Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@@H:9]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[C@H:8]([N+:21]([O-])=O)[CH2:7][CH2:6]2.Cl>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@@H:9]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[C@H:8]([NH2:21])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](c1ccc(C)s1)[C@H]([N+](=O)[O-])CC2
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@@H](c1ccc(C)s1)[C@H](N)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a suspension of 1.52 g of trans-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(5-methyl-2-thiophenyl)-2-nitro-naphthalene (4.5 mmol), from step 1c above, in 40 mL of 95% ethanol and 12 mL of 6 N HCl was added 2.97 g of Zn dust (45 mmol), added in four portions. The mixture was stirred at room temperature for 30 min, filtered, and the flitrate concentrated to half the original volume, then extracted with methylene chloride after addition of aqueous sodium bicarbonate solution. The organic extract was dried over Na2SO4 and concentrated to yield 1.35 g of the title product. MS (M+H)+ : 304. NMR (CDCl3) δ:6.70 (d, 1H, J=3 Hz), 6.60 (bs, 2H), 6.46 (s, 1H), 3.88 (d, 1H, J=8 Hz), 3.85 (s, 3H), 3.69 (s, 3H), 3.18 (m, 1H), 2.92-2.78 (m, 2H), 2.43 (s, 3H), 2.12-2.04 (m, 1H), 1.78-1.64 (m, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([C:17]([F:20])([F:19])[F:18])[CH2:16][CH2:15]2)=O)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].O>O1CCCC1>[F:19][C:17]([F:18])([F:20])[C:14]1([CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([CH2:4][OH:3])[CH2:11][CH2:10]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C(F)(F)F)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCN(CC2(C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
1-(1-Trifluoromethyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (50 g; 170.48 mmol) in tetrahydrofuran (350 mL) is added to a solution of 1 M lithium aluminum hydride (170.48 mL; 170.48 mmol) in tetrahydrofuran. The reaction mixture is allowed to warm to room temperature and stirred for 1 h. The reaction mixture is cooled at 0° C. and water/2 M aqueous solution of sodium hydroxide/water (1:3:1) are added sequentially (8.5 mL:12 mL:8.5 mL). The resulting slurry is filtered over a celite® pad and washed with tetrahydrofuran (200 mL). The organic layer is concentrated under controlled vacuum to afford 17 g of the volatile title compound as colorless oil. The crude material is used without further purification. MS (m/z) 238 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[CH3:13][N:14]=[C:15]=[O:16]>CCOCC>[CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:15](=[O:16])[NH:14][CH3:13])[CH2:5][CH2:4]1
Reactant: COC1CCC(N)c2ccsc21
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)NC1CCC(OC)c2sccc21
Reaction time: 8 h
Yield: 75 %

Procedure:
Crude 4,5,6,7-tetrahydro-7-methoxybenzo[b]thiophen-4-amine (2.3 g, 12.57 mm) is dissolved in ether (50 ml) and the stirred solution treated with a solution of methyl isocyanate (2.9 ml) in ether (10 ml), added over a period of 20 minutes. After stirring overnight the product is filtered off, washed twice with ether (50 ml total) and air dried to afford the title compound (2.25 g, 75% Y) m.p. 152° C-159° C. The analytical sample is recrystallized from acetone and has m.p. 164° C-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11](/[CH:10]=[CH:9]/[C:8]([NH:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([CH:20]=[CH:19][CH:18]=2)[O:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:17])[CH:12]=1
Reactant: COC(=O)CCl
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (1.07 g, 4.0 mmol) obtained in Example 81 and methyl chloroacetate (0.52 g, 4.8 mmol) were dissolved in dimethylformamide (12 ml) and potassium carbonate (1.66 g, 12 mmol) was added and stirred at 60° C. for 8 hours. After allowing to cool, ethyl acetate was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was recrystallized to yield the titled compound (0.83 g, 61%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([S:13]([CH2:16][C:17]#[N:18])(=[O:15])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>>[CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([S:13]([C:16](=[CH:22][O:21][CH2:19][CH3:20])[C:17]#[N:18])(=[O:15])=[O:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: N#CCS(=O)(=O)N1CCC(Cc2ccccc2)C1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)S(=O)(=O)N1CCC(Cc2ccccc2)C1
Yield: 46.5 %

Procedure:
To a solution of 0.14 g (0.53 mmol) of 2 in 0.43 mL (2.6 mmol) of triethylorthoformate was added 0.25 mL (2.6 mmol) of acetic anhydride. The resulting solution was heated to reflux for 4 h before being concentrated to an oil. The crude oil thus obtained was purified by flash chromatography eluting with 75% hexanes/AcOEt to give 0.079 g (46%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 1.42 (t, J=7.2 Hz, 3H), 1.67-1.77 (m, 1H), 2.01-2.09 (m, 1H), 2.53-2.62 (m, 1H), 2.71 (d, J=7.4 Hz, 2H), 3.05 (dd, J=8.4, 9.8 Hz, 1H), 3.35-3.41 (m, 1H), 3.48 (dd, J=7.0, 9.5 Hz, 1H), 3.53-3.59 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 7.15-7.17 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.31 (m, 2H), 7.76 (s, 1H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[C:34]([C:32]([CH2:31][N:10]1[C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1=[O:3])=[O:33])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
60% Sodium hydride (33 mg) was suspended in anhydrous N,N-dimethylformamide (10 ml), under ice-cooling 2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (200 mg) obtained from Referentioal Example 5, and the mixture was stirred for one hour at room temperature. Subsequently, bromomethyl-tert-butylketone (147 mg) was added, stirred for one hour at room temperature. Ice-water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue for crystallization, crystals so precipitated were collected by filtration, to thereby obtain 140 mg of the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][NH:10][CH2:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCNCCc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
4-Nitrophenethylamine (4 g), 4-nitrophenethyl bromide (5.54 g) and potassium carbonate (3.32 g) were heated under reflux in acetonitrile (50 ml) for 2 days. The solvent was then evaporated, the residue taken up in ethyl acetate and washed three times with aqueous sodium carbonate and three times with brine. The organic phase was dried (Na2SO4), filtered and evaporated, and the residual oil was purified by chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and the solvent evaporated to give a solid which was recrystallised from ethyl acetate/hexane to give the title compound, yield 2.0 g, m.p. 86°-91°.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:32])[CH2:7][N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[CH:23]2)[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)C.Cl>CO>[CH3:30][N:26]1[C:27]2[C:22](=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][N:8]([CH2:7][C:6]([OH:32])=[O:5])[CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]1=[O:31]
Reactant: CCOC(=O)CN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCCN(CC(=O)O)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A 1N-sodium hydroxide aqueous solution (3 ml) was added to a methanol solution (15 ml) of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid ethyl ester (614 mg). The mixture was stirred at room temperature overnight. 1N-Hydrochloric acid (3 ml) was added to the reaction mixture and condensed under reduced pressure. Metanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (468 mg) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]2)[CH2:27][NH:26]1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]2[CH2:27][C@H:28]3[C@H:33]([CH2:32][CH:31]=[CH:30][CH2:29]3)[CH2:25]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 1.13 g of 3,4-dichlorophenylacetic acid in 6 mL of THF was added 0.90 g of 1,1'-carbonyldiimidazole. After 30 minutes a solution of 0.61 g of cis-3a,4,7,7a-tetrahydroisoindoline in 2 mL of THF was added and the mixture was stirred at room temperature overnight. Toluene (50 mL) was added, and the solution was washed successively with 5% hydrochloric acid, water, and 10% aqueous sodium carbonate solution, dried, and concentrated to give 1.50 g of cis-2-(3,4-dichlorophenylacetyl)-3a,4,7,7a-tetrahydroisoindole.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([OH:24])([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Brc1cccc2occc12
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cccc2occc12
Yield: 68.3 %

Procedure:
Beginning with 2.0 gm (10.2 mMol) 4-bromobenzofuran and 2.06 gm (10.2 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 2.24 gm (69%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]1[O:10][CH2:9]1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(O)(C)C>[CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]([OH:10])[CH2:9][NH:14][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: Cc1csc(C2CO2)c1C
Solvent: CC(C)O
Product: Cc1csc(C(O)CNC(C)C)c1C
Yield: 153.5 %

Procedure:
To 5.7 g of 3-methyl-4-methylthiophenylethylene oxide in 30 cc of isopropanol, 7.6 g of isopropylamine are added. The solution is refluxed overnight. The solvent and excess of amine are evaporated under vacuum. The oil obtained crystallises a little moment later. 12.1 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol are obtained (yield of 61 %) which are recrystallised from cyclohexane. Melting point: 89.5°-90.5°. The hydrochloride is recrystallised from a methanol-ether mixture; melting point: 154°-155.5°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:14]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl.Cl>[O:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:14]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]1
Reactant: COC(=O)C1CC(O)CCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(=O)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml flask, flamed dry under N2 was added CH2Cl2 (65 mL) followed by oxalyl chloride (5.2 mL, 59.6 mmol). After cooling the reaction mixture to −78° C., dimethyl sulfoxide (8.4 mL, 118.4 mmol) was added, followed by 1-benzyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate, 13b, (8.6 g, 29.2 mmol) in CH2Cl2 (65 mL). The reaction was allowed to stir at −78° C. for 45 min. To the mixture was added triethylamine (24.4 mL, 175.1 mmol) and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2 and 1N HCl. The layers were separated and the aqueous phase was re-extracted with CH2Cl2. The combined organic phases were washed with water, dried over MgSO4, filtered and evaporated to dryness. The crude was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give the desired product, 13c.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.NN>C1COCC1.CCO.[Ni]>[F:21][C:19]([F:20])([F:22])[CH:15]1[NH:16][CH2:17][CH2:18][N:13]([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([NH2:1])[CH:5]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1cc(N2CCNC(C(F)(F)F)C2)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(N2CCNC(C(F)(F)F)C2)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
1-(5-Nitro-1-benzofuran-7-yl)-3-(trifluoromethyl)piperazine (96.6 mg, 0.31 mmol; Intermediate 46) was dissolved in THF (6 mL) and EtOH (25 mL). Raney nickel (slurry in ethanol; 1 mL) and H2NNH2 (61.4 mg, 1.23 mmol) were added and the mixture was stirred at room temperature overnight. Filtration through Celite and concentration gave 7-[3-(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-amine (55 mg, 63%). This material was used in the next reaction step without further purification.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][N:8]([CH3:16])[C:9]([O:11][CH:12]=[CH:13][CH:14]=[CH2:15])=[O:10]>C(=O)([O-])O.[Na+]>[CH3:6][O:5][C:1]([CH:2]1[O:3][CH:12]([O:11][C:9]([N:8]([CH3:16])[CH3:7])=[O:10])[CH:13]=[CH:14][CH2:15]1)=[O:4]
Reactant: C=CC=COC(=O)N(C)C
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1CC=CC(OC(=O)N(C)C)O1
Temperature: -70 °C
Reaction time: 10 h
Yield: 36 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 282 mg (2 mmole) of 1-dimethylaminocarbonyloxy-1,3-butadiene. Reaction was then allowed to proceed at -30° C. for 10 hours, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 82 mg of desired optically active 6-methoxycarbonyl-2-dimethylaminocarbonyloxy-5,6-dihydropyran (yield: 36%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:18])([O:14]C(C)C)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:3][CH:2]=1.Cl.O.O1CCCC1>CCOCC>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([Si:7]([OH:14])([CH3:18])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:6]=1
Reactant: CC(C)O[Si](C)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](O)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 3.0 g (8.9 mmol) of (1,1'-biphenyl-4-yl)methyl(2-propoxy)(1H-1,2,4-triazol-1-ylmethyl)silane, 3 ml of concentrated hydrochloric acid, 10 ml of water, and 10 ml of tetrahydrofuran was stirred at room temperature overnight. The resulting solution was diluted with ether, washed with saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated to leave 2.3 g of viscous oil. Chromatography over silica gel, eluting with hexane followed by ether, provided 1.1 g (42%) of the title compound as a viscous oil that solidified on standing: m.p. 97°-99°; nmr (CDCl3) 0.5 (3H, s), 3.9 (2H, s), 5.2 (1H, broad s), 7.3-7.8 (9H, m), 7.9 (1H, s), 8.0 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][CH3:18])[CH3:14].N1CCCCC1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[C:17]1[O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:18]=1)[CH3:14]
Reactant: CCOC(CC)OCC
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCOC(OCC)c1cc2cc(C(=O)OC)ccc2o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Methyl 4-hydroxy-3-iodo-benzoate (9.9 g, 35 mmol) is combined with propioaldehyde diethylacetal (5.6 ml, 39 mmol), bis(triphenylphosphine)palladium(II) chloride (523 mg, 0.7 mmol), cuprous iodide (266 mg, 1.4 mmol), and piperidine (3.9 ml, 39 mmol) in DMF (50 ml) in a dry flask under nitrogen. The reaction is warmed to 60° C. for 6 h and is stirred overnight at RT. The mixture is diluted with EtOAc (250 ml) and is washed with 2:1:1:0.1 water/brine/saturated NaHCO3/conc. NH4OH (4×100 ml). The organic layer is dried (MgSO4) and is concentrated in vacuo to a dark oil. The crude material is chromatographed over 300 g silica gel (230-400 mesh), eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 5.2 g (48%) methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylate as an amber oil. HRMS (EI) calcd for C15H18O5: 278.1154, found 278.1156 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[CH2:34][CH2:35][CH2:36][CH2:37]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.C(#N)C.O.C(OCC)(=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[CH:7]=[N:6][C:5]2[N:4]([N:3]=[C:2]([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:24]=2[C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: ClCCCCCl
Reactant: Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1CCCC1)c1c(N2CCCC2)nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of the compound obtained in Example 40 (60 mg) in water/acetonitrile (0.3 mL/2.4 mL) was added 1,4-dichlorobutane (81.6 mg), potassium carbonate (88.8 mg) and sodium iodide (6.8 mg) and the mixture was stirred at 150° C. for 3 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added ethyl acetate and water and the mixture was stirred. The organic layer was extracted and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=90/10 to 70/30) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)-2-(1-pyrrolidinyl)-pyrazolo[1,5-a]pyrimidine (25 mg; yield: 37%) as a yellow solid.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6](Cl)[C:5]=1[Cl:12].[CH3:13][O:14][CH2:15][CH2:16][OH:17]>>[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6]([O:17][CH2:16][CH2:15][O:14][CH3:13])[C:5]=1[Cl:12]
Reactant: COCCO
Reactant: Nc1c(Cl)cnc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Product: COCCOc1ncc(Cl)c(N)c1Cl
Temperature: 118 °C

Procedure:
A solution of 16.5 grams (0.25 mole) of 86 percent potassium hydroxide dissolved in 100 milliliters of 2-methoxyethanol was added to a mixture of 49.5 grams (0.25 mole) of 4-amino-2,3,5-trichloropyridine in 150 milliliters of 2-methoxyethanol. The mixture was heated, with agitation, to 118° C. and held between 118°-120° C. for 31/2 hours. The reaction mixture was cooled to 75° C. and filtered under reduced pressure to remove the insoluble solids. The excess 2-methoxyethanol was evaporated off under reduced pressure and the liquid residue remaining was crystallized from hexane. The 4-amino-3,5-dichloro-2-(2-methoxyethoxy)pyridine product was recovered by filtration under reduced pressure, and obtained in a yield of 57 grams melting at 92°-93.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]([NH:8][C:9](=S)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:41][OH:42]>O>[Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)[C:5]([NH:8][C:9](=[N:41][OH:42])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(NC(=S)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(Br)cnc(NC(Cc2ccc(S(C)(=O)=O)cc2)=NO)c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of N-[5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-2-(4-methanesulfonyl-phenyl)-thioacetamide (Int. 11, 190 mg, 0.35 mmol) in IMS (3 mL) was added triethylamine (63 μL, 0.45 mmol) followed by hydroxylamine hydrochloride (29 mg, 0.42 mmol). After stirring at room temperature for 30 mins, water (10 mL) was added and the resultant orange solid was collected by filtration then dried at 50° C. under vacuum to give the title compound (165 mg).