Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][CH:33]([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH3:42])[C:34]([OH:36])=O)=[O:31]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][CH:33]([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH3:42])[C:34]1=[O:36]
Reactant: CCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC=CCC1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.047 g, 0.15 mmol) and diisopropylethylamine (0.043 g, 0.25 mmol) were added sequentially at ambient temperature to a stirred solution 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}oct-4-enoic acid (0.051 g, 0.11 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 48 hours, then it was added dropwise to ice-cold water (10 ml). The resulting solid was collected by filtration and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-hex-2-enylpyrrolidine-2,5-dione (0.029 g) as an off-white solid, m.pt. 146–149° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.8–1.0 (m, 3H) (CH3), 1.2–1.4 (m, 2H) (—CH2CH3), 1.9–2.1 (m, 2H) (—CH2CH2CH3), 2.3–2.5 (m, 2H) (—CH2CH═CH—), 2.5–2.6 (m, 1H) (ring CH), 2.8–3.0 and 3.0–3.2 (2×m, 2H) (ring CH2), 4.4 (s, 2H) (ArCH2—), 5.25–5.45 and 5.45–5.7 (2×m, 2×1H) (—CH═CH—) 7.2–7.3 (m, 1H) (ArH), 7.3–7.5 (m, 1H) (ArH), 7.5–7.6 (m, 1H) (ArH), 7.8–8.05 (m, 3H) (3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+. 434, 95.8% purity.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].C([O-])(=O)CCC([O-])=[O:14].[C:18]([O-])(=[O:22])[CH:19](C)[OH:20]>>[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[O:20]=[CH:19][C@@H:18]([C@H:5]([C@@H:4]([C@@H:2]([CH2:1][OH:9])[OH:3])[OH:14])[OH:7])[OH:22]
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: CC(O)C(=O)[O-]
Agent: O=C([O-])CC(O)C(=O)[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Although malate was the dominant fermentation product of XZ658 (FIG. 1B), cell growth (0.75 g/L) and malate productivity (0.15 g liter−1 h−1) were low in comparison to our previous biocatalysts for succinate (12-13, 31) and lactate (8) production (Table 4). Microaerobic (3-4) and two-stage processes (aerobic cell growth followed by anaerobic fermentation) were investigated as approaches to improve malate production. After 6 days under microaerobic conditions (0.1 vvm air), malate production (120 mM) and malate yield (0.49 mol per mol glucose) were even poorer than observed during anaerobic fermentations (Table 4). A two stage process proved more effective for malate production. Cells were grown aerobically (1.0 vvm air) for 16 h (2.5 g liter−1 dcw) and then shifted to anaerobic conditions for malate production (72 h). With this approach, 253 mM malate was produced with a yield of 1.42 mol per mol glucose. Productivity during the anaerobic phase averaged 0.47 g liter−1 h−1.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[OH:22][CH2:23][CH2:24][CH2:25][NH:26][OH:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:26]([OH:27])[CH2:25][CH2:24][CH2:23][OH:22])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: OCCCNO
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(c1cc2ccn(Cc3ccc(F)cc3)c2cn1)N(O)CCCO

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-(3-hydroxypropyl)hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (CD3OD) δ ppm 8.71 (s, 1H), 8.20 (s, 1H), 7.71 (d, 1H, J=3.0 Hz), 7.26 (m, 2H), 7.05 (d, 2H, J=8.9 Hz), 6.75 (d, 1H, J=3.0 Hz), 5.55 (s, 2H), 3.90 (m, 2H), 3.65 (t, 2H, J=6.0 Hz), 1.94-2.00 (m, 2H). LCMS (API-ES, M+H+): 344.1. HRMS calcd for C18H19FN3O3 (M+H) 344.1405, found 344.1402. HPLC: 99.1% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O>ClCCl>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)[N:1]=[C:21]([OH:20])[N:22]=1
Reactant: COc1cc(N)c(C#N)cc1OCc1ccccc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nc(O)nc(N)c2cc1OCc1ccccc1
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
A solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (26.7 g, 0.10 mol) in dichloromethane was treated with sodium cyanate (17.1 g, 0.26 mol) and then trifluoroacetic acid (20.9 ml, 0.26 mol) was added dropwise to the resulting mixture at room temperature. After 45 minutes, the mixture was diluted with dichloromethane (11) and stirred for a further 18 hours. The mixture was then concentrated under reduced pressure and partitioned between methanol and 2N aqueous sodium hydroxide and stirred for 2 hours. The methanol was then removed under reduced pressure and the yellow solid isolated by filtration, washing sequentially with water, acetone and diethyl ether to afford the subtitle compound as a yellow solid (18.0 g, 54%). A further quantity of product was obtained by concentration of the filtrate, acidification with concentrated hydrochloric acid (95 ml), warning on a steam bath for 5 minutes, cooling and neutralisation with solid potassium carbonate. The solid obtained was isolated by filtration, washing sequentially with water, ethanol and diethyl ether to afford the subtitle compound as a yellow solid (12.11 g, 93% combined yield). Rf 0.23 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 298 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[N:18]=[N:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)=[CH2:2].[H][H]>[Pd].CO>[CH2:1]([C:3]1[N:18]=[N:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cc2c(nn1)Nc1ccccc1NC2=O
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c(nn1)Nc1ccccc1NC2=O
Yield: 100.4 %

Procedure:
A solution of 2-vinyl-5,10-dihydro-3,4,5,10-tetraaza-dibenzo[a,d]cyclohepten-11-one from Example 10 (40 mg, 0.17 mmol) and 5 mg of palladium on charcoal (10%) in 50 ml of methanol was stirred under 1 atm of hydrogen for 70 min. Filtration and evaporation to dryness afforded the title compound as a pale yellow solid (41 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]2[NH:37][N:36]=[CH:35][CH:34]=2)[CH:3]=1.IC.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]2[CH:34]=[CH:35][N:36]([CH3:40])[N:37]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccn[nH]1)c(OCc1ccccc1)c2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1ccc(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.4 %

Procedure:
A solution of N-(4-fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.185 g, 0.36 mmol) in N,N-dimethylformamide (3 ml) was treated with iodomethane (0.025 ml, 0.4 mmol) and potassium carbonate (0.076 g, 0.55 mmol) and the resulting mixture was stirred at 25° C. for 5 h. The reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried over anhydrous magnesium and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in dichloromethane) gave 0.120 g (64% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.62 (6H, s, 2×CH3), 3.84 (3H, s, NCH3), 3.95–4.05 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.21 (2H, s, OCH2), 6.49 (1H, d, J=2.2 Hz, CH), 7.01 (1H, m, aromatic), 7.24–7.3 (4H, m, aromatics), 7.40 (1H, d, J=2.2 Hz, CH), 7.42–7.45 (2H, m, aromatics), 7.64 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.75 (1H, broad t, NH). HRMS (ESI+) calculated for C28H29FN5O4 [M+H+]: 518.2204. found: 518.2222.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li].O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.00 mL, 27.0 mmol, 1.00 equiv, Aldrich) in anhydrous ether at −78° C. under argon was added methyllithium (1.4M in Et2O, 54.0 mL, 53.9 mmol, 2.00 equiv). Stirring was continued at −78° C. for 1.5 hours. Ether (200 mL) and water (40 mL) were added, and the two phases were separated. The aqueous solution was extracted with Et2O (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc to EtOAc-MeOH 9:1) to give 4.81 g (87%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Br:32]N1C(=O)CCC1=O.C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC>C(Cl)(Cl)Cl>[Br:32][CH:23]1[C:9]2[C:10](=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:31])=[CH:6][CH:5]=3)[N:8]=2)[N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:21][CH2:22]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3)cc1
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3Br)cc1

Procedure:
To a stirred solution of tert-butyl 2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (stepl) (530 mg, 1.275 mmol) in chloroform (10 ml) was added N-bromosuccinimide (272 mg, 1.531 mmol) followed by lauroyl peroxide (50.8 mg, 0.128 mmol) and the mixture was heated to reflux for 1 hour. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound which was used directly into the next step
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[O:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20]CCCC)[CH2:15][CH2:14]1)[N+:10]([O-:12])=[O:11].O(C1CCNCC1)[N+]([O-])=O.C(Br)CCCCC>C(O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([O:9][N+:10]([O-:12])=[O:11])[CH2:14][CH2:15]1)[CH3:20]
Reactant: CCCCCCN1CCC(O[N+](=O)[O-])CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=[N+]([O-])OC1CCNCC1
Solvent: CCCCCCBr
Solvent: CCO
Product: CCN1CCC(O[N+](=O)[O-])CC1
Yield: 50 %

Procedure:
4-nitroxy-1-hexylpiperidine fumarate from 4-nitroxypiperidine and n-hexyl bromide; yield 50% of theory; solvent: ethanol; m.p. 102°-103° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][OH:14])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(OCC)(=O)C>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:1][CH2:2][CH3:3])(=[O:25])=[O:24]
Reactant: CCCOc1ccccc1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 3-(2-propoxyphenyl)-1-propanol (729 mg) dissolved in THF (35 ml) were added at 0° C. triethylamine (1.57 ml) and methanesulfonyl chloride (0.44 ml). The resulting mixture was stirred at 0° C. for 20 minutes and at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) as a colorless oil.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH2:41]([C:43]1[S:44][C:45]([CH:51]=O)=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=1)[CH3:42].O>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:45]1[S:44][C:43]([CH2:41][CH3:42])=[N:47][C:46]=1[CH:48]([CH3:49])[CH3:50]
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: CCc1nc(C(C)C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Solvent: O
Product: CCc1nc(C(C)C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)OC)s1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
1,1,3,3-Tetramethylguanidine (107 mg, 0.93 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 300 mg, 0.62 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then 2-ethyl-4-(1-methylethyl)thiazole-5-carboxaldehyde (Example 61; 224 mg, 1.24 mmol) was added. The solution was stirred over a weekend at room temperature, then water was added and the layers were separated. The aqueous layer was extracted with two portions of dichloromethane then the combined organic layers were washed in turn with brine, 0.5N hydrochloric acid solution, water and brine. The dried (MgSO4) organic extracts were evaporated and the resulting oil was purified by chromatography over silica gel. Evaporation of the appropriate fractions afforded (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]3-[2-ethyl-4-(1-methylethyl)thiazole-5-yl]propenoic acid methyl ester (220 mg, 65% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH3:12])[CH:11]=1)=[O:4].C([Li])CCC.[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](OC)=O)=[CH:33][CH:32]=1)[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C:9]3=[N:8][CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:22])([CH3:21])[CH3:1])[CH:11]=[C:10]3[CH:12]=2)=[CH:33][CH:32]=1)[CH3:29]
Reactant: CCOc1ccc(CC(=O)OC)cc1
Reactant: Cc1cc(NC(=O)C(C)(C)C)cnc1NCC1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc3cc(NC(=O)C(C)(C)C)cnc3n2CC2CCOCC2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a solution of 2,2-dimethyl-N-[5-methyl-6-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]-3-pyridinyl]-propanamide (2.0 g, 6.55 mmol) in THF (70 ml) at −78° C. was added n-butyl lithium (11.5 ml of 2.0 M solution in cyclohexane, 23.0 mmol). The mixture was stirred for one hour at −20° C. and then cooled to −78° C. To this reaction mixture was cannulated a solution of methyl 4-ethoxy-benzeneacetate (1.72 g, 7.88 mmol) in THF (50 ml) at −78° C. After stirring for 3 hours at room temperature, the mixture was quenched with NaHCO3 saturated aqueous solution (200 ml) and diluted with EtOAc (100 ml). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (100 ml). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MeOH+0.5% NH4OHaq] in CH2Cl2) to provide 750 mg of the title compound N-[2-[(4-ethoxyphenyl)methyl]-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2,2-dimethyl-propanamide. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.31 (m, 2 H) 1.34 (s, 9 H) 1.40 (t, J=7.03 Hz, 3 H) 1.56 (m, 2 H) 2.04 (m, 1 H) 3.22 (m, 2 H) 3.35 (m, 2 H) 3.90 (t, J=3.32 Hz, 2 H) 4.00 (m, 2 H) 4.06 (s, 2 H) 6.12 (s, 1 H) 6.83 (m, 2 H) 7.07 (d, J=8.79 Hz, 2 H) 7.32 (m, 1 H) 8.09 (d, J=2.34 Hz, 1 H) 8.15 (d, J=2.34 Hz, 1 H). MS (ESI) (M+H)+: 451.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1>>[NH2:16][C:17]1[NH:18][N:19]=[C:20]([S:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:15])[C:6]=2[CH2:12][CH2:13][CH3:14])[N:21]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Product: CCCc1c(CSc2n[nH]c(N)n2)ccc(C(C)=O)c1O
Yield: 61.7 %

Procedure:
Using 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.18 g of 3-amino-5-mercapto-1,2,4-triazole as starting materials, 0.25 g of 4'-[[(5-amino-1,2,4-triazol-3-yl]thio]methyl]-2'-hydroxy-3'-propylacetophenone was obtained in a manner similar to Example 25.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[O-:17][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[Na+].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5](=[O:17])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O

Procedure:
Known in the present-day practice is a method of producing the bisulfite compound of 2-fluorenonyl-glyoxal, said method consisting in that fluorene is acylated by acetic anhydride in the presence of aluminum chloride to obtain 2-acetylfluorene at a yield of 60 weight percent. Then the thus-obtained 2-acetylfluorene is oxidized by sodium bichromate in an acetic-acid medium at 70°-75° C during 6 hours and 2-acetylfluorenon is isolated at a yield of 50 weight percent.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C1C=CC=CN=1)C.[F:26][C:27]1[C:32]([F:33])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:29][C:28]=1O.FC(C(F)CCCCC)COC1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.[Li].C(OO)(C)(C)C.C([Li])CCC.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.ClCCl>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:32]([F:33])[C:27]=2[F:26])=[O:13])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OO
Agent: CC(C)(C)OOC(C)(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OCCCCCC)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.1 mol of 4-hexyloxybenzoic acid, 0.01 mol of dimethylaminopyridine and 0.1 mol of 2,3-difluoro-4octyloxyphenol (preparable from 2,3-difluorooctyloxybenzene by lithiation at -70° to -80° and dropwise addition of a solution of lithium t-butylperoxide in ether prepared from 0.12 mol of t-butyl hydroperoxide and 0.12 mol of butyllithium) are introduced into 150 ml of dichloromethane, a solution of 0.1 mol of dicyclohexylcarbodiimide in 30 ml of dichloromethane is added dropwise with stirring at 10o, and the mixture is subsequently stirred at room temperature for 15 hours. The mixture is filtered through silica gel, the solvent is evaporated, and 2,3-difluoro-4-octyloxyphenyl 4-hexyloxybenzoate is obtained as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][CH2:32][CH2:31]2>>[CH2:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][CH:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: Nc1ccc2c(c1)CCC2
Product: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.40 g) and 5-aminoindan (680 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[CH:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1)#[N:8].S([CH2:31][N+:32]#[C-:33])(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:31][NH:32][CH:33]=2)[CH:12]=[CH:13][CH:14]=1)#[N:8]
Reactant: COC(=O)/C=C/c1cccc(C#N)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a suspension of 12.0 g (107 mmol) of potassium tert-butoxide at 60% in oil, in 100 ml of anhydrous tetrahydrofuran, is added dropwise a mixture of 13.3 g (71.1 mmol) of methyl (E)-3-(3-cyanophenyl)acrylate (CAS 193151-10-9) and 13.9 g (71.1 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 100 ml of tetrahydrofuran, while maintaining the temperature of the reaction medium at about 25° C. The mixture is then stirred for 2 hours at room temperature, and is then partially concentrated under reduced pressure. This solution is then poured into ice-water and the reaction product is then extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is triturated in chloroform to give 10.8 g of methyl 4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured solid after cooling, filtering off and drying.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Br)=[CH:11][N:10]=[C:9]1[S:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([F:18])[CH:20]=2)=[CH:11][N:10]=[C:9]1[S:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CSc1ncc(Br)c(=O)n1Cc1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(SC)n(Cc3ccccc3)c2=O)cc1F
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
In a separate flask, 3-benzyl-5-bromo-2-(methylthio)pyrimidin-4(3H)-one (580.5 mg, 1.87 mmol), tris(dibenzylideneacetone)dipalladium (0) (65.0 mg, 0.0710 mmol), 3-fluoro-4-methoxyphenylboronic acid (492.3 mg, 2.90 mmol), S-Phos (97.7 mg, 0.238 mmol), and potassium phosphate (1.250 g, 5.89 mmol) were suspended in toluene (15 ml) and nitrogen was bubbled through for about 30 seconds. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100 C) and stirred under nitrogen for 105 minutes. The reaction was then cooled to room temperature and allowed to stand overnight.