Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([F:38])[CH:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH3:39])[C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([F:38])[CH:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c(-c3ccnc(F)c3)[nH]2)CC1
Solvent: Cc1ccccc1
Product: Cn1c(C2CCN(C(=O)OCc3ccccc3)CC2)nc(-c2cccc(C(F)(F)F)c2)c1-c1ccnc(F)c1
Temperature: 120 °C

Procedure:
To a stirring solution of 4-[5-(2-fluoropyridin-4-yl)-4-(3-trifluoromethylphenyl)1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (13.1 g, 0.025 mmole) in toluene (130 mL) was added N,N-dimethylformamide dimethyl acetal (13.1 mL). This mixture was heated to 120° C. under argon for 28 hours. The reaction was cooled, concentrated in vacuo, poured into a saturated aqueous solution of sodium bicarbonate (300 mL) which was extracted with ethyl acetate (1×1 L, 2×300 mL). The organic extracts were combined, washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate and concentrated to an oil. The oil was dissolved in methylene chloride (5 mL) and chromatographed on silica using 2% acetone/methylene chloride to give upon concentration of the product containing fractions the title compound 2.00 g.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:57]([CH:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:58]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:66][CH:59]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH2:57][CH3:58])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18]
Reactant: CCC(N)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(F)cc2F)c2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(F)cc1F)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a mixture of 1-(2,4-difluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid in DMF was added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture was stirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added. The reaction mixture was stirred at rt for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the title compound. LC-MS 433 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:19][C:20]1[NH:24][C:23]2[CH:25]=[C:26]([O:34][CH2:35][CH:36]([F:38])[F:37])[C:27]([C:29]([O:31]CC)=O)=[CH:28][C:22]=2[N:21]=1.[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C[Al](C)C.C1(C)C=CC=CC=1>O1CCOCC1>[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:29]([C:27]2[C:26]([O:34][CH2:35][CH:36]([F:37])[F:38])=[CH:25][C:23]3[NH:24][C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]5([C:15]([F:18])([F:17])[F:16])[CH2:13][CH2:14]5)=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:21][C:22]=3[CH:28]=2)=[O:31])=[CH:42][CH:41]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cc1)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F

Procedure:
The title compound was prepared in accordance with Example 59 (i) using ethyl 2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylate (0.200 g; 0.36 mmol), 4-bromoaniline (0.184 g; 1.07 mmol), Me3Al in toluene (0.900 mL; 2 M; 1.80 mmol) and 1,4-dioxane (10 mL). Yield: 0.115 g (47%). 400 MHz 1H-NMR (DMSO-d6, ppm) 11.3-11.1 (1H, br s) 10.17 (1H, s) 9.1-8.8 (1H, br s) 8.65-8.57 (1H, m) 8.53 (1H, t, J=5.8 Hz) 7.95-7.90 (1H, m) 7.80-7.73 (2H, m) 7.63-7.57 (2H, m) 7.49 (1H, d, J=8.4 Hz) 7.31-7.26 (1H, m) 6.94 (1H, dd, J=8.2, 1.6 Hz) 6.59 (1H, tt, J=54.3, 3.1 Hz) 4.57 (2H, td, J=14.9, 3.0 Hz) 4.38 (2H, d, J=5.8 Hz) 1.54-1.47 (2H, m) 1.38-1.31 (2H, m). MS m/z: 686, 688, 690 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])=[N:7]2
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(Br)cccc2n1

Procedure:
5-Bromo-2-chloroquinoline (CAS 99455-13-7, 2.4 g, 10 mmol) and 2-methoxybenzylamine (2.7 g, 20 mmol) were stirred in a sealed tube at 120° C. for 3 days. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a light yellow solid (2.3 g, 67%), MS: m/e=343.1, 345.0 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C([O+]([B-](F)(F)F)CC)C.[Cl-].Cl[C:27](Cl)=[N+:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCOCC>C1(C)C=CC=CC=1>[Br:15][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]2[C:13]=1[O:14][C:27]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:2][C:1]2=[O:3]
Reactant: ClC(Cl)=[N+]1CCOCC1
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Agent: CC[O+](CC)[B-](F)(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a stirred solution methyl 3-acetyl-5-bromo-4-hydroxybenzoate (106 g, 388 mmol) in toluene (1 L) was added dropwise (diethyloxonio)trifluoroborate (0.201 L, 1630 mmol), under nitrogen. The resulting solution was left to stir overnight at room temperature, then 4-(dichloromethylene)morpholin-4-ium chloride (143 g, 698 mmol) was added and mixture heated at 90° C. for 12 h. Upon cooling to room temperature, ether (1.5 L) was added and the solid was collected by filtration. This solid was then suspended in MeOH (1 L) and the mixture was heated at 50° C. for 2 h. Upon cooling to room temperature, the solid was collected by filtration then solubilized in DCM (1 L) and washed with water and a saturated solution of sodium bicarbonate. The organic layer was dried over MgSO4, filtered and evaporated to dryness to afford methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (68.0 g, 47.6%) as an off-white solid. Mass Spectrum: m/z [M+H]+=368.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:40][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4ccccn4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a solution of (E)-N-[4-(2-pyridylmethyl)phenyl]3-(4-methylphenyl)cinnamamide (302 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give (E)-N-[4-(1-oxidopyridin-2-ylmethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (Compound 191) (180 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([CH3:16])=[CH:6][N:5]2[C:17]=1[C:18]([O:20]CC)=[O:19].[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([CH3:16])=[CH:6][N:5]2[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2c(OCCC(C)C)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCC(C)C)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C

Procedure:
2.25 g (7.4 mmol) of ethyl 2,6-dimethyl-8-(3-methylbutoxy)imidazo[1,2-a]pyridine-3-carboxylate Example 88A were initially charged in 157 ml of THF/methanol (5:1), 37 ml (37 mmol) of 1N aqueous lithium hydroxide solution were added and the reaction mixture was stirred at RT over the weekend. The mixture was then cooled to 0° C., acidified to pH 4 with 6 N aqueous hydrochloric acid and freed from organic solvent on a rotary evaporator. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 1.64 g (80% of theory; purity 100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH:16]([O:19][CH3:20])[O:17][CH3:18].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:29])[CH3:28])=[C:3]([CH:16]([O:17][CH3:18])[O:19][CH3:20])[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(OC)c1cc(C(=O)c2ccccc2)ccc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1NC(C)=O
Yield: 100 %

Procedure:
To a stirred and cooled (10° C.) solution of 22.1 parts of intermediate 64, namely [4-amino-3-(dimethoxymethyl)phenyl] phenylmethanone, in 147 parts of pyridine were added dropwise 12.1 parts of acetyl chloride. After stirring for 1/2 hour at 10° C. and overnight at room temperature, the reaction mixture was poured into water. The product was extracted with 2,2'-oxybispropane and dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was dissolved in dichloromethane. This solution was washed successively with HCl 0.1N, ammonia and water and was then dried, filtered and evaporated, yielding 27.5 parts (100%) of N-[4-benzoyl-2-(dimethoxymethyl)phenyl]acetamide (interm. 65).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:16]1[N:17]=[C:18]([Cl:27])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[NH:22][C:21]=12)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:28])[N:7]([C:16]1[N:17]=[C:18]([Cl:27])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]=12)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1[nH]c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)nc(Cl)cc2c1C
Reactant: BrCc1ccccc1
Product: Cc1c(C)n(Cc2ccccc2)c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)nc(Cl)cc12
Yield: 70 %

Procedure:
In accordance with the same procedures as in Example 657, except for using (5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 2 and benzyl bromide, the titled compound was obtained as yellow oil. (Yield: 70%)
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([OH:7])=[O:6].[NH2:8][CH:9]1[CH:12]2[S:13][CH2:14][C:15]3[CH:19](O)[O:18][C:17](=[O:21])[C:16]=3[N:11]2[C:10]1=[O:22]>O>[NH2:8][CH:9]1[C:10](=[O:22])[N:11]2[C:16]([C:17]([OH:21])=[O:18])=[C:15]([CH:19]=[N:2][O:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:14][S:13][C@H:12]12
Reactant: NOCC(=O)O
Reactant: NC1C(=O)N2C3=C(CSC12)C(O)OC3=O
Agent: Cl
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(C=NOCC(=O)O)CS[C@H]12
Reaction time: 8 h

Procedure:
A solution of 1.86 g of the hydrochloride of aminooxyacetic acid in 20 ml of water is treated under stirring at 0° with 3.16 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin. The mixture is stirred for ca. 8 hours at 0°. 7-Amino-3-[[(carboxymethoxy)imino]methyl]-3-cephem-4-carboxylic acid precipitates in form of colourless crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:12][C:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)([CH3:11])[C:9]([OH:23])=[O:8]
Reactant: CC(C)(C(=O)OCc1ccccc1)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc2ccccc2c1
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 2,2-dimethyl-(2-naphthyl)acetic acid benzyl ester (0.46 g, 1.5 mmol) and 10% Pd/C (0.040 g) in ethanol (5 mL) was hydrogenated at 1 atmosphere for 16 hours. The catalyst was removed by filtration, and the solvent was evaporated to give 2,2-dimethyl-(2-naphthyl)acetic acid (0.33 g, 1.5 mmol. 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (10.0 g, 41 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (1.2 equiv) was added, followed by methanesulfonyl chloride (1.2 equiv). The mixture was stirred at room temperature for 48 hours, then diluted with DCM (100 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (11.9 g, 37 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:41])[C@@H:10]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([Cl:39])[C:32]=1[CH3:40])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:39][C:33]1[C:32]([CH3:40])=[C:31]([NH:30][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:41])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
Deprotection of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(tert-butyldimethyl silyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 8c) (327 mg, 0.5 mmol) was performed as described for the preparation of example 7 using tetrabutylammonium fluoride (1.0 M solution in THF, 2.1 mL, 2.1 mmol). After column chromatography (80% EtOAc/hexanes) the title compound was isolated as a white solid (176 mg, 86%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.84 (AA′XX′, J=9.0 Hz, 2H), 7.49 (d, J=8.7 Hz, 1H), 6.99 (AA′XX′, J=9 Hz, 2H), 6.86 (d, J=8.7 Hz, 1H), 5.67 (d, J=8.4 Hz, 1H), 5.06 (dd, J=3.8, 8.3 Hz, 1H), 4.60 (dd, J=3.6, 6.3 Hz, 1H), 2.39 (s, 3H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)/[CH:6]=[CH:7]/[CH:8]=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=[C:30]1[S:26][C:27](=[O:32])[NH:28][C:29]1=[O:31]
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(/C=C/C=O)ccc1OCc1coc(-c2ccccc2)n1
Product: COc1cc(C=CC=C2SC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Yield: 57 %

Procedure:
According to the same manner as that described in Example 1, (E)-3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamylidene]-2,4-thiazolidinedione (yield: 57%). This product was recrystallized from chloroform-methanol. Yellow needles, mp: 230-231° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:15]3[C:16]([CH2:24][CH3:25])=[C:17]([C:19]([O:21]CC)=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:15]3[C:16]([CH2:24][CH3:25])=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc2c1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(CC)c(C(=O)O)sc3c2)nc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Ethyl 6-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethyl-1-benzothiophene-2-carboxylate obtained in Example (183f) (49 mg) was dissolved in methanol (2 ml) and THF (2 ml). A 2 N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at 50° C. for 30 minutes. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water and ethyl acetate, and dried under reduced pressure at 45° C. to obtain 40 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:19][C:20]1[N:21]=[CH:22][C:23]([C:26](Cl)=[O:27])=[N:24][CH:25]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:26]([C:23]2[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][N:24]=2)=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cnc(Cl)cn1
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cnc(Cl)cn2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mmol) and triethylamine (0.557 ml, 4 mmol) in dichloromethane (20 ml) was added 5-chloro-pyrazine-2-carbonyl chloride (0.354 g, 2 mmol) at 0-5° C. The mixture was allowed to stir at room temperature for 3 hours. The mixture was diluted with methylene chloride (20 ml), washed with saturated NaHCO3 (20 ml), brine (20 ml), dried (anhyd. Na2SO4) and concentrated to get 0.42 g of crude 5-chloro-pyrazine-2 carboxylic acid(3,4-dimethoxy-phenyl)-amide, which was directly used in the next reaction.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([OH:17])[C:13](=[O:16])[CH2:14][OH:15])=O)(C)(C)C.[ClH:21]>>[ClH:21].[CH3:6][NH:8][CH2:9][C@H:10]([OH:19])[C@@H:11]([OH:18])[C@H:12]([OH:17])[C:13](=[O:16])[CH2:14][OH:15]
Reactant: CN(C[C@H](O)[C@@H](O)[C@H](O)C(=O)CO)C(=O)OC(C)(C)C
Agent: Cl
Product: CNC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO

Procedure:
8 g (0.027 mole) of N-tert.-butoxycarbonyl-6-methylamino-6-desoxy-L-sorbose were deblocked hydrolytically in a manner analogous to that in Example 9. 5 g of the syrupy hydrochloride, which was immediately further processed because of its readiness to decompose, were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=1N1C=CN=C1CO.C1(=O)NC(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 17, 2'-chloro-5-nitro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-5-nitro-2-[2-phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH:1]([C:4]1[C:9](C[C@@H](C2C=CC=CC2(O)C)OS(O)(=O)=O)=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:7]([CH2:32][CH2:33][CH3:34])=[C:6]([CH:35]([CH3:37])[CH3:36])[N:5]=1)([CH3:3])[CH3:2].[CH2:38]([OH:40])[CH3:39]>[Ni]>[CH:1]([C:4]1[C:9]([CH:38]([OH:40])[CH3:39])=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:7]([CH2:32][CH2:33][CH3:34])=[C:6]([CH:35]([CH3:36])[CH3:37])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1c(C(C)C)nc(C(C)C)c(C[C@H](OS(=O)(=O)O)C2C=CC=CC2(C)O)c1-c1ccc(F)cc1
Reactant: CCO
Agent: [Ni]
Product: CCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A suspension of Raney nickel (40 g, washed with 3×100 mL ethanol) in ethanol (80 mL) was stirred under hydrogen atmosphere for 1.5 hours. The suspension was treated with a solution of the intermediate obtained in Step B (4.1 g, 8.5 mmol) in ethanol (180 mL) at room temperature and stirred vigorously for 5 hours. The suspension was carefully filtered through celite and concentrated. Filtration through silica gel (CH2Cl2) afforded the title compound (99% e.e.) as a white solid (2.74 g, 8 mmol, 94%). 1H NMR (300 MHz, CDCl3): δ 7.11 (m, 3H), 7.04 (m, 1H), 4.64 (dq, J=3.7, 6.6 Hz, 1H), 3.73 (sept, J=6.6 Hz, 1H), 3.18 (sept,. J=6.6 Hz, 1H), 2.15 (m, 2H), 1.56 (d, J=3.7 Hz, 1H), 1.39 (d, J=6.6 Hz, 3H), 1.28 (m, 14H), 0.73.(t, J=7.35 Hz, 3H). FAB-MS calculated for (C22H31FNO, M+H) 344, found 344. Anal. Calcd for C22H30FNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53; Found: C, 77.20; H, 8.97; N, 4.01; F, 5.60. [a]D=+39.4° (CH2Cl2). mp 104-106° C. Rf=0.4 (CH2Cl2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)O1.Br[C:28]1[S:29][CH:30]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:32]=1>>[CH2:36]([O:35][C:33]([C:31]1[N:32]=[C:28]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[S:29][CH:30]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: CCOC(=O)c1csc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and ethyl 2-bromo-1,3-thiazole-4-carboxylate (Combi-Blocks, Cat. No. HI-1116). LCMS (M+H)+: m/z=389.0.