Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc2cccc(Cl)c2nc1-c1cccnc1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (5.0 g, 22.2 mmol), Na2CO3 (3.51 g, 33.2 mmol) and 3-pyridylboronic acid (2.72 g, 22.2 mmol) in DME (60 mL) and water (30 mL) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (1.28 g, 1.11 mmol) was added and the mixture heated at 90° C. for 7 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (5.4 g, 91%) as a tan solid. δH (DMSO-d6) 10.15 (s, 1H), 9.15 (s, 1H), 8.94 (dd, J 2.3, 0.8 Hz, 1H), 8.77 (dd, J 4.9, 1.7 Hz, 1H), 8.31 (dd, J 8.3, 1.3 Hz, 1H), 8.20-8.19 (m, 1H), 8.18-8.16 (m, 1H), 7.75 (dd, J 7.9, 7.5 Hz, 1H), 7.62 (ddd, J 7.7, 4.9, 0.8 Hz, 1H). LCMS (ES+) 269 (M+H)+, RT 1.82 minutes.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH3:19])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl>[CH2:18]([C:15]1[N:14]=[C:13]([CH:12]=[CH:11][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:17][N:16]=1)[CH3:19]
Reactant: CCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-ethyl-[1,2,4]oxadiazole (compound of Example 2, Method A, Step 2; 0.3 g, 1.15 mmol) was dissolved in dichloromethane (6 mL) and cooled to −78° C. A solution of boron tribromide (0.41 mL, 4.40 mmol) in dichloromethane (4 mL), which was cooled to −50° C., was added slowly over a period of 30 min. After 3 h, the reaction mixture was allowed to warm to room temperature and stirred for 12 h. After the completion of the reaction, the mixture was quenched by dropwise addition of methanol (5 mL) at 0° C. and stirred for 30 min at room temperature. The solvent was evaporated and the residue obtained was redissolved in 10% methanol in chloroform at 0° C., and stirred with solid sodium carbonate to obtain pH ˜9. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]2)=[CH:12][CH:11]=1
Reactant: N#Cc1cn[nH]c1
Reactant: COc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C#N)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 1 g (10.7 mmol) of 1H-pyrazole-4-carbonitrile and 2.4 g (11.8 mmol) of 4-methoxybenzyl bromide were initially charged in 22 ml of THF. 1.3 g (11.8 mmol) of potassium tert-butoxide were added a little at a time, and the reaction was stirred at RT overnight. The precipitated solid was then filtered off, and the mother liquor was freed from the solvent on a rotary evaporator. The residue was dissolved in ethyl acetate and the solution was washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. This gave 2 g (87% of theory) of the title compound, which was used without further purification for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[N:16](CC4C=CC(OC)=CC=4)[N:15]=[C:14]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:13]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[NH:16][N:15]=[C:14]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:13]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2Cc2c[nH]c3ncc(Cl)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(CNc2cc(Cc3c[nH]c4ncc(Cl)cc34)[nH]n2)cc1
Temperature: 70 °C

Procedure:
Into a round bottom flask, [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-(4-methoxy-benzyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine (149, 0.060 g, 0.13 mmol) was dissolved in 5 mL of trifluoroacetic acid (60 mmol) and the reaction was heated at 70° C. overnight. The reaction was cooled to room temperature, then concentrated under vacuum and ethyl acetate was added. This was washed with 1 M aqueous potassium carbonate and brine, dried with sodium sulfate and purified by silica gel column chromatography, eluting with 2-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum, and the solid further washed with ethyl acetate and hexane to provide the desired compound. 1H NMR was consistent with compound structure. MS (ESI) [M+H+]+=356.85.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[C:21](=[O:27])[CH2:20][CH2:19][CH2:18]2.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[CH:35]=O.Cl>C1COCC1>[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1/[CH:35]=[C:20]1/[C:21](=[O:27])[C:22]2[C:17]([CH2:18][CH2:19]/1)=[CH:16][C:15]([O:14][CH3:13])=[C:24]([O:25][CH3:26])[CH:23]=2
Reactant: O=Cc1ccncc1Br
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Br)CC2
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of (i-Pr)2NH (0.3 mL, 2.2 mmol) at 0° C. in dry THF (15 mL) was added n-BuLi (1.22 M solution in hexane, 2.7 mL, 2.2 mmol), the mixture was stirred for 15 min at this temperature, after which the 6,7-dimethoxy-1-tetralone (0.412 g, 2 mmol) in dry THF (7 mL) was slowly added at −78° C. After 30 min at this temperature, 3-bromo-4-pyridinecarboxaldehyde (0.446 g, 2.4 mmol) in dry THF (7 mL) was slowly added and the solution was stirred for 30 min at −78° C. before allowed to reach room temperature and being stirred for a night. Then, the mixture was hydrolyzed by HCl 1N and extracted by AcOEt to eliminate the possible excess of tetralone. The aqueous layer was neutralized by NaHCO3 and the compound was extracted by CH2Cl2 three times. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the expected product 84 (Yield 598.7 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:46][C:47]([NH2:49])=[O:48].O>CN(C=O)C>[C:47]([CH2:46][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1)(=[O:48])[NH2:49]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCC(N)=O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.83 h
Yield: 35.9 %

Procedure:
In DMF (1.6 ml) was dissolved 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (131 mg). To the mixture was added potassium carbonate (41 mg), and the mixture was stirred for 50 minutes. To the mixture was added iodoacetamide (50 mg), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-carbamoylmethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 95) (52 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]>N1C=CC=CC=1>[S:7]([O:18][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCCCO
Solvent: c1ccncc1
Product: C=CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In this preparation 1.0 mole of p-toluenesulfonyl chloride is dissolved in 700 ml. of pyridine at 0° C, under nitrogen, and then 1.0 mole of hex-5-en-1-ol is added dropwise. The mixture is then stirred at room temperature for 16 hours, then poured into ice water and extracted with ethyl ether. The ethyl ether extract is then sequentially washed with water, 10% aqueous hydrochloric acid, water, aqueous 10% sodium bicarbonate solution and water, and then dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording hex-5-en-1-ol tosylate as a residue.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O:24]C)=[O:23])[CH:15]=[CH:14]1)[CH2:2]2.O.[OH-].[Li+:28]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O-:24])=[O:23])[CH:15]=[CH:14]1)[CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Yield: 185.1 %

Procedure:
A mixture of (R)-methyl 1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (317 mg, 0.93 mmol) from Step C above and lithium hydroxide monohydrate (117 mg, 2.8 mmol) in tetrahydrofuran/water (1:1, 20 mL) was stirred at reflux until the reaction was complete by LC-MS. The solvent was removed under reduced pressure to give lithium (R)-1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate as an off-white solid (574 mg, quantitative yield): 1H NMR (500 MHz, CD3OD) δ 7.49 (d, J=7.5 Hz, 1H), 7.26 (d, J=7.0 Hz, 1H), 7.19 (d, J=3.0 Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 4.51 (d, J=7.0 Hz, 2H), 3.05-2.99 (m, 1H), 2.83-2.68 (m, 5H), 2.49-2.32 (m, 3H), 2.01-1.92 (m, 2H), 1.71-1.61 (m, 3H), 1.51-1.47 (m, 1H), 1.36-1.28 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]([CH2:16][CH2:17][C:18](Cl)=[O:19])([O:14][CH3:15])=[O:13]>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:18](=[O:19])[CH2:17][CH2:16][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.3 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (26.9 g, 0.202 mol) in dichloromethane (415 mL) at 5° C. under nitrogen was added dropwise neat bromobenzene (10.0 mL, 0.0950 mol), and the mixture was stirred briefly. To the mixture was added dropwise a solution of 3-carbomethoxypropionyl chloride (12.9 mL, 0.105 mol) in dichloromethane (200 mL) over 70 minutes, and the mixture was allowed to slowly warm to room temperature. After 4 days, the mixture was recooled to 5° C. and quenched with the dropwise addition of water (600 mL). The organics were washed with additional water (200 mL), aqueous sodium bicarbonate, water, and brine. The organics were dried (Na2SO4), and rotary evaporated to an oil, which crystallized. The residue was dissolved in chloroform, and the solution was purified by chromatography on silica gel (435 g, 230-400 mesh), eluting with hexanes-acetone (9:1, 10×400 mL; 8:1, 7×400 mL),to give 21.2 g of 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester as an off-white solid; mp 49-51° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 73 %

Procedure:
A solution of 4-benzyloxyphenol (6.01 g, 30 mmol) in anhydrous dimethylformamide (50 ml) under a nitrogen cover was treated with sodium hydride (1.2 g of 60% oil dispersion, 30 mmol) in one portion at room temperature. A moderate gas evolution ensued, and the reaction temperature rose to 41° C. After stirring an additional 35 minutes, 4-Fluoronitrobenzene was added rapidly dropwise, neat via syringe. A mild exotherm brought the reaction temperature to 32° C., after which the reaction was stirred for 18 hours at room temperature. The reaction mixture was poured over ice/water (250 ml), stirred for thirty minutes and the yellow solid collected by suction filtration. Silica gel chromatography (Waters® LC2000; two Pre-Pak® columns, P eluting with 3/1 hexanes/methylene chloride) afforded 4-(4-benzyloxyphenoxy)-1-nitrobenzene (5.9 g, 73%) as a white solid. 1H NMR(400 MHZ): 5.08(2H,s), 6.94-6.99(2H,m), 7.02(4H,s), 7.32-7.47(5H,m), 8.15-8.20(2H,m); MS(ESI)m/z 320.2([M−H]−,100).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=[O:7])#[N:2]>[Co].N>[F:23][C:18]1[CH:17]=[C:16]([C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][CH2:1][NH:2][C:6]2=[O:7])[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ccc(F)c(F)c1
Agent: [Co]
Agent: N
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.3 %

Procedure:
A mixture of diethyl (2-cyanoethyl)(3,4-difluorophenyl)propanedioate (15.2 g), Raney cobalt (75 g) and ammonia (2M ethanol solution, 150 mL) was stirred at room temperature for 3 days under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropylether to give the title compound (10.5 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[CH2:12]([Li])CCC.CCCCCC.IC>O1CCCC1.O>[C:1]([CH:3]([C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:12])#[N:2]
Reactant: [Li]CCCC
Reactant: N#CCc1cccnc1C#N
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C#N)c1cccnc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3-(cyanomethyl)pyridine-2-carbonitrile (synthesized by the method of Synthesis 1973, 47, 530 mg, 3.70 mmol) in tetrahydrofuran (14 mL) was added dropwise a solution of 1.65 mol/L n-butyllithium in hexane (2.60 mL, 4.29 mmol) at −78° C. under argon atmosphere. The mixture was stirred at the same temperature for 30 minutes, and then thereto was added dropwise iodomethane (300 μL, 4.81 mmol) in tetrahydrofuran (7 mL). The mixture was stirred at the same temperature for 1 hour. The reaction solution was slowly warmed to room temperature, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate four times. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→50:50) to give 3-(1-cyanoethyl)pyridine-2-carbonitrile (514 mg, 88%) as a yellow oil.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[C:6]([NH:11][NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)([O-])=O.O>C(O)(C)C>[ClH:1].[NH2:2][C:5]1[C:6]([NH:11][NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)NNc1ncccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)NNc1ncccc1N

Procedure:
The ethyl 3-(3-nitro-2-pyridyl)carbazate hydrochloride 34 g (0.13 mole) was slurried in 300 ml of isopropanol and treated with 4.4 g of 5% pd/C (50% H2O) in 40 ml of isopropanol. The reaction mixture was subjected to hydrogenation at 50 psig. A 24 psig drop at 27°0 was observed (theory 30 No. at 27°), and the mixture was cooled overnight. The crystalline product was collected along with the catalyst. The product was taken up in 300 ml of hot methanol, the catalyst filtered, and the product precipitated from the filtrate, m.p. 217°-219° dec. Yield: 11 g (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Br)cc1
Yield: 76.8 %

Procedure:
Example 20 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-bromo-4-isocyanatobenzene (0.027 g) to give the title compound (0.033 g). LC-MS (System A): Rt 2.49 mins, Mass Spectrum m/z 472 [MH+].
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[Cl:30])=[O:19])[CH3:16].[O:31]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:39]=2)=[CH:25][C:24]=1[Cl:30])=[O:19])[CH3:16]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Sodium triacetoxyborohydride (0.424 g, 2.00 mmol) was added to a solution of the enantiomerically enriched-(trans)-ethyl-2-(4-amino-2-chlorophenyl)cyclopropanecarboxylate (III-1d) (0.191 g, 0.80 mmol) and 3-phenoxybenzaldehyde (0.160 g, 0.80 mmol) in 8 mL of dichloroethane. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned between chloroform and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by chromatography on silica gel with hexane:ethyl acetate to give 0.269 g (80% yield) of the title compound as a colorless oil. NMR (400 MHz, CDCl3) δ 7.32 (t, J=7.51 Hz, 2H), 7.28 (t, J=8.42 Hz, 1H), 7.10 (t, J=8.24 Hz, 1H), 7.06 (d, J=8.24 Hz, 1H), 6.99 (d, J=7.69 Hz, 2H), 6.98 (m, 1H), 6.90 (dd, J=8.06 Hz, 2.38 Hz, 1H) 6.79 (d, J=8.42 Hz, 1H), 6.61 (d, J=2.38 Hz, 1H), 6.40 (dd, J=8.42 Hz, 2.38 Hz, 1H), 4.25 (d, J=5.49 Hz, 2H), 4.19 (q, J=7.14 Hz, 2H), 4.12 (br s, 1H), 2.60 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H), 1.28 (t, J=7.14 Hz, 3H), 1.25 (m, 1H). ES-MS m/z 422 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1[N+](=O)[O-]
Yield: 62.3 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (262 mg, 1.00 mmol) and 2-bromothiazole (0.14 mL, 1.50 mmol) according to the general procedure F. Obtained as a yellow solid (215 mg).
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:36]OS(C)(=O)=O)[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:8]1)(=O)=O.[BH4-].[Na+]>CN(C=O)C>[CH3:6][C:7]1([CH3:36])[CH2:8][C:9]([CH2:33][C:34]#[N:35])([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:10]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(COS(C)(=O)=O)(COS(C)(=O)=O)C4)c3)ncnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1

Procedure:
3-(Cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutane-1,1-diylbis(methylene) dimethanesulfonate (0.06 g, 0.0001 mol) was reacted with sodium tetrahydroborate (0.02 g, 0.0004 mol) in DMF (0.8 mL) (˜0.5 M) at 65° C. under nitrogen for 2 h. The reaction was quenched with water, and extracted with dichloromethane. The organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified with Combiflash (silica gel, 0-60% EtOAc/Hex) to give the desired product. LCMS calculated for C23H33N6OSi(M+H)+: 437.2; Found: 437.4.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>C(C(C)=O)C(C)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:11][CH:12]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(=O)OCc1ccc(O)cc1
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)OCc1ccc(O[Si](C)(C)C)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1500 g of methyl isobutyl ketone and 100 g of 4-hydroxybenzyl acrylate were charged into a separable flask of the same type as used in Reference Example 1, and cooled to -5° C. while replacing the flask inside gas with a nitrogen gas, and then 67 g of trimethylchlorosilane was dropwise added thereto over one hour, and then stirring was continued for 2 hours. After completion of the reaction, the reaction mixture was washed with water and methyl isobutyl ketone was distilled off, whereby 83 g of p-trimethylsilyloxybenzyl acrylate of the following chemical formula was obtained (yield: 59%): ##STR13##