Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Product: CCCCN(c1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 302 from methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate and n-butylbromide. colorless crystals (yield 57%). MS (APCI−): 402 (M−H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[N:20]=[C:19]([C:21]#N)[CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl.[O:24]1CCCC1>C(OCC)(=O)C>[C:11]([C:15]1[N:20]=[C:19]([CH:21]=[O:24])[CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C#N)n1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(C=O)n1
Reaction time: 1.5 h

Procedure:
Diisobutylaluminum hydride (1.02 mol/L toluene solution, 23.5 mL, 24.1 mmol) was added to a solution of 6-tert-butylpyridine-2-carbonitrile obtained (2.57 g, 16.0 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at −78° C., and the mixture was stirred for 1.5 hr while cooling in ice. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was diluted with ethyl acetate and stirred at room temperature for 45 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=4:1) to afford the title compound as a yellow oil (1.71 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+].O1CCCC1.[ClH:40]>C(O)C.O>[ClH:40].[ClH:40].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(OCCCCCCOC)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A mixture of ethyl 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoate (3.00 g) in ethanol (30 ml) was treated with 1N-sodium hydroxide aqueous solution (6.81 ml) then the mixture was refluxed for 24 hours, during which period tetrahydrofuran (20 ml) and 1N-sodium hydroxide aqueous solution (6.81 ml) was added. After cooling, water was added to the mixture, and the acidity of the mixture was adjusted to pH 1 with 1N-hydrochloric acid. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acid dihydrochloride (2.25 g) as an ocher solid.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:13]3[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][C:19]([CH3:26])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4C(OC(C)(C)C)=O)([OH:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][CH:23]([F:24])[O:22][C:21]1[C:13]([C:10]([C:8]2[NH:7][C:6]3[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)([OH:12])[CH3:11])=[C:14]2[C:18](=[C:19]([CH3:26])[CH:20]=1)[NH:17][CH:16]=[CH:15]2
Reactant: Cc1cc(OC(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc(OC(F)F)c(C(C)(O)c2nc3ccc(C#N)cc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: Cc1cc(OC(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 60 °C

Procedure:
To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (310 mg, 0.504 mmol) in THF (5 mL) at room temperature, ethylenediamine (0.34 mL, 5.04 mmol) was added followed by TBAF (1M in THF, 5.04 mL, 5.04 mmol) and the reaction was stirred at 60° C. After 2 days the reaction was cooled to room temperature, quenched with sat. aq. WWI and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (s, 1H) 11.12 (br. s., 1H) 8.06 (m) 7.81 (m) 7.65-7.74 (m) 7.46-7.56 (m) 7.29 (t, J=2.78 Hz, 1H) 6.72 (br. s., 1H) 6.68 (s, 1H) 6.65 (t, J=75.8 Hz, 1H) 6.22 (s, 1H) 2.45 (s, 3H) 2.09 (s, 3H). HRMS calcd. for C20H16F2N4O2 (M+H)+ 383.1314. found 383.1321.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:26])[NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])[CH3:17])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@H:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[NH:8]2)=[O:26])[CH3:17])[CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C)c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R,3S,5R)-3-[(R)-1-(3-chloro-2-fluoro-phenyl)-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (3.2 g, 8.36 mmol) in CH2Cl2 (30 mL) was added TFA (15 mL, 195 mmol) and the solution was stirred at RT for 1 h. The crude reaction mixture was concentrated under vacuum, the residue was suspended in MeOH and concentrated again under vacuum. The crude product was used without further purification in the next step. MS (LC/MS): 283.0 [M+H]+; tR (HPLC conditions c): 3.41 min.
Reaction SMILES: [H-].[Na+].C(OCCOCCO)C.Cl[C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15].[C:24](=[S:26])=[S:25]>>[SH:26][C:24]1[S:25][C:13]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCOCCO
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a mixture of sodium hydride (0.98 g, 40.91 mmol) and diethylene glycol monoethyl ether (25 mL) was added 2-chloro-5-(trifluoromethyl)aniline (5.00 g, 25.57 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 30 minutes, and then carbon disulfide (3.89 g, 51.13 mmol) was added. The reaction mixture was then heated at 140° C. for 6 hours. After cooling the solution to rt, the product was precipitated by addition of conc. HCl, collected by filtration, and recrystallized from isopropyl ether to afford 2-mercapto-5-(trifluoromethyl)benzothiazole (2.65 g, 44%). 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.61 (d, 1H), 7.94 (d, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:15])[CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][CH:17]1[CH2:19][NH:18]1>>[OH:15][CH:8]([CH2:9][O:10][C:11](=[O:14])[CH2:12][CH2:13][N:18]1[CH2:19][CH:17]1[CH3:16])[CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1CN1
Reactant: C=CC(=O)OCC(O)COC(=O)C(=C)C
Product: C=C(C)C(=O)OCC(O)COC(=O)CCN1CC1C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a 250 mL round bottomed flask were added 3-(acryloyloxy)-2-hydroxypropyl methacrylate (32.1 g, 0.15 mol, available from Aldrich, cat. 454982) and 2-methylaziridine (10.8 g, about 0.17 mol, 90% pure, available from Aldrich). The reaction flask was cooled briefly in an ice bath and then allowed to stand at room temperature overnight. Excess 2-methylaziridine was removed at reduced pressure to leave the desired product (40.4 g) as a colorless liquid. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2S([O-])(=O)=O)[CH:4]=[CH:3][CH:2]=1.[Na+].[OH-:16].[Na+]>O>[OH:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=S(=O)([O-])c1cccc2cccnc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc2cccnc12
Yield: 97.2 %

Procedure:
Sodium quinoline-8-sulfonate (231 g) was added to 170 g of a 50% aqueous solution of sodium hydroxide, and the mixture was stirred. Then, 900 g of a hydrogenated triphenyl mixture was mixed, and the mixture was dehydrated. The dehydrated mixture was reacted at 260° C. for 15 minutes in a nitrogen stream. After cooling, 600 ml of water was added to the reaction mixture to separate the reaction medium layer. The aqueous layer was decolorized with activated carbon, acidified and then extracted with 200 ml of chloroform. The chloroform was recovered to give 140.9 g (yield 97.2%) of 8-hydroxyquinoline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)(=[O:19])[CH3:18]
Reactant: Nc1nc2cnccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cnccc2s1
Yield: 46 %

Procedure:
To a suspension of 2-aminothiazolo[4,5-c]pyridine [prepared according to the procedure in T. Takahashi et al., Pharm. Bull. (Japan) 2, 34 (1954)] (151 mg, 1 mmole) in acetic anhydride (1 ml) was added pyridine (1 ml), and the mixture was heated at 100°-120° C. for an hour. After cooling, the mixture was diluted with CH2Cl2 (20 ml). The resulting precipitate was collected by filtration and recrystallized from methanol (20 ml) to give 90 mg of the title compound as fine needles (46%). Mp. >212° C. (sub.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29].C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:33]4[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[CH:31][CH:32]=4)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3ccc(C#N)cc3)cc21
Temperature: 110 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
4-(2-bromo-9,9-dihexyl-9H-fluoren-7-yl)benzonitrile was prepared through the following procedure. A mixture of 2,7-dibromo-9,9-dihexyl-9H-fluorene (0.985 g, 2 mmol), 4-cyanophenylboronic acid (0.146 g, 1 mmol), and tetrakis(triphenylphosphine) palladium (11.6 mg, 0.01 mmol) were added to an air-free two-phase mixture of toluene (25 mL) and aqueous 2M Na2CO3 solution (15 mL). The resulting mixture was vigourously stirred under argon atmosphere at 110° C. for 24 hours. The organic layer was separated and the aqueous phase was extracted with ether. The organic layers were washed with brine (2×50 mL), and dried with anhydrous MgSO4. The solvent was evaporated and the residue passed through a silica-gel column. 0.27 g of pure product were obtained by recrystallization in heptane with a yield of 51%. 1H NMR (400 MHz, CDCl3): δ(ppm) 7.766-7.751 (m, 5H), 7.605-7.583 (d, J=8.8 Hz, 1H), 7.583-7.564 (d, J=7.6 Hz, 1H), 7.524 (s, 1H), 7.495-7.476 (m, 2H), 2.013-1.964 (m, 4H), 1.140-1.053 (m, 12H), 0.781-0.746 (t, J=7.0 Hz, 6H), 0.658-0.624 (m, 4H).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[CH2:14][C:15]([C:17](=[N:23][O:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O>C(Cl)(Cl)Cl>[S:2]1[CH:14]=[C:15]([C:17](=[N:23][O:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:5][CH2:4][CH2:3]1
Reactant: NCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1=CSCCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-mercaptoethylamine hydrochloride (10.0 g.) in chloroform (100 ml.) were added triethylamine (18.7 g.) and ethyl 2-chloroacetyl-2-methoxyiminoacetate (26.2 g., purity 70%) under ice-cooling and stirred at room temperature for 1.5 hours. After the resultant solution was concentrated in vacuo, water was added to the residue and extracted with diethyl ether four times. The extract was washed with a saturated aqueous solution of sodium chloride, and extracted with 10% hydrochloric acid 4 times. The hydrochloric acid extract was washed with diethyl ether twice and adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate, and further extracted with diethyl ether 4 times. The extract was dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.2 g.), oil.
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26]Br>O1CCCC1>[CH3:23][O:24][CH2:25][CH2:26][N:11]1[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:20])[CH2:9][C:10]1=[O:19]
Reactant: COCCBr
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28.6 gm (0.1 mol) of 5-phenyl-7-chloro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione were suspended in 750 ml of absolute tetrahydrofuran, 5 gm of a 50% dispersion of sodium hydride in tetrahydrofuran were added to the Suspension and the mixture was stirred for two hours at room temperature, whereby everything went into solution. 21-28 gm (0.15 - 0.2 mol) of β-bromo-ethyl methyl ether were then added to the solution, and the resulting mixture was refluxed for 15-20 hours. Thereafter, the reaction solution was evaporated in vacuo, residue was admixed with water, and the aqueous mixture was extracted with methylene chloride. The methylene chloride extract was vacuum-filtered to remove insoluble components, the filtrate was evaporated, and the residue was recrystallized from isopropyl ether, yielding 22 gm (64% of theory) of the compound of the formula ##SPC7##
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([N+:8]([O-])=O)[CH:4]=[N:3]1.[ClH:11]>CO.[Pd]>[ClH:11].[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[CH:4]=[N:3]1
Reactant: Cc1c([N+](=O)[O-])cnn1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(N)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 1,5-dimethyl-4-nitro-1H-pyrazole (1.01 g, 7.2 mmol) in MeOH (15 mL) was added Pd/C (10%, 0.20 g) and concentrated HCl (1 mL, 12 mmol) in a high pressure autoclave under 2 MPa H2. The reaction mixture was stirred at rt overnight and filtered. The filtrate was concentrated in vacuo to give the title compound as brown oil (763.0 mg, 95.9%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[CH:19]([O:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([Cl:30])[C:27](Cl)=[N:26][CH:25]=1)([CH3:21])[CH3:20].O>C1COCC1>[CH3:18][O:17][N:16]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][C:27]1[C:28]([Cl:30])=[CH:29][C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:32])=[CH:25][N:26]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)OC(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
NaH (60% dispersion in mineral oil, 0.23 g, 12.0 mmol) was washed (2×) with hexanes then suspended in THF (10 mL) to which 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.89 g, 4.0 mmol) in THF solution was added. The solution was stirred at room temperature for 10 minutes at which time isopropyl-5,6-dichloronicotinate (1.00 g, 4.3 mmol) in THF solution was added. After 15 minutes of stirring at room temperature, the solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL) . The organics were dried over MgSO4 and concentrated to 1.5 g tan, viscous oil. Crude product was chromatographed using silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 petroleum ether/ethyl acetate as the mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(isopropoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (0.72 g) as a white solid.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]([CH3:26])([CH3:25])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([N+:22]([O-])=O)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8]>C(O)C.[Pd]>[NH2:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]([CH3:5])([CH3:25])[CH3:26])[CH2:10][CH2:11]2)=[N:16][CH:17]=1
Reactant: Cc1cc(N2CCN(C(=O)C(C)(C)C)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(N2CCN(C(=O)C(C)(C)C)CC2)ncc1N
Temperature: 90 °C

Procedure:
Add ammonium formate (1.55 mmol, 0.1 g) and palladium (Carbon) 10% (0.031 mmol) over a solution of 2,2-dimethyl-1-[4-(4-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-propan-1-one (0.31 mmol, 0.09 g) in 2 mL of ethanol. Stir the solution for an hour at 90° C. Cool down and filter through a pad of Celite®, and concentrate under reduced pressure. Residue can be used without further purification. MS(ES): m/z=277 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[C:19]2[C:10]([CH2:11][CH2:12][C:13]3[S:17][C:16]([SH:18])=[N:15][C:14]=32)=[CH:9][CH:8]=1)C.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:18][C:16]2[S:17][C:13]3[CH2:12][CH2:11][C:10]4[C:19](=[CH:20][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=4)[C:14]=3[N:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)-c1nc(S)sc1CC2
Product: O=C(O)COc1ccc2c(c1)-c1nc(SCC(c3ccccc3)c3ccccc3)sc1CC2
Yield: 69 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 69%.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[O:12]>CC(C)=O>[C:1]([NH:9][CH:11]([OH:12])[C:10]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=CC(=O)O
Solvent: CC(C)=O
Product: O=C(NC(O)C(=O)O)c1ccccc1

Procedure:
A mixture of commercially available benzamide 35 and glyoxylic acid 41 was heated at reflux in acetone to give pure N-benzoyl-2-hydroxyglycine 65 as a colourless solid in quantitative yield (Scheme 4.12). The 1H n.m.r. spectrum supported formation of the α-hydroxyglycine derivative 65 with the appearance of a methine (H2) doublet and broad amide (NH) doublet at δ 5.60 and δ 9.26 respectively. Spectroscopic data were in agreement with those reported in the literature.209
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:31])[C@@H:15]([NH:23]C(=O)OC(C)(C)C)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]([CH3:32])[N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][C:11]1[N:10]([CH3:32])[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:12]=1)=[O:31]
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To a 250 ml flask was added 18.8 g of tert-butyl (S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 1.D, 100 ml of DCM and 50 ml of TFA. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed with a stream of nitrogen. The crude was partitioned between 2000 ml of DCM and 500 ml of saturated aqueous sodium bicarbonate. The organic layer was extracted twice more with 500 ml of water, dried over sodium sulfate and the organic solvent was removed by rotary evaporation. The crude was purified using a silica gel column (eluting with 5% MeOH in DCM) to give 8.6 g of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 17.7.E as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])=[O:13].C(OCC)C>CO>[CH3:10][O:11][C:12](=[O:13])[CH:14]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CC(Nc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
3,5-Dichloroaniline (104 g) and dimethylacetylene dicarboxylate (79 ml) were dissolved in dry methanol (100 ml) and heated under reflux for 14 h. On cooling a yellow solid crystallised out and this was collected by filtration. The mother liquors were concentrated in vacuo to leave a residue from which a second crop of product was obtained by recrystallisation from diethyl ether/60-80 petrol. The combined crops of material weighed 167.5 g (after drying at 40° C. under a pressure of 20 mmHg for 18 h). A portion of this material (105 g) was dissolved in ethyl acetate (1000 ml) and hydrogenated at 50 psi over 10% palladium on carbon catalyst (4 g) for 40 h. The catalyst was removed by filtration and the solvent evaporated under vacuum to leave a residue which was recrystallised from diethyl ether/hexane to give the title compound as a white crystalline solid (84.8 g, m.p. 66°-67° C.); δ (360 MHz, CDCl3 ) 2.88 (2H, m, CHBHC), 3.71 (3H, s, CH3), 3.78 (3H, s, CH3), 4.36 (1H, t, J=5.4 Hz, CHACHBHC), 4.71 (1H, br, s, NH), 6.51 (2H, d, J=1.8 Hz, 2-H and 6-H), 6.73 (1H, t, J=1.8 Hz, 4-H); m/e 305 (M+), 246 (100%, M-CO2CH2); Found C, 47.14; H, 4.27; N, 4.56. C12H13Cl2NO4 requires C, 47.08; H, 4.28; N, 4.58%.