Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][CH:25]=O)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.[OH-].[NH4+:38].II>O>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:38])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Agent: II
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.8 %

Procedure:
Method B. A solution of (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37, 169 mg, 0.399 mmol) in tetrahydrofuran (THF, 1.2 mL, 15 mmol) at room temperature was added a 14.3 M solution of ammonium hydroxide (NH4OH) in water (1.2 mL), followed by iodine (I2, 112 mg, 0.439 mmol, 1.1 equiv). The resulting reaction mixture was stirred at room temperature for 25 min. When LCMS showed that the reaction was deemed complete, the reaction mixture was quenched with 10% aqueous Na2S2O3 (10 mL) before being extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-60% EtOAc/hexane gradient elution to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-12, 145.6 mg, 167.8 mg theoretical, 86.8% yield) as a colorless foam.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[O:8]([CH2:15][C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[CH:22]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C:23](=[CH2:27])[CH2:24][S:25](=O)[C@H:20]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(=O)C.C(OCC)(=O)C>[O:8]([CH2:15][C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[CH:22]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C:23]([CH2:27][O:4][C:1](=[O:3])[CH3:2])=[CH:24][S:25][C@H:20]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 5 ml. of fresh acetic anhydride were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting mixture was added one drop of acetyl chloride. The mixture was refluxed at 130°--140° C. for 2.75 hours and then was cooled. Ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate and then with water. The resulting organic layer was separated and evaporated to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate as a foam.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].CN(C)C1C=CC=CC=1.[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:6]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CCCCl
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)CCCCl

Procedure:
A mixture of 4-chlorobutyryl chloride (93 g, 0.66 mol), N,N-dimethylaniline (80 g, 0.66 mol) and tert-butanol (0.66 mol) in ethyl ether (100 mL) was refluxed for 5 h. The reaction was cooled, diluted with ether and washed with water, 10% citric acid, saturated NaCl and dried over Na2SO4. Crude product obtained after evaporation of the solvent was distilled under vacuum (10 mmHg). Pure product (79 g, 67%) boiling at 57-58° C. was collected. 1H NMR (DMSO-d6) δ 3.64 (t, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 1.93 (q, 2H), 1.41 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C@H:18]2[NH:21]C(=O)OC(C)(C)C)=[CH:14][CH:13]=1)=[O:11]>ClCCl>[NH2:21][C@H:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([C:10]([N:9]([CH3:8])[CH:29]3[CH2:30][CH2:31][N:32]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[CH2:33][CH2:34]3)=[O:11])[CH:20]=2)[CH2:16][CH2:17]1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2)C1CCN(c2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccc2c(c1)[C@H](N)CC2)C1CCN(c2ccncc2)CC1
Reaction time: 1 h

Procedure:
TFA (1 ml) was added dropwise at 0° C. to a solution of (R)-tert-butyl 6-(methyl(1-(pyridin-4-yl)piperidin-4-yl)carbamoyl)-2,3-dihydro-1H-inden-1-ylcarbamate (0.2 g, 0.44 mmol, 1 eq) in dichloromethane (5 ml), and stirring was carried out for 1 h at RT. Then the solvent was concentrated under reduced pressure. The residue was taken up in dichloromethane and concentrated again. Then the TFA salt was stirred for 1 h with Amberlyst-21 in MeOH (10 ml) and filtered. The filtrate was concentrated under reduced pressure and used in the next stage without being purified further.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[C:26]([CH3:34])=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=3)[C:30]#[N:31])[C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[C:29]([C:30]#[N:31])[C:28]([Cl:33])=[CH:27][C:26]=1[CH3:34])([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(N)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3cc(C#N)c(Cl)cc3C)[C@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (0° C.) solution of 5-((1R,2S)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-4-methylbenzonitrile (intermediate 77d) (200 mg, 0.40 mmol) in CH2Cl2 (4.0 mL) and pyridine (1.04 mL) was added, portion wise, acetyl chloride (0.14 mL, 2.0 mmol). Upon complete addition the reaction mixture was warmed slowly to room temperature and stirred for 23 h. The reaction mixture was then cooled to 0° C. and quenched with 10% ap HCl (5 mL) then H2O (15 mL) was added. The solution was extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange oil, which was used without further purification (199 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 7.80 (br s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 5.57 (d, J=8.9 Hz, 1H), 4.99 (dd, J=1.8, 8.9 Hz, 1H), 4.76-4.68 (m, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.27 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].[CH2:23](O)[CH2:24][CH2:25][CH3:26].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2c(=O)n1CC1CC1
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 6-bromo-2-cyclopropylmethyl-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (7.32 g, 20 mmol), 1-butanol (2.7 mL, 30 mmol) and tributylphosphine (10.0 mL, 40 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (10.09 g, 40 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified, by silica gel column chromatography to give ethyl 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (7.24 g, 85.8%) as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8]Cl)[N:3]=[CH:2]1.[C:10]1([CH2:16][CH2:17][CH2:18][SH:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>C(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][S:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: ClCCCc1c[nH]cn1
Reactant: SCCCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: c1ccc(CCCSCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propyl chloride are introduced into a solution of 6 mmol of 3-phenylpropanethiol and 10 mmol of sodium in 30 ml of ethanol and the mixture is brought to reflux for 3 h. The suspension is evaporated under vacuum until dryness, potassium carbonate is added and the mixture is stirred in methanol/water. The residual semi-solid oil is brought to boiling in ethanol with active charcoal, filtered and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [C:1](C1C=C2C(=CC=1)C(=O)CCC2(C)C)#[CH:2].Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][CH:20]2[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([O:29][CH:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([C:1]#[CH:2])[CH:18]=3)[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)CCC(OC2CCCCC2)c2cc(Br)ccc21
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Product: C#Cc1ccc2c(c1)C(OC1CCCCC1)CCC2(C)C

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 2.1 g (8.8 mmol) of 6-bromo-4-cyclohexyloxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound J) was converted into the title compound using 1 g (10.2 mmol) of trimethylsilyl acetylene, 0.14 g (0.20 mmol) of bis(triphenylphosphine)palladium(II) chloride, 19 mg (0.1 mmol) of cuprous iodide and 80 mg (0.6 mmol) of K2CO3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=C(OC)C=1OC)(=O)C1C=CC=CC=1.[N+]([O-])(O)=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])cc(OCc2ccccc2)c1OC
Agent: COc1cccc(C(=O)c2ccccc2)c1OC
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COc1cccc(OCc2ccccc2)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
from 2-chloro-N-(3-methoxyphenyl)-4-pyrimidineamine (1 62 mg, 0.69 mmol) [see Example 92] and 3-benzyloxy-4,5-dimethoxyaniline (180 mg, 0.69 mmol) to afford the title compound (255 mg) as an off-white solid m.p. 83-84°. δH (CDCl3) 8.01 (1H, d, J 5.8 Hz), 7.45-7.22 (6H, m), 6.95 (3H, m), 6.90 (1H, d, J 7.6 Hz), 6.79 (1H, d, J 2.4 Hz), 6.68 (1H, d, J 7.6 Hz), 6.48 (1H, s), 6.17 (1H, d, J 5.8 Hz), 5.11 (2H, s), 3.86 (3H, s), 3.82 (3H, s) and 3.78 (3H, s). MS m/z 369 (M+H)+. The 3-benzyloxy-4,5-dimethoxyaniline was prepared by heating a solution of 1-benzyloxy-2,3-dimethoxy-5-nitrobenzene (1.80 g, 6.23 mmol) in ethanol (15 ml) with saturated aqueous sodium hydrosulphite (20 ml) at reflux for 2 h. An additional quantity of sodium hydrosulphite (20 ml) was added and reflux continued for a further 4 h. The reaction mixture was reduced to a small volume then diluted with water and extracted three times with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give the crude product which was recrystallised from etherhexane to give the desired product (356 mg) as a white crystalline solid m.p. 118-120°. MS m/z 260 (M+H)+. The 1-benzyloxy-2,3-dimethoxy-5-nitrobenzene used as starting material was prepared by treating a solution of 1-benzoyl-2,3-dimethoxybenzene (7.25 g, 29.66 mmol) in glacial acetic acid (15 ml) portionwise with 70% nitric acid (2.84 ml) at room temperature. After 2 h, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with 1 M NaOH, then brine, dried (MgSO4) and evaporated. The crude product was purified by column chromatography [silica 20% ethyl acetate-hexane] to give, after recrystallisation from CH2Cl2 -hexane, the desired product (1.89 g) as a white solid m.p. 101-102°. MS m/z (relative intensity) (M+H)+ 289 [(M+H),+ 2%] 91 [100%]. 1-Benzyloxy-2,3-dimethoxybenzene was prepared by the method of F Dietl et al Synthesis, 626 (1985).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1-c1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(-c4ccc(F)cc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 44 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-(2,5-dichloropyrimidin-4-yl)-5-fluoro-N,N-dimethylbenzenesulfonamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 44% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.39 (m, 2H), 8.08 (m, 1H), 7.48 (d, 2H, J=8.4 Hz), 7.30-7.20 (m, 4H), 3.41 (s, 2H), 2.82 (s, 6H), 2.40 (bs, 8H), 2.22 (s, 3H); MS (ESI): 519.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:12](=[O:13])[NH:23][N:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(CC(=O)O)c2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)CC2c2ccccc2)cc1
Yield: 99 %

Procedure:
A solution of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid (1.5 g, 5.28 mmol) and hydrazine hydrate (1.5 eq., 363 μL) in 20 mL of EtOH was stirred at 80° C. overnight. The solvent was reduced and the solid was filtered and then washed with cold EtOH to give 6-(4-methoxy-phenyl)-5-phenyl-4,5-dihydro-2H-pyridazin-3-one (1.46 g, 99%): mp 176-7° C.; MS m/z 281 (M+H).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].Br[C:13]1[N:14]=[C:15]([CH3:28])[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17]=1[CH:18]=O.CCCCCC>C(O)C>[CH3:28][C:15]1[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:17]2[CH:18]=[C:6]([C:5]([O:9][CH2:10][CH3:11])=[O:8])[S:7][C:13]=2[N:14]=1
Reactant: Cc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1cc2c(nc(C)n2COCC[Si](C)(C)C)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.68 M Sodium ethylate was dissolved in ethanol (50 ml) and a solution (25 ml) of ethyl thioglycolate in ethanol was added. Thereto was added a solution (150 ml) of 4-bromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazol-5-carboxaldehyde (3.16 g) in ethanol and the mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure and water was added. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was obtained by silica gel column chromatograhy (hexane/ethyl acetate=9/1). Hexane was added to the purified product and crystals were collected by filtration to give the objective compound (765 mg) as pale-brown crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].C1C(CCCCC(N)=O)SSC1>C(O)C>[CH3:11][C:9]([CH2:8][C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])=[O:12])=[O:10]
Reactant: OCC(O)CO
Reactant: CCOC(=O)CC(C)=O
Agent: NC(=O)CCCCC1CCSS1
Solvent: CCO
Product: CC(=O)CC(=O)OCC(O)CO

Procedure:
In accordance with at least one other embodiment of the present technology, glycerol can be treated with ethyl acetoacetate in presence of a lipase at from about 55° C. to about 70° C., alternatively from about 20 to about 75, for approximately 14 to 48 hours, alternatively 20 to 36 hours. The lipase can be, for example, Novozyme® 435, Lipozyme® RM IM, or Lipozyme® TL IM, all available from Novozymes A/S, Franklinton, N.C. The reaction can be performed in an inert (e.g., nitrogen) atmosphere. During the reaction, ethyl alcohol by-product can be removed, for example, via distillation. At the end of the reaction, the remaining ethyl acetoacetate can be removed through distillation (e.g., at 60° C., 1 mmHg). The structure of the triglyceride of acetoacetin produced can be confirmed through, for example, NMR analysis and/or GC.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Yield: 100.2 %

Procedure:
To a well stirred solution of (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (1.167 g, 3.576 mmol) and 4-(N,N-dimethylamino)pyridine (0.655 g, 5.364 mmol) in CH2Cl2 (20 mL) was added powdered 4-nitrophenyl chloroformate (0.937 g, 4.65 mmol) at room temperature. Solvent was evaporated and the residue was purified by column chromatography on silica gel using hexanes/EtOAc (7/3%) as the eluent to give (−)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.761 g, 100%) as a viscous oil. [α]D=−335.3 (c=1.0 g in 100 mL CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:41])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O>CCCCCC.C(OCC)(=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:21]([CH2:20][CH2:19][C:18]([OH:41])=[O:17])[CH:26]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(C)=O)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 11 and starting with 0.2 g (1 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.39 g (1 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester (from example 32), 5-acetyl-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid was obtained in 64.3% overall yield, as a colorless solid, mp 115°-118° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.C([O:23][C:24](=O)[CH:25]([Cl:27])[Cl:26])C>CO>[Cl:26][CH:25]([Cl:27])[C:24]([NH:1][C@H:2]([CH2:12][F:13])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:23]
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol (5.0 g, 20.0 mmol) in methanol (100 mL) is added triethylamine (9.56 mL, 67.8 mmol) and ethyldichloroacetate (6.22 mL, 50.8 mmol) and the mixture heated to reflux for 16 hours. After allowing to cool to room temperature, the solvent is removed under reduced pressure the resultant oil purified by column chromatography eluting from neat heptanes to 80% ethylacetate/heptanes to give the title compound (5.94 g). m/z (Cl) M+H 405.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8]([CH:15]=[CH2:16])=[CH:7]3.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:15]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]1=[N:13][C:12]=2[NH2:14])[CH3:16]
Reactant: [H][H]
Reactant: C=Cc1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cnc2c(N)nc3cc(C)ccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 8-methyl-2-vinylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite and washed with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethyl-8-methylbenzo[f][1,7]naphthyridin-5-amine as an offwhite solid. 1H NMR (CDCl3): δ 8.61 (d, 1H), 8.42 (d, 1H), 8.10 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 2.84 (q, 2H), 2.45 (s, 3H), 1.33 (t, 3H). LRMS [M+H]=238.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:14]=[CH:13][S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CS(=O)(=O)C=CSc1ccc(C(C)(C)C)cc1

Procedure:
In a manner analogous to Example 1, 4-t-butylphenylsulfenyl chloride was added in 1:1 proportion to divinyl sulfone, subjected to treatment with triethylamine in benzene, and purified by column chromatography. The product, vinyl 2-(4-t-butylphenylthio)vinyl sulfone, was obtained as a brown oil which crystallized on standing, m.p. 62-64° C; calculated for C14H18O2S2 :S, 22.7; found: S, 22.0; Cl, O.