide (8.8 mL, 1 N in dichloromethane) was added and the reaction mixture was stirred at −20° C. for 30 hours. Water was added to the reaction mixture, the organic phase separated and concentrated. The residue was filtered on a short column (silica, dichloromethane/ethyl acetate 1:1), to give 0.73 g (90%) of methyl [3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)-phenyl]acetate as a beige solid mass.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:39])[C@@H:24]([NH:25][C:26](=[O:38])[C:27]([C:31]4[N:32]=[C:33]([NH2:37])[S:34][C:35]=4[Cl:36])=[N:28][O:29][CH3:30])[C@H:21]3[S:20][CH2:19][C:18]=2Cl)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>ClCCl.[Zn]>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:39])[C@@H:24]([NH:25][C:26](=[O:38])[C:27]([C:31]4[N:32]=[C:33]([NH2:37])[S:34][C:35]=4[Cl:36])=[N:28][O:29][CH3:30])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12)c1nc(N)sc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(N)sc1Cl
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid diphenylmethyl ester (180 mg) in dichloromethane (5 ml) are added zinc powder (120 mg) and acetic acid (1 ml), and the mixture is stirred at -10° C. for 10 minutes. The reaction mixture is filtered, poured into iced water and extracted with ethyl acetate. The extract solution is washed with aqueous sodium hydrogen carbonate solution and water, dried and concentrated. Conventional work-up of obtained residue affords 7β-[2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester. Similarly prepared are compounds of Table 1.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[O:14]=O>C(O)(=O)C>[C:1]([C:4]12[CH2:13][CH:8]3[CH2:7][CH:6]([CH2:12][C:10]([OH:14])([CH2:9]3)[CH2:11]1)[CH2:5]2)([OH:3])=[O:2]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: O=O
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 56 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of 1-carboxyadamantane, 1 mmol of NHPI and 0.05 mmol of V (AA)3, and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 5 hours. And, as a result, the 1-carboxyadamantane was converted into a 1-carboxy-3-adamantanol (yield: 56%, white solid), a 1-carboxy-3,5-adamantanediol (yield:28%, light yellow solid), a 1-carboxy-4-adamantanone (yield: 4%) with a conversion of 99%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O-:26].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1

Procedure:
To 100 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 100 mg of 4-(3-bromo-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 138-139° C.; mass spectrum (m/e): M+H 411.9, 413.9.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[O:22][N:21]=[C:20]([CH:23]([CH3:25])[CH3:24])[N:19]=4)[CH2:14][CH2:13]3)[C:5]=2[N:4]([CH3:26])[CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O-:29])=[O:28].CS(C1C=CC(B(O)O)=CC=1)(=O)=O>>[CH:23]([C:20]1[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([O:11][C:10]3[C:5]4[N:4]([CH3:26])[CH:3]=[C:2]([C:33]5[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)[C:6]=4[N:7]=[CH:8][N:9]=3)[CH2:13][CH2:14]2)[O:22][N:21]=1)([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(Oc3ncnc4c(Br)cn(C)c34)CC2)n1
Agent: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)c1noc(N2CCC(Oc3ncnc4c(-c5ccc([N+](=O)[O-])cc5)cn(C)c34)CC2)n1

Procedure:
The procedure of Example 27 was repeated except for using 7-bromo-4-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine and 4-nitrophenylboronic acid instead of 7-bromo-4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine and 4-methanesulfonyl-phenylboronic acid in Step 27-2 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCC=Cc1cccc(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
In a reaction vessel were placed 0.53 g of 4-(3-fluorophenyl)-3-buten-1-ol and 50 ml of ethyl acetate, and the air in the vessel was exchanged for nitrogen. Then, 0.1 g of 10% palladium carbon was added thereto, and the nitrogen in the vessel was exchanged for hydrogen, followed by vigorous stirring at room temperature for 24 hours. After the hydrogen in the vessel was exchanged for nitrogen, the reaction solution was filtered through a celite bed, and the filtrate was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.48 g of 4-(3-fluorophenyl)-1-butanol.
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH3:6])[CH3:5])=O.Cl.[N+:8]([C:11]1[CH:12]=[C:13]([NH:17][NH2:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].O.O.O.C([O-])(=O)C.[Na+]>O.CCO>[N+:8]([C:11]1[CH:12]=[C:13]([NH:17]/[N:18]=[C:2](/[CH:4]([CH3:6])[CH3:5])\[CH3:1])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(=O)C(C)C
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C/C(=N\Nc1cccc([N+](=O)[O-])c1)C(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of isopropyl methyl ketone (2.5 g, 29 mol), 3-nitrophenylhydrazine hydrochloride (6.1 g, 32 mmol) and sodium acetate trihydrate (4.8 g, 35 mmol) in H2O (50 mL) and EtOH (50 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (100 mL) and CHCl3 (150 mL). The organic layer was removed and the aqueous phase was further extracted with CHCl3 (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=222 (M+1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[C:19]([F:18])([F:28])[F:29])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: NCc1ccccc1C(F)(F)F
Product: CCCCCCCCOc1ccc(CNCc2ccccc2C(F)(F)F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(octyloxy)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. HPLC (Condition A), Rt: 4.24 min (HPLC purity: 91.0%).
Reaction SMILES: [OH2:1].O.P([O-])([O-])(O)=O.[Na+:8].[Na+].[O-:10][Si:11]([O-:13])=[O:12].[Na+].[Na+]>>[Si:11]([O-:1])([O-:13])([O-:10])[O-:12].[Na+:8].[Na+:8].[Na+:8].[Na+:8]
Reactant: O=[Si]([O-])[O-]
Reactant: O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
1104 g of disodium hydrogenphosphate dihydrate and 683 g of anhydrous soda are dissolved in 50 kg of water glass having the composition as in Example 1, and the solution is spray-dried in a laboratory spray dryer (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of about 83%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)c1ccc(F)cc1
Agent: Cn1cncc1C(O)c1ccccn1
Product: Cn1cncc1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step b using (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (Intermediate 29: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][CH2:14][CH2:15][C:16]1[C:17](=[O:35])[O:18][C:19]2[C:24]([C:25]=1O)=[CH:23][CH:22]=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)C.C1(C)C=CC=CC=1>O>[NH2:5][C:25]1[C:24]2[C:19](=[C:20]([O:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([O:27][CH3:28])=[CH:22][CH:23]=2)[O:18][C:17](=[O:35])[C:16]=1[CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc2c(O)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(N)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammonium acetate (27.7 g, 360 mmol) was added to a solution of 3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (5 g, 12 mmol), acetic acid (25 mL), and toluene (100 mL). The reaction was refluxed with the water being removed using a Dean-Stark apparatus. After 2 h, the toluene was removed by distillation. After an additional 5 h at reflux, the reaction was allowed to cool to rt, poured into cold water (100 mL), and then extracted with ethyl acetate (100 mL×3). The combined extracts were washed with sat'd NaHCO3 (100 mL×4) and then brine (50 mL×3), filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give 4-amino-3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: MS (ESI): 410.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[CH3:11][N:12]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>C(O)C>[CH3:11][N:12]([CH:20]1[CH2:21][CH2:22][N:23]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:25]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ncnc3[nH]ccc23)CC1

Procedure:
a mixture of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (307 mg, 2 mmol, commercially available from e.g. Aldrich, Apollo or Matrix) and 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (429 mg, 2.000 mmol, commercially available from e.g. Fluorochem, Astatech or Apollo)) in Ethanol (4 ml) was microwaved at 120° C. for 1 h on normal absorption. After evaporation of the solvent, the crude product was purified via MDAP using the High pH extended method. Fractions containing product from each MDAP were combined and evaporated to give D12 as a white solid in 158 mg. LCMS [M+H]+332.06@0.76 min (2 min run)