Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.[OH-].[Na+]>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1
Reactant: c1cc2c(s1)CCNC2
Reactant: ClCc1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: c1ccccc1
Product: Clc1ccccc1CN1CCc2sccc2C1
Reaction time: 40 h
Yield: 79.7 %

Procedure:
To a solution of 4,5,6,7-tetrahydrothieno-[3,2-c]pyridine hydrochloride (24.0 g, 0.137 mol) and 2-chlorobenzyl chloride (26.4 g, 0.164 mol) in benzene (100 ml) were added an aqueous 2.5N NaOH solution (150 ml, 0.375 mol) and tetra-n-butyl ammonium hydrogen sulfate (1.0 g, 0.003 mol). The mixture was stirred for 40 hours at toom temperature. The reaction mixture was allowed to stand, thereby separating an organic layer from an aqueous layer. The aqueous layer was extracted with benzene (100 ml×2 times). The originally separated organic layer was combined with the extracted benzene layer, and the combined organic layer was washed with water and then with saturated NaCl solution, dried (over K2CO3), and concentrated. The residue was distilled under reduced pressure to prepare 28,8 g (yield 80.0%) of 5-(2-chlorobenzyl)-4,5,6,7tetrahydrothieno[3,2-c]pyridine as an oily product, b.p. 155.0°-158.0° C. (1.5 mmHg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][C:15]=1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(-c2ccc(Cl)c(CNC(=O)OC(C)(C)C)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Yield: 100.7 %

Procedure:
Methyl 3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-chlorophenyl)benzoate (199 mg) was dissolved in 3 ml of methanol, 100 mg of 10% palladium-carbon was added thereto, and the mixture was stirred at room temperature for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, then washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 182 mg of the title compound.
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[C@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16]([OH:18])=[O:17])(C(C)(C)C)(C)C.Cl.[OH-].[Na+]>CO.CN(C=O)C>[N:13]([C@H:10]1[C:11](=[O:12])[NH:8][C@@H:9]1[C:16]([OH:18])=[O:17])=[N+:14]=[N-:15]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](N=[N+]=[N-])[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
In 39 ml of methanol was dissolved 1.78 g of compound (23) and 9.85 ml of 1N hydrochloric acid was added to the solution. The mixture was stirred for 1.75 hours at room temperature. The reaction mixture was cooled to 0° C. and 9.85 ml of 1N sodium hydroxide was added thereto. The mixture was concentrated to dryness under reduced pressure to obtain an oil. The oil was dissolved in 10 ml of DMF and 3A molecular sieve was added thereto. After the mixture was allowed to stand overnight, the solvent was removed by distillation under reduced pressure to obtain (2S,3R)-3-azido-4-oxo-2-azetidinecarboxylic acid (24). This compound was used in the following Example 7 as it was.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O>>[C:32]1([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3)cs2)C1

Procedure:
42 mg (0.064 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 15 mg (0.077 mmol) of 2-bromo-1-phenylethanone were reacted according to the General Method 3. Yield: 11 mg (34% of theory)
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18]([O:22][CH3:23])([O:20][CH3:21])[CH2:17][CH2:16][NH:15]2)=[C:10]([CH3:24])[CH:9]=1>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][C:18]([O:22][CH3:23])([O:20][CH3:21])[CH2:17][CH2:16][NH:15]2)=[C:10]([CH3:24])[CH:9]=1
Reactant: COC1(OC)CCNC(c2ccc(F)cc2C)C1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC1(OC)CCN[C@@H](c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 29.1 %

Procedure:
To 130 ml of ethyl acetate suspension of 10.1 g of 2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine and 3.18 g of L-N-acetylvaline was added 35 ml of methanol, and the mixture was heated to dissolve, and then, cooled down at room temperature. After 3.5 hours, precipitated crystals were collected by filtration, and washed with 20 ml of ethyl acetate. The obtained crystals were dried under reduced pressure. Subsequently, 50 ml of chloroform was added thereto, and the mixture was washed with 30 ml of a 2M aqueous sodium hydroxide solution and 30 ml of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the obtained residue was added ether, and precipitated crystals were further concentrated under reduced pressure, to give 2.94 g of (2R)-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine (optical purity:97.0% ee) as shown in Table 125 below.
Reaction SMILES: [C:1]([O:22]C(CCC=C(C)C)(C=C)C)(=[O:21])[C:2]1[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:4]([O:6]C(CCC=C(C)C)(C=C)C)=[O:5]>O1CCCC1.[Pd]>[C:1]([OH:22])(=[O:21])[C:2]1[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:4]([OH:6])=[O:5]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)c1ccccc1C(=O)OC(C)(C=C)CCC=C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
A solution of 10 g (22.8 mmol) dilinalyl phthalate (prepared by the procedure of Example 1) in 100 mL tetrahydrofuran was treated with 2 g palladium on charcoal catalyst and hydrogenated quickly at 40 psi. A small amount of cleavage gave some phthalic acid byproduct, so the mixture was chromatographed on silica gel to give 7.1 g (70% yield) of pure viscous liquid Compound 6, confirmed by its nmr spectrum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:24][CH:23]=[CH2:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]c(C(=O)OCC)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of 5-hydroxyindole-2-carboxylic acid ethyl ester (14.2 g, 68.5 mmol) in DMF (150 mL) was added cesium carbonate (26.8 g, 82.3 mmol). The resulting mixture was stirred at room temperature for 20 min followed by the addition of allyl bromide (5.94 mL, 68.5 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was diluted with ethyl acetate, washed with H2O, brine and dried (Na2SO4). The solvent was removed in vacua and the resulting crude product was purified by flash column chromatography on silica gel (0-20% EtOAc/hexanes) to give the desired material as solid (8.9 g, 52%). LC/MS (ES+) m/e 248 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:18]2[CH:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.CC(O)(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]2[C:18]3[CH:17]=[C:16]([C:19]([F:21])([F:20])[F:22])[CH:15]=[CH:14][C:13]=3[S:12][C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1ccc2c(c1)N(CC1CO1)c1ccccc1S2
Solvent: CC(C)(C)O
Product: OC(CN1CCOCC1)CN1c2ccccc2Sc2ccc(C(F)(F)F)cc21

Procedure:
Utilizing the procedure outline in Example 1, Step 2, (±)-10-(oxiran-2-ylmethyl)-2-(trifluoromethyl)-10H-phenothiazine and 2-methyl-2-propanol (127 mg, 0.39 mmol) was reacted with morpholine (41 μL, 0.48 mmol) to afford the title compound. LCMS m/z 411 (M+H)
Reaction SMILES: C([O-])(=O)C.[OH-].[Ba+2].[OH-].[NH2:8][CH:9]1[CH2:13][CH:12]([CH2:14][OH:15])[CH:11]=[CH:10]1.[C:16]([C@:24]([C:39]([OH:41])=[O:40])([OH:38])[C@:25]([C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([OH:29])[C:26]([OH:28])=[O:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(O)C.C(#N)C.C(O)(=O)C>[C:30]([C@:25]([C:26]([OH:28])=[O:27])([OH:29])[C@:24]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:38])[C:39]([OH:41])=[O:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH2:8][C@@H:9]1[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]1
Reactant: NC1C=CC(CO)C1
Agent: CC(=O)[O-]
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: [Ba+2]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: N[C@H]1C=C[C@@H](CO)C1
Temperature: 25 °C

Procedure:
(±)-cis-4-Acetamidocyclopent-2-enemethyl acetate was hydrolyzed with barium hydroxide as in Example 1. The resulting syrup (acetic acid salt of (±)-4-amino-2-cyclopentene-1-methanol) was converted to free amine by stirring with an excess of Amberlite IRA-400 (OH-) resin in water. The resin was filtered off, washed with water, and the filtrate-wash evaporated to a pale yellow syrup which was dried by evaporation of portions of ethanol. Such a sample of amine (2.26 g, 20.0 mmol) and dibenzoyl-D-tartaric acid (Aldrich, 3.62 g, 10.0 mmol as 99%) were dissolved in hot absolute ethanol (35 mL). Refluxing acetonitrile (ca. 150 mL) was added to the cloud point and the solution was allowed to cool slowly to room temperature. The white needles which formed were recrystallized three times from the same solvent combination to give title compound as white plates (1.07 g, 37%); m.p. 160°-162°; [α]20D +66.9°, [α]20436 +165°, [α]20365 +325° (c=0.28, methanol). X-ray crystallography of this salt allowed the absolute configuration of the cation to be fixed by the known configuration of the D-dibenzoyl tartaric acid dianion. This salt crystallized in the space group C2 with one C6H12NO cation and one-half C18H14O8 dianion as the asymmetric unit.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[O:24].C1(C)C=CC=CC=1>O1CCCC1>[OH:24][CH:23]([C:8]1[N:7]([CH3:6])[C:15]2[C:10]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C=O
Reactant: Cn1cc(-c2ccccc2)c2ccccc21
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(-c2ccccc2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A solution of butyllithium (1.6 M, 3.44 mL, 5.5 mmol) was added at −20° C. to a solution of 1-methyl-3-phenyl-1H-indole (1b) (1.08 g, 5.3 mmol) in anhydrous tetrahydrofuran (20 mL) under a nitrogen atmosphere. After 1 hour, a solution of ethyl glyoxylate in toluene (50%, 1.1 mL, 5.5 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 hours, quenched with water (5 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (1c) as a white solid (360 mg, 1.16 mmol, 22%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[CH2:34]([NH:38][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[CH:35]([CH3:37])[CH3:36]
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CNC(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 mg (1.05 mmol) of CDI were added to a solution of 323 mg (1.00 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (16 ml), and the mixture was stirred for 1 hour at RT. 99 μl (1.00 mmol) of isobutylamine were then added, and stirring was continued for a further 5 days at RT. The reaction solution was then washed in each case twice with a 4 M aq. ammonium chloride solution and a 1 M aq. sodium hydrogen carbonate solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue obtained was taken up in ethyl acetate (30 ml) and washed with 0.4 M hydrochloric acid (5 ml). The organic phase was again dried over MgSO4, filtered and concentrated in vacuo. 160 mg (0.42 mmol, 42 of N-(isobutyl)-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue. MS: m/z 379.1 [M+H]+
Reaction SMILES: C[Si](C)(C)[O-].[K+].C[O:8][C:9](=[O:41])[C@@H:10]([NH:16][C:17]([C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][N:25]2[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:21][C:20]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40])=[O:18])[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl>C1COCC1>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[O:32][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:19]=1[C:17]([NH:16][C@@H:10]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[C:9]([OH:41])=[O:8])=[O:18])[N:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[N:24]=[CH:23]2
Reactant: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@@H](CCN(C)C)C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
Potassium trimethylsilanolate (1.77 g, 13.8 mmol) was added to a solution of (S)-2-{[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-dimethylaminobutyric acid methyl ester (3.36 g, 6.88 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 4 hours. HCl (17 mL of 4M in dioxane) was added to the mixture before it was concentrated under reduced pressure. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated under reduced pressure to afford 2.23 g of product (68% yield). MS (ESI+) m/z 475 (M+1) detected; 1H NMR (400 mHz, DMSO-D6) δ 8.81 (d, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.48 (m, 1H), 7.25 (m, 1H), 7.22 (s, 1H), 7.11 (m, 1H), 4.50 (m, 1H), 4.28 (d, 2H), 3.17 (m, 1H), 3.04 (m, 1H), 2.70 (s, 6H), 2.25 (m, 2H), 2.13 (m, 1H), 0.87 (d, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([OH:27])[CH2:24]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][C:23](=[O:27])[CH2:24]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(O)CC2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CCC(=O)CC2C1
Temperature: -78 °C
Reaction time: 0.28 h
Yield: 86.8 %

Procedure:
4.9 g of oxalyl chloride was dissolved in 250 ml of dichloromethane and cooled to −78° C. in a nitrogen atmosphere. Then a solution of 4.83 g of dimethyl sulfoxide in dichloromethane (20 ml) was dropped thereinto over 17 minutes. Subsequently, a solution of 3.73 g of 8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol in dichloromethane (40 ml) was dropped thereinto over 10 minutes. After stirring for 10 minutes, 7.82 g of triethylamine was dropped thereinto over 10 minutes and stirring was continued for additional 1 hour. The reaction mixture was brought back to room temperature, diluted with dichloromethane, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.21 g of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@@H:13]([C:15]2[N:19]([CH2:20][CH3:21])[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH2:38][CH2:37][C:32]5(OCC[O:33]5)[CH2:31][CH2:30]4)[CH:24]=3)=[N:17][N:16]=2)[CH3:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+]>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@@H:13]([C:15]2[N:19]([CH2:20][CH3:21])[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH2:30][CH2:31][C:32](=[O:33])[CH2:37][CH2:38]4)[CH:24]=3)=[N:17][N:16]=2)[CH3:14])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCn1c(Oc2cccc(N3CCC4(CC3)OCCO4)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(Oc2cccc(N3CCC(=O)CC3)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of the compound (0.981 g) of Example 7 in THF (10 mL), 2N aqueous hydrochloric acid (8.4 mL) was added, and the mixture was stirred at room temperature for one hour. Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 50° C. for six hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (acidic OH SiO2, ethyl acetate) and then recrystallized (chloroform-hexane) to give the titled compound (0.572 g, colorless powder).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[O:20]1[CH2:25][C:24](=[O:26])[NH:23][C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]1=2>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:23]2[C:24](=[O:26])[CH2:25][O:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]2=3)=[CH:14][CH:15]=1
Reactant: O=C1COc2ccccc2N1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: O=C1COc2ccccc2N1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 2H-benzo[b][1,4]oxazin-3(4H)-one. M/e+ 390 for C22H17ClN3O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.32 (d, J=6.9 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.53 (m, 3H), 7.19 (ddd, J=9.1, 6.9, 1,1 Hz, 1H), 6.82 (m, 3H), 6.48 (m, 1H), 6.26 (d, J=7.7 Hz, 1H), 5.68 (s, 2H), 4.60 (s, 2H) ppm.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH:14]#[C:15][C@@H:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:22][C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:15]#[CH:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@H](O)CCCCC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#C[C@H](CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The procedure of Noyori (Suzuki, M., et al., J. Med. Chem. 41, 3084-3090 (1998)) was used. Imidazole (971 mg, 14.3 mmol) and t-butylchlorodimethylsilane (1.43 g, 9.51 mmol) were added to a solution of (S)-1-octyn-3-ol SI-8 (1.00 g, 1.16 ml, 7.92 mmol) in CH2Cl2 (18 ml), cooled to 0° C. The reaction mixture was then stirred at room temperature for 24 h before being poured into 1 M HCl (50 ml). The mixture was extracted with 40/60 petroleum ether (3×50 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgSO4), filtered, and concentrated to give the title compound SI-7 (1.89 g, 99%) as a clear, colourless oil. Analytical data consistent with the literature (Nicolaou, K. C. et al., A. J. Am. Chem. Soc. 107, 7515-7518 (1985); Cmrecki, V. et al., Tetrahedron 66, 6550-6564 (2010)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:14][C:13](=[O:15])[C:12]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[CH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1

Procedure:
Methanol (3L) was added to thoroughly dried Compound IV (427.5 g, 1.42 mol) under argon. To this stirred suspension concentrated sulfuric acid (100 mL) was added and heated at reflux for 20 h under argon. Methanol was evaporated under reduced pressure at 30° C. The residue was taken up in ethyl acetate (3 L) and washed with water (2×1 L), saturated aqueous Na HCO3 (pH 8, 2×1 L), saturated aqueous sodium chloride solution (2×1 L). Organic layer was dried on anhydrous magnesium sulfate, filtered and the solvent was evaporated. The crude product obtained was dried thoroughly under high vacuum and used as such in the next step. Yield: white solid, 433.6 g (97%). 1HNMR(CDCl3): δ 7.72(s, 1H), 7.06(d, J=7.9 Hz, 2H), 6.77(d, J=7.9 Hz, 2H), 6.33(t, J=2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 2H), 5.74(s, 1H), 3.81(s, 3H), 3.60(s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([OH:18])=O)[CH:3]=1.S(Cl)([Cl:21])=O.CN(C)C=O.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([Cl:21])=[O:18])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
To a mixture of 4,5-dichloro-6-(4-chlorophenyl)picolinic acid (3.00 g, 9.9 mmol) in toluene (25 mL) was added thionyl chloride (1.08 mL, 14.9 mmol) and dimethylformamide (0.04 mL, 0.5 mmol). Reaction mixture was heated at 80° C. for 2.5 h. HPLC analysis of the reaction mixture treated with methanol and dimethylaminopyridine indicated starting material remaining. Reaction mixture was allowed to cool to room temperature and additional thionyl chloride (0.5 mL, 6.9 mmol) and dimethylformamide (0.04 mL, 0.5 mmol) were added. Reaction was heated at 80° C. for an additional 2 h. Reaction was allowed to cool to room temperature and concentrated under reduced pressure to provide a white solid. Toluene (40 mL) was added to dissolve the solid and concentrated under reduced pressure and then this process was performed a second time. 4,5-Dichloro-6-(4-chlorophenyl)picolinoyl chloride was isolated as a white solid (3.05 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.79-7.72 (m, 2H), 7.53-7.46 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 168.66, 157.63, 146.48, 145.44, 136.35, 135.10, 134.28, 131.04, 128.63, 124.90. LRMS: Calcd. for C12H5Cl4NO, 320.91. Found: m/z=257 (M+-COCl), 222, 207, 186, 151.