Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:20]1>C(O)CCC>[O:28]1[C:27]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:22][C:21]=2[O:20][CH2:19]1
Reactant: OCc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CCCCO
Product: OCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 g (5.8 mmol) of [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol and 1.58 g (11.5 mmol) 3,4-methylendioxy-aniline in 30 ml n-butanol is stirred for 16 h at 115° C. under N2atmosphere. After cooling to ambient temperature, the title compound can be filtered off and washed with n-butanol; MS-ES+: (M+H)+=361; HPLC (conditions see Examples 67-78) tR=8.7 min.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].O.[NH4+].[Cl-]>CO.[Zn]>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)cc2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-(4-nitro-benzyl)-piperazine (as prepared in the previous step, 279 mg, 0.735 mmol) in MeOH (4 mL) and water (4 mL) was treated with solid NH4Cl (393 mg, 7.35 mmol) and Zn powder (240 mg, 3.67 mmol). The mixture was stirred at 50° C. for 2 h and at RT for 16 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with EtOAc afforded the title compound (204 mg, 79%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C19H35N3OSi, 350.3 (M+H). found 350.2.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.C(OC([NH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CCOC(C)=O.O.CN(C=O)C>[NH2:40][C:41]([CH3:46])([CH3:45])[C:42]([NH:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][N:6]2[N:5]=[C:4]([CH3:3])[C:16]([C:17]3[S:18][C:19]([C:28]4[N:32]=[CH:31][NH:30][N:29]=4)=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=3)=[C:7]2[CH:8]=1)=[O:43]
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn2ccc(OCCNC(=O)C(C)(C)N)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.8 %

Procedure:
A mixture of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i), TEA (1.5 mL), 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (75 mg, 0.37 mmol), HOBT (50 mg, 0.37 mmol), EDCI (210 mg, 1.1 mmol) and DMF (20 mL) was stirred at rt for 14 h. To the reaction mixture were added water (200 mL) and EtOAc (200 mL) and the mixture was stirred for 30 min. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the above residue in MeOH (10 mL) and THF (15 mL) was added 6N hydrochloric acid (3 mL), and the mixture was stirred at 70° C. for 1 h. The reaction mixture was allowed to cool to rt and then the solvent was evaporated. To the reaction mixture were added EtOAc (100 mL), 8N aqueous sodium hydroxide solution (3 mL) and water (100 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether and dried to give the title compound (46 mg, 45%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][Cl:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Cl:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C(CBr)c1ccc(OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(OCC(=O)c2ccc(OCCCl)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 27.7 g. (0.1 mol.) of α-bromo-p-(2-chloroethoxy)acetophenone, 12.4 g. (0.1 mol.) of p-methoxyphenol and 13.8 g. (0.1 mol.) of potassium carbonate in 75 ml. of dry acetone is refluxed with stirring for 16 hours. After cooling, the reaction mixture is poured into 500 ml. of water. The product is collected and dissolved in chloroform and the chloroform solution is washed with water, dried (MgSO4) and concentrated to give p-(2-chloroethoxy)-α-(p-methoxyphenoxy)acetophenone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[C:16]([C:39]4[S:43]C(C(O)=O)=CC=4)=[N:17][N:18]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[CH2:47]([N:49](CC)[CH2:50]C)C.ClC(OCC(C)C)=O.CNC.[O:65]1[CH2:69][CH2:68][CH2:67][CH2:66]1>O>[CH3:47][N:49]([CH3:50])[C:66]([C:67]1[S:43][C:39]([C:16]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]4[N:10]([C:6]([C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[CH:7][N:8]=4)[CH:11]=3)=[CH:19][N:18]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:17]=2)=[CH:69][CH:68]=1)=[O:65]
Reactant: O=C(O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: O
Product: CN(C)C(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg 5-{4-[3-(1,3-thiazol-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl}-2-thiophene carboxylic acid (compound in Example 443), together with 66 μL triethylamine and 25 μL isobutyl chloroformate, was stirred for 30 minutes in 4 mL tetrahydrofuran under ice-cooling in a stream of nitrogen, and then 0.79 mL dimethylamine was added thereto and stirred at room temperature for 3 hours. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 29 mg of the title compound (colorless solid).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:10][CH:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:26]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:27]>O1CCCC1>[CH2:1]([O:5][C:6]([C:8]1[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:10]([C:26]([O:28][CH2:29][CH:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:27])[C:11]([CH3:15])=[N:12][C:13]=1[CH3:14])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1Cl
Reactant: CCCCC(CC)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC(CC)CCCC)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
A solution of 1.4 g of 5-(n-butyloxycarbonyl)-4-(2-chlorophenyl)-2,6-dimethyl-dihydropyrimidine in 10 ml of tetrahydrofuran was added at room temperature to a suspension of 1 g of sodium hydride (as 50% suspension) in 5 ml of tetrahydrofuran. After 20 minutes, a solution of 1 g of 2-ethylhexyl chloroformate in 5 ml of tetrahydrofuran was added dropwise and after 30 minutes the reaction solution was diluted with ice water and extracted three times with ether. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate and evaporated to remove the solvent to obtain 2 g of the residue. It was purified on 50 g of silica gel by column chromatography and eluted with 0.5% methanol/chloroform to obtain 1.47 g (71% yiled) of title compound.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:10][C:11]1[C:19]([N+:6]([O-:9])=[O:7])=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Yield: 49 %

Procedure:
To a 3 liter round bottom flask was charged with 500 ml H2SO4. Fuming nitric acid was added (40 mL) and the mixture gently stirred. 2-Bromo-5-fluorobenzoic acid (60 g, 219 mmol) was added in 5 g portions over 90 minutes at 5-10° C. The mixture was stirred for 60 minutes at which time the reaction was completed. The mixture was poured into 1 liter of an ice/water mixture and extracted with EtOAc (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 minutes. The solid was collected on filter to provide 2-bromo-5-fluoro-3-nitrobenzoic acid as yellow solid (35 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.CC1(C)N([O])C(C)(C)CCC1>ClCCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C=O)cc1
Yield: 5 %

Procedure:
The effect of the additive was then examined for the oxidation of 4-methoxybenzylalcohol using 8 (2 mol %) in 1,2-dichloroethane (Table 2). Triethylamine, diisopropylethylamine, and TEMPO were all effective promoters of the vanadium complex, affording high yields of 4-methoxybenzaldehyde after 24 h at 60° C. (Entries 2 to 5). In contrast, less than 5% yield was observed with the vanadium complex alone (no additive, Entry 1), suggesting a key role for the nitrogen base.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][NH:2]1.Br[C:7]1[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)CCC>O1CCOCC1.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>[N:12]1[CH:7]=[CH:8][CH:9]=[C:10]([O:13][C:3]2[CH2:4][CH2:5][O:1][N:2]=2)[CH:11]=1.[S:20]1[CH:21]=[CH:22][N:23]=[CH:19]1
Reactant: Oc1ccc(Br)nc1
Reactant: C1=CONC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1cncc(OC2=NOCC2)c1
Product: c1cscn1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-162a and I-162b were prepared according to the following procedure: Racemic dihydroisoxazole I-161 was prepared in 1 step from compound I-14 and 6-bromopyridin-3-ol using Method 5. Compound I-161 placed in a microwave vial and then dissolved in dioxane (0.02 M). 2-(tributylstannyl)thiazole and palladium tetrakis were added and the reaction was purged with Argon. At this point the reaction was heated in the microwave reactor for 20 min after which there was no starting material by TLC analysis. The mixture is concentrated and purified by flash silica gel chromatography (hexanes/ethyl acetate) to provide the desired racemic thiazole I-162 in 50% yield. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M−H]−=407.3 m/z. Activity: A
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9](I)([CH3:11])[CH3:10]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:8])[CH:3]=1
Reactant: CC(C)I
Reactant: O=c1cc(I)cc[nH]1
Product: CC(C)n1ccc(I)cc1=O

Procedure:
4-iodo-1-isopropylpyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and isopropyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])[CH3:3].S(=O)(=O)(O[C:36]1[C:41](C(C)C)=CC=C[C:37]=1C(C)C)N.S(=O)(=O)(OC1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)N>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][C:21]=1[CH:36]([CH3:41])[CH3:37])=[O:15])[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1OS(N)(=O)=O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cc(C(C)C)c(OS(N)(=O)=O)c(C(C)C)c1
Product: CC(C)c1cccc(C(C)C)c1CC(=O)c1c(C(C)C)cc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisoproplyphenyl sulfamate was replaced with 2,4,6-triisoproplyphenyl sulfamate, mp 152°-155° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br>CC(N(C)C)=O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][O:27][CH2:34][CH2:33][O:32][CH3:31])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one (0.25 g, 0.00055 mol) in dimethyl acetamide at 0° C., was added NaH (0.016 g, 0.00067 mol) and stirred for 15 min. 2-Methoxyethyl bromide (0.09 g, 0.00-65 mol) was then added, and the mixture was stirred at room temperature for 6 h. Dimethylacetamide was distilled in vacuo and the product was purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z=510) were combined and freeze dried to afford the title compound (0.32 g, 80%) as a white powder:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18](OCC[Si](C)(C)C)=[O:19])(=[O:14])=[O:13])[CH2:7][CH2:6]1)=[O:4].CN(C=[O:34])C.Br[CH2:36][CH2:37][O:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([CH2:36][CH2:37][O:38][CH3:39])[S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([OH:19])=[O:34])(=[O:13])=[O:14])[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C=O
Reactant: COCCBr
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.00 g of 2-(trimethylsilyl)ethyl 3-{[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate and 10 mL of DMF were added 0.63 g of 2-bromoethylmethyl ether and 0.94 g of potassium carbonate at room temperature, followed by stirring at 60° C. overnight. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure, and to a mixture of the obtained residue and 10 mL of THF was added a solution of TBAF in THF (1.0 M, 4.0 mL), followed by stirring at room temperature for 3 hours. A solution of TBAF in THF (1.0 M, 2.0 mL) was further added thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, and then washed with 0.2 M hydrochloric acid, water, and saturated brine in this order. The obtained organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 915 mg of 3-{[trans-4-(methoxycarbonyl)cyclohexyl](2-methoxyethyl)sulfamoyl}benzoic acid as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=1
Reactant: CCCCN
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Cl)nc(N)nc32)O[C@@H]1CO
Solvent: CO
Product: CCCCNc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 60 °C

Procedure:
2-Amino-9-(3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-6-chloro-9H-purine (Example 3d) (0.40 g, 1.29 mmol) and n-butylamine (Aldrich, #06221JP, 1.28mL, 12.9 mmol) were combined in 25 mL MeOH and placed in a sealed tube. The reaction was heated at 60° C. for 18 hours followed by evaporation of the solvents. Chromatography of the residue on basic alumina eluted with 2% MeOH in CHCl3 gave, after combination and evaporation of appropriate fractions, 0.279 g (0.8 mMol. 62.3%); mp=44°-47°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:14](Cl)[CH:15]=[CH2:16].C[Si]([C:22]#[N:23])(C)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:22]#[N:23])[C:9]([C:12]#[N:13])([C:10]#[N:11])[CH2:14][CH:15]=[CH2:16])=[CH:4][CH:3]=1
Reactant: C=CCCl
Reactant: C[Si](C)(C)C#N
Reactant: N#CC(C#N)=Cc1ccc(Cl)nc1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: C=CCC(C#N)(C#N)C(C#N)c1ccc(Cl)nc1
Temperature: 75 °C
Yield: 70.9 %

Procedure:
To tetrahydrofuran (13 ml) were added ((6-Chloro-3-pyridyl)methylidene)malononitrile (0.50 g), tris(dibenzylideneacetone)dipalladium chloroform complex (70 mg) and 1,1′-bis(diphenylphosphino)ferrocene (0.15 g) under nitrogen atmosphere, and then allyl chloride (0.41 g) and trimethylsilylcyanide (0.53 g) were added thereto. The solution was stirred at 75° C. for a day. Then the reaction mixture was filtered through silica gel, and concentrated. The residue was subjected to silica gel column chromatography to give 0.48 g of 1-(6-Chloro-3-pyridyl)-1,2,2-tricyano-4-pentene represented by the following formula (hereinafter referred to as the present invention compound (2)).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12](OS(C)(=O)=O)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH:12]1[CH2:13][CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:22])([F:21])[F:1])[CH:5]=2)[C:11]1=[O:20])=[N+:24]=[N-:25]
Reactant: CS(=O)(=O)OC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Reaction time: 16 h
Yield: 104.6 %

Procedure:
A stirred solution of crude 1-(3-trifluoromethoxyphenyl)-3-methanesulfonyloxy-2-pyrrolidinone (4.00 g) in DMF (15 ml) was treated with sodium azide (0.76 g) and the mixture stirred for 16 hours. The mixture was poured into water and extracted with diethyl ether (x2). The combined ether extracts were washed with water (x3) and brine, then dried (MgSO4). Evaporation of the solvent under reduced pressure gave the crude sub-title compound (3.50 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:7](=[O:16])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1>C1COCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:7](=[O:16])[CH:8]([CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)[N:9]=[C:10]([C:11]3[CH:15]=[N:14][NH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(CN2C(=O)CN=C(c3cn[nH]c3)c3cc(Cl)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(c3cn[nH]c3)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
7-Chloro-1-(4-methoxybenzyl)-5-(1H-pyrazol-4-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (163 mg) was dissolved in THF (3 mL) and the solution was cooled to −78° C. A solution of KOtBu in THF (1 M, 1.1 mL, 2.6 eq) was then added dropwise and the anion was stirred for 10 minutes. 2-Bromomethyl naphthalene (123 mg, 1.3 eq) was then added and the reaction was allowed to warm to room temperature where it was held for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride and the crude product was partitioned between water and EtOAc. The organic fraction was washed with brine, then dried over sodium sulfate, and concentrated onto silica gel then purified by flash chromatography (gradient: 3:1 hexanes:EtOAc to EtOAc) delivering the product as a solid (106 mg, 48% yield). MS (ES+) m/z 521.2 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH:7]([S:25][CH3:26])[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]#[C:20][Si](C)(C)C)=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:27])[CH:7]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]#[CH:20])=[CH:12]2)[S:25][CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1)C(=O)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C)C)cc2c1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A solution of N-tert-Butyl-2-methylsulfanyl-2-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetamide (215 mg) in methanol (5 ml) was treated with potassium carbonate (18 mg) at room temperature. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with 30 ml sat. aq. sodium hydrogen carbonate. The aqueous layer was extracted with 3×50 ml ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate 6:4) to give N-tert-Butyl-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (125 mg) as brownish solid.