Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][N:21]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate (180 mg, 0.59 mmol) in dichloromethane (10 ml) was added Et3N (202 mg, 2 mmol) and methanesulfonyl chloride (110 mg, 0.98 mmol). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by the addition of ice-water (20 ml) and extracted with dichloromethane (3×15 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (0.14 g, 70%).
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[SH:42].CN(C=O)C>O>[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][C:2]1[C:3]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3
Reactant: CCCCC(CC)COc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A 250 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 27 g of 3-bromo-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one, 5.0 g sodium carbonate, 8.5 g 2-aminothiophenol and 80 g DMF. The mixture was agitated well, heated to 120-130° C., and held at 120-130° C. for three hours. Sodium carbonate (1.0 g) and 1.2 g 2-aminothiophenol were added and the mixture heated for an additional one hour. The reaction mixture was cooled to 25° C. and 250 g of water were added. The reaction mixture was extracted twice with 200 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator, then the crude product was passed through a flash silica gel column using methylene chloride as the elutant. The product fractions were collected and the solvent removed using a rotary evaporator. The yield of semi-solid 3-[(2-aminophenyl)thio]-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one was 27.5 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]([CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:21]=2)[CH:16]=[N:15]1)[CH2:10][CH3:11])[CH3:8]>C1COCC1>[CH2:7]([N:9]([CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH:21]=2)[CH:16]=[N:15]1)[CH2:10][CH3:11])[CH3:8]
Reactant: CCN(CC)CCn1ncc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCn1ncc2ccc(C3CCN(C)CC3)cc21
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of LAH in THF (1M, 0.25 mL, 0.25 mmol) was added to a solution of 1-(2-(N,N-diethylamino)ethyl)-6-(N-Boc-tetrahydro-4-pyridinyl)-1H-indazole (10.2 mg, 0.025 mmol) in THF (0.5 mL) at room temperature under argon and the resulting solution was refluxed for 2 h. After cooling to room temperature, the reaction was quenched using sodium sulfate decahydrate solid and the resulting solid was removed by filtration, extracting the product into ethyl acetate. The solvent was removed in vacuo and purification using an SPE (solid phase extraction) cartridge containing 1 g of silica gel by eluting with 0-10% 2M methanolic ammonia in dichloromethane yielded 1-(2-(N,N-diethylamino)ethyl)-6-(N-methyltetrahydro4-pyridinyl)-1H-indazole (5.9 mg, 74%).
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:17][O:18]C(=O)C)[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=O)C.N>Cl.C(O)C.O1CCCC1>[OH:4][CH2:5][CH:6]([CH2:17][OH:18])[CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(CCC(COC(C)=O)COC(C)=O)OCC
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(CCC(CO)CO)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
Diethyl 4-acetoxy-3-(acetoxymethyl)butylphosphonate (4.6 g, 14.18 mmol) was dissolved in hydrochloric acid/ethanol solution (14 ml, 2.2M) and the reaction mixture was stirred at 80° C. for 90 minutes. It was then cooled to 5° C., neutralized with aqueous ammonia solution and diluted with tetrahydrofuran. The resulting ammonium hydrochloride was filtered off, washed with tetrahydrofuran and the combined filtrates concentrated to an oil which was chromatographed on silica gel (eluting with 94:6 CHCl3 :EtOH) to give the title compound (2.1 g, 62%). 1H NMR δH ](CD3)2SO] 1.22 (6H, t, 7=7Hz, (OCH2CH3)2), 1.46 (3H, m, CH2CH) 1.72 (2H, m, PCH2), 3.35 (4H, m, 2xH2OH), 3.5-3.75 (2H, br.s, D2O exchangeable, 2xOH), 3.96 (4H, m, (OCH2CH3)2). Found: C,44.79: H,8.93%. C9H21O5P 0.2 H2O requires: C,44.43; H,8.86.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:31]=[O:32])C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([CH:31]=[O:32])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](Cn1ncnc1C=O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane (1.3 g, 0.004 mol) was lithiated as described in Example 1 using 3.7 mL (0.0044 mol) of 1.2M n-butyllithium in 10 mL of THF. DMF (1.2 mL, 0.016 mol) was added and the solution was allowed to warm to 0° C. After 1 hour, the reaction mixture was diluted with 1:1 ether/hexanes, washed with 7% aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated. Flash chromatography using 10% ether/methylene chloride gave 1.1 g of the title compound as a clear oil: nD 1.5612; ir (neat) 2840, 1705, 1587, 1499, 1228, 1160, 1106, 821 cm-1 ; nmr (CDCl3) δ, 0.7 (3H, s), 4.7 (2H, s), 7.0 (4H, t), 7.4 (4H, m), 7.9 (1H, s), 9.8 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:20]=[C:11]3[C:12]4[C:17]([CH2:18][CH2:19][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.[O-][CH2:22][CH3:23].[Na+].C(I)C>C(O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:20]=[C:11]3[C:12]4[C:17]([CH2:18][CH2:19][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: CC[O-]
Reactant: Oc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Hydroxyphenyl)-5,6-dihydro-s-triazolo-[5,1-a]isoquinoline (3.95 g.) is added to 60 ml. of ethanol containing one equivalent proportion of sodium ethoxide. To this mixture is added 1.57 ml. of ethyl iodide in 15 ml. of ethanol. After stirring for one hour at room temperature, a further 1.57 ml. of ethyl iodide is added and the mixture is refluxed for 18 hours. The solvent is distilled off and the residue is washed with water and extracted with dichloromethane. Evaporation of the solvent and crystallization of the residue from ethanol gives 3.87 g. of the title product; m.p. 102°-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20]I.[H-].[Na+]>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH3:20])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CI
Reactant: Clc1ccc(-c2nc[nH]c2-c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 4,5-di-(4-chlorophenyl)imidazole (300 mg, 1.0 mmol) from Step A and methyl iodide (0.10 mL, 2.0 mmol) in DMF (5 mL) was added sodium hydride (80 mg 60% in mineral oil, 1.5 mmol) all at once at rt. After stirring for 1 hr, the reaction was quenched into water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (10% methylene chloride, 30% ethyl acetate in hexanes) to provide the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Na].[H-].[Na+]>CN(C)C=O>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCn1ccnc1

Procedure:
A 99.0 g amount of 2-(10-bromodecyl)-1H-isoindole-1,3(2H)-dione (prepared as described above) was dissolved in 300 ml of warm N,N-dimethylformamide with stirring. This solution was added to a stirred solution of 1H-imidazole, sodium salt (prepared by stirring a mixture of 20 g of imidazole and 14.0 g 50% sodium hydride in 500 ml of N,N-dimethylformamide at room temperature for 48 hours). The resulting mixture was heated on a steam bath for 14 hours, then taken to dryness in vacuo. The residue was partitioned between 500 ml of dichloromethane and 250 ml of water. The organic layer was washed with 250 ml of water, dried over magnesium sulfate and filter. The filtrate was evaporated in vacuo and gave 85.4 g of 2[10-(1H-imidazol-1-yl)decyl]-1H-isoindole-1,3(2H)dione as an oil which solidified on standing at room temperature.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]([NH:14][CH3:15])=[C:10]([NH2:13])[C:11]=1[Cl:12])=[O:5])[CH3:2].[CH2:17](OC(OCC)OCC)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]2[N:13]=[CH:15][N:14]([CH3:17])[C:9]2=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1c(C)nc(NC)c(N)c1Cl
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl

Procedure:
2.4 g. of 5-Amino-6-methylamino-4-chloro-2-methylpyridine-3-carboxylic acid ethyl ester (0.01 mol.) and 10 ml. of orthoformic acid triethyl ester are refluxed for 12 hours. After the excess ortho ester has been removed, the residue is recrystallized from ethyl acetate to obtain 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester, m.p. 56°-58°. Yield 2.2 g. (88%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[O:32][CH2:30][CH3:31])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCOc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OCC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100.1 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-ethoxybenzaldehyde (570 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was unified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (402 mg) as yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C=O.CN.[CH3:21][N:22]1[CH2:27]COC[CH2:23]1>CCO.O>[CH2:1]([N:3]1[CH2:23][N:22]([CH3:27])[CH2:21][N:6]([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[C:4]1=[O:5])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Agent: C=O
Agent: CN
Solvent: CCO
Solvent: O
Product: CCN1CN(C)CN(c2nc3c(s2)C(=O)CCC3)C1=O
Temperature: 60 °C
Yield: 100.9 %

Procedure:
To a suspension of N-ethyl-N′-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)urea (10.0 g, 41.79 mmol) in EtOH/H2O (1/1, 300 mL) were added formaldehyde (37 wt % in H2O, 20.4 g, 417.87 mmol), methylamine (40 wt % in H2O, 10.8 mL, 125.37 mmol) and N-methylmorpholine (11.8 mL, 83.6 mmol). The suspension was heated to about 60° C. for about 5 hrs, then a solution had been formed. The reaction mixture was pumped down in vacuo to give 12.41 g (quantitative yield) pure product.
Reaction SMILES: [H-].[Na+].C([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>O1CCCC1>[Cl:18][C:16]1[CH:17]=[C:12]2[C:13]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:29]([C:30]([O:32][CH3:33])=[O:31])[NH:11]2)=[CH:14][CH:15]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)c1ccc(F)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a mixture of a 50% sodium hydride suspension in mineral oil (52.5 g) (which was extracted with dry heptane) and dry tetrahydrofuran (250 ml) was added a solution of N-benzoyl 5-chloro-2-(4-fluorobenzoyl)aniline (129 g) in dry tetrahydrofuran (500 ml) during 0.5 h at 20° C. (ice bath). After 1 h methyl 2-bromoacetate (101 ml) was added during 0.5 h at 20° C. (ice bath) and the mixture was stirred for another 1 hour. The solvents were evaporated in vacuo. The remaining oil was diluted with methanol (250 ml) and 5.4M sodium methoxide in methanol (670 ml) was added carefully. After 1 h at room temperature the solvents were evaporated in vacuo and water (0.5 l) was added. The thus obtained mixture was extracted with ethyl acetate (2×0.75 l) and the combined organic phases were washed with brine and dried (Na2SO4). Evaporation of the solvents in vacuo afforded the title compound, which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3) and crystallized from heptane. Yield: 33 g, mp 172°-183° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([C:21]1[CH:26]=[CH:25][N:24]2[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)([CH3:38])[CH3:37])[N:31]=3)=[CH:28][N:29]=[C:23]2[N:22]=1)([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12].O.C([O-])(O)=O.[Na+]>ClCCCl>[F:7][C:36]([C:32]1[N:31]=[C:30]([C:27]2[N:24]3[CH:25]=[CH:26][C:21]([C:11]([CH3:12])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:10])=[N:22][C:23]3=[N:29][CH:28]=2)[CH:35]=[CH:34][N:33]=1)([CH3:38])[CH3:37]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(C)O)n3)cnc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(C)F)n3)cnc2n1
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(Diethylamino)sulphur trifluoride (150 mg, 0.95 mmol) was added to a stirred solution of 2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}propan-2-ol (Example 115, Step 1) (200 mg, 0.47 mmol) in 1,2-dichloroethane (5 ml) at room temperature under N2 and the reaction was stirred overnight. Water (20 ml) was added followed by NaHCO3 solution (20 ml) and then the organics were extracted with CH2Cl2 (3×50 ml) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 7% EtOH/EtOAc to yield 3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (60 mg, 30%): 1H NMR (400 MHz, CDCl3) δ 10.25 (1H, d, J 7.3), 8.71 (1H, d, J 5.5), 8.48 (1H, s), 7.60 (1H, d, J 7.2), 7.55 (1H, d, J 5.5), 1.87 (6H, d, J 21.6), 0.99 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES+) 430 (M+H+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[NH:10][C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[N:10]([CH3:27])[C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2[nH]c3cc(-c4ccccc4)nn3c(=O)c2CN1C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a suspension of 6-cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8(6H)dione (2.00 g, 5.75 mmole) and potassium carbonate (795 mg, 5.75 mmole) in dry dimethylformamide (DMF, 30 mL) was added methyl idodide (0.72 mL, 12 mmole). The flask was stoppered tightly and stirred at room temperature for 24 hours. The mixture was diluted with water (150 mL), stirred for 10 minutes and suction filtered. The collected solid was washed once with water and once with 95% ethanol. Drying under vacuum left 1.91 g of white powdery solid. Crystallization from 95% ethanol (500 mL) afforded the titled product as fine white needles (1.73 g, 83%, m.p. 276°-279°). 1H NMR (CDCl3, δ) 8.05 (m, 2H, 2-phenyl H), 7.45 (m, 3H, 3,4-phenyl H), 6.45 (s, 1H, pyrazole-H), 4.33 (s, 2H, lactam CH2), 4.16 (s, 3H, CH3), 4.15 (m, 1H, cyclohexyl CH), 1.1-2.0 (m, 10H, cyclohexyl CH2); IR (mull, cm-1) 1693, 1627, 1590, 1574; UV (ethanol) λmax (ε) 206 (27,300), 226(23,920), 268(33,740), 285sh(15,570), 295(10,940), 338(6,090); MS m/e (rel. intens.) 363 (M+1, 25) 362 (M+, 100), 319(35), 280(66); Analysis calc'd for C21H22N4O2 =C, 65,59; H, 6.12 N, 15.46; Found=C, 69.64; H, 6.21; N, 15.43. TLC (silica, ethylacetate) Rf 0.80.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:6](=[O:22])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[CH2:8][CH2:9][CH:10]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:6]1=[O:22]
Reactant: COC(=O)CC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCCN(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
26 mg of [1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic acid methyl ester (o) (0.08 mmol) was dissolved in methanol solution under Ar atmosphere. 1.7 mg of 10% Pd—C was added thereto and the mixture was hydrogenated under a hydrogen balloon. The reaction mixture was stirred for 5 hrs at room temperature, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography to give 25 mg of [1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-acetic acid methyl ester (r) (yield: 99%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([CH2:43][NH2:44])[OH:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([NH:44][CH2:43][CH2:41][OH:42])=[O:40])=[CH:34]3)(=[O:31])=[O:32])=[CH:29][C:16]=2[N:15]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: NCCO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCCO)c3)ccc2n1CC1CCOCC1
Yield: 70.2 %

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (47 uL, 35 mg, 0.27 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (60 mg, 0.14 mmol) (see following step B for preparation), ethanolamine (17 mg, 0.27 mmol) and HATU (103 mg, 0.27 mmol) in DMF (5 mL). The crude product was purified by MPLC using EtOAc/MeOH (9:1) on silica gel to give 48 mg (72%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.42-1.58 (m, 4H), 1.61 (s, 9 H), 2.23-2.36 (m, 1 H), 3.25-3.34 (m, 2 H), 3.38 (t, J=5.76 Hz, 2 H), 3.61 (t, J=5.76 Hz, 2 H), 3.86-3.94 (m, 2 H), 4.44 (d, J=7.42 Hz, 2 H), 6.67 (dd, J=3.32, 1.76 Hz, 1H), 7.30 (dd, J=3.32, 2.34 Hz, 1 H), 7.82-7.85 (m, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.98 (d, dd, J=8.7, 1.5 Hz, 1 H), 8.28 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=489.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][CH2:12]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[CH3:15].[O-]CC.[Na+].[Na]>C(O)C>[CH2:27]([O:26][C:24](=[O:25])[C:18]([NH:17][C:14](=[O:16])[CH3:15])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][C:11]#[C:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC#CCCl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC#CCNC(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Yield: 49.4 %

Procedure:
Ex-8d) 12.1 g 1-t-Butyloxycarbonylamino-4-chloro-2-butyne is refluxed for 16 h with a mixture of 8 g diethyl acetamidomalonate and sodiumethoxide prepared from 900 mg of sodium in 100 mL of absolute ethanol. Ethanol is then removed under vacuum and the residual mass is partitioned between water and ethylacetate/ether (1:1). The organic layer is treated with 0.5N NaOH and 0.5N HCl and washed with water. It is then dried over Na2SO4, filtered and concentrated. The product is crystallized from ethylacetate/petroleum ether to give ˜7 g of Ethyl-2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoate.