Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH3:3].[O:18]1[CH:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1>CO>[OH:18][CH:20]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:1][CH2:2][N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:10][CH:11]=1
Reactant: CCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CCCN(CCN(Cc1ccccc1)CC(O)COc1ccccc1)C(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7.95 9 (20 mmol) N-[2-(phenylmethyl)amino)ethyl]-N-propyl-4-[(methylsulfonyl)amino]benzamide in 20 mL 10% aqueous methanol is added 2.89 mL (21 mmol) 1,2-epoxy-3-phenoxypropane. The solution is stirred at room temperature for 24 h. After this time, the solvents are evaporated and the title compound is obtained as a foamy solid via column chromatography on silica gel (hexane:acetone, 9:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][OH:11].C([O-])(O)=O.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: ON=Cc1cccnc1
Yield: 97 %

Procedure:
3-Pyridine carboxaldehyde (21.4 g, 200 mmol) and hydroxylamine hydrochloride (14.6 g, 210 mmol) were dissolved in CH3OH (125 ml) and heated at reflux for 12 hours. The solution was then concentrated under vacuum to give a white solid. To this solid was added saturated NaHCO3 solution, with stirring until slightly basic. A white precipitate was obtained which was filtered, washed with water, and dried in vacuo, to give 3-pyridine aldoxime as a white solid, 23.6 g, 97% yield, mp 148°-150° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](O)=[O:26]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:21]3[NH:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc[nH]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1ccc[nH]1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless prisms, melting at 136°-137° C., in an 80% yield.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.C1CCCCC=1>C(O)C>[OH:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(COCCOCc1ccccc1)OCC
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOP(=O)(COCCO)OCC

Procedure:
Paladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in accordance with the process of Example II above (0.9 g,2.8 mmol) and cyclohexene (2.0 ml, 20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][N:9]=1.O>C(OCC)C>[OH:13][CH2:12][C:11]1[CH:17]=[CH:18][C:8]([CH3:7])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CO)cn1
Temperature: 0 °C
Yield: 80.4 %

Procedure:
To a stirred suspension of 11.4 g of lithium aluminum hydride in 500 ml of dry diethyl ether, 32.7 g of ethyl 6-methylnicotinate in 250 ml of dry diethyl ether is added dropwise at room temperature, and the mixture is refluxed for 1.5 hours. The reaction mixture is cooled to 0° C., and the remaining lithium aluminum hydride is decomposed by the cautious addition of 60 ml of water. The ether layer is decanted, and the residual solid is extracted with three 150-ml portions of diethyl ether. The combined extracts are dried over potassium carbonate and concentrated to give 19.6 g of crude 5-hydroxymethyl-2-methylpyridine.
Reaction SMILES: [Mg].II.[C:4]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](=[O:26])=[O:25].Cl>CCOCC>[C:4]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]([OH:26])=[O:25])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To 400 ml of ether were added 15 g of magnesium (flaked) and 3.2 g of iodine. 27.9 g of triphenylchloromethane was carefully added thereto and the mixture was refluxed by heating for 3 hours. To the reaction solution was gradually added a large excess of dry ice. The reaction solution was acidified with hydrochloric acid and then extracted with ethyl acetate. After distilling off the solvent, the crystals thus obtained were recrystallized from ethanol to obtain 16.5 g of triphenylacetic acid. The melting point was 258° to 260° C. (decomposed).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O.CCOCC>[CH3:27][C:26]([Si:23]([O:21][CH2:20][C:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH2:22])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5.0 g of 2-[(hexadecyloxy)-methyl]-2-propen-1-ol in 50 ml of dry N,N-dimethylformamide is added 6.05 g of tert-butyldimethylsilyl chloride followed by 8 g of imidazole. This mixture is stirred overnight, then diluted with ether, washed with saturated aqueous sodium bicarbonate, water and brine, dried and evaporated, to give 6.49 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](O)([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[CH:15]=2)[C:6]1=[O:25].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClC(Cl)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[CH:15]=2)[C:6]1=[O:25]
Reactant: COc1c(C)cc(C2(O)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: COc1c(C)cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Temperature: 50 °C
Yield: 77.5 %

Procedure:
Dissolve 1-(2-chloro-benzyl)-3-hydroxy-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (430 mg, 1.05 mmol) in dichloroethane (15 mL) and treat with triethylsilane (0.503 mL, 3.15 mmol) and boron trifluoride diethyl etherate (0.038 mL, 0.3 mmol) under nitrogen. Heat at 50° C. for 24 h. Add more triethyl silane (0.250 mL, 1.57 mmol) and boron trifluoride diethyl etherate (0.030 mL, 0.24 mmol) and continue for 6 h. at which time reaction complete. Concentrate in vacuo and purify by flash chromatography (gradient of 5% EtOAc/hexanes to 25% EtOAc/hexanes) to obtain 319 mg (78%) of the title compound as a white solid. MS (ES): m/z=392 (M+1), 390 (M−1); 1H NMR(DMSO-d6): δ7.54 (m, 1H), 7.36-7.29 (m, 2H), 7.25 (t, J=7.9, 7.6 Hz, 1H), 7.18-7.13 (m, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.85 (s, 2H), 5.02 (s, 2H), 4.90 (s, 1H), 3.65 (s, 3H), 2.20 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1Cl)CC1C=C(C(N)C(C)C)C=C[N:18]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH2:18])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C(N)c1ccnc(Cc2ccc(Cl)c(Cl)c2)c1
Reactant: COc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(NC(N)=O)c1
Reaction time: 1 h

Procedure:
3-methoxyphenyl isocyanate (37 μl, 0.28 mmol) was added to a solution of provide 1(RS)-[(3,4-dichlorobenzyl)pyridin-4-yl]-2-methylpropylamine (88 mg, 0.28 mmol) in methylene chloride solution (2 ml) at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution (5 ml). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated to provide 1-{1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-2-methylpropyl)}-3-(3-methoxyphenyl)urea. (104 mg) as a white solid. mp 161.4-161.8° C.
Reaction SMILES: BrC1C=CC(Br)=CC=1.[C:9]1(C=CC(O)=C[CH:11]=1)[OH:10].[F:17][C:18]([F:34])([F:33])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][CH:22]=1>>[CH3:11][C:9]([C:23]1[CH:22]=[C:21]([O:20][CH2:19][C:18]([F:33])([F:34])[F:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:10]
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Solvent: Brc1ccc(Br)cc1
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Compound [III] is prepared by a multi-stage process, comprising the conversion of 1,4dibromobenzene or hydroquinone to 1,4-bis(2,2,2-trifluoroethoxy)benzene, which is acetylated to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The acetophenone is then oxidized to form the corresponding benzoic acid derivative, which is then converted to its acid chloride and reacted either with 2-(aminomethyl)piperidine to form the Flecainide product in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide in two steps.
Reaction SMILES: C([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]4)=[C:26]([F:46])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:47])C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH3:43][C:42]([CH3:45])([CH3:44])[CH2:41][CH2:40][N:37]1[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]([N:14]3[CH2:13][CH2:12][C:11]4[N:10]=[C:9]([CH3:47])[NH:8][C:17]=4[C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]3=4)=[O:23])=[CH:25][C:26]=2[F:46])[CH2:39][CH2:38]1
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)CC2
Yield: 51 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-methanone from Example E69.3 (90 mg, 0.14 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and hydrogenated over 20 wt. % palladium hydroxide catalyst (90 mg) for 8 h. The mixture was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (39 mg, 51%).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])#[N:2].[N:22]([Si](C)(C)C)=[N+:23]=[N-:24].C([Sn](=O)CCCC)CCC.Cl>ClCCCl>[CH:9]1([C:8]2[C:3]([C:1]3[NH:24][N:23]=[N:22][N:2]=3)=[C:4]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1c(NS(=O)(=O)c2ccccc2)cccc1C1CC1
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(Nc1cccc(C2CC2)c1-c1nnn[nH]1)c1ccccc1
Temperature: 140 °C
Yield: 65.5 %

Procedure:
N-(2-Cyano-3-cyclopropylphenyl)-benzenesulfonamide (Intermediate 9, 0.052 g), azidotrimethyl-silane (0.087 g) and dibutyltin oxide (0.038 g) were suspended in 1,2-dichloroethane (3 mL). The mixture was heated by microwave irradiation at 140° C. for 45 minutes. Six further aliquots of azidotrimethylsilane (0.174 g) were added and after each addition the mixture was heated by microwave irradiation at 140° C. for 60 minutes. The reaction mixture was acidified to pH 1 using 1N hydrochloric acid, and then extracted with ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was triturated with a mixture of pentane and cyclohexane and the solid was collected by filtration, to give the title compound as a white solid (0.039 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([Cl:13])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(N)cc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(Cl)c(Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 404 (3.120 g) and N-chlorosuccinimide (2.456 g) were suspended in dimethyl formamide (100 mL) and stirred at 50° C. overnight. The reaction mixture was heated at 70° C. for a further 3 hours. The reaction mixture was added drop-wise to a stirred solution of 1:1 saturated aqueous sodium bicarbonate and water. The slurry was filtered and the solids dried under high vacuum to furnish the title compound (2.438 g), possessing the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:29])=[CH:22][CH:23]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]
Reactant: CS(N)(=O)=O
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}butanoic acid (42c) (0.049 g, 0.1 mmol), 2,4,6-trichlorobenzoyl chloride (0.244 g, 1 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol) and methanesulfonamide (0.019 g, 0.2 mmol) in dichloromethane was stirred at room temperature for 20 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-(4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}-butanoyl)-methanesulfonamide (42f) [RD157] (0.053 g, 0.094 mmol, 94%), the structure of which is illustrated in Formula 8, as a white powder.
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:11]([Cl:13])[Cl:12])[Si:7]([Cl:10])([Cl:9])[Cl:8])[Cl:5]>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.C1C=CC=CC=1>[Cl:5][Si:4]1([Cl:3])[CH:2]=[CH:1][Si:11]([Cl:12])([Cl:13])[CH:6]1[Si:7]([Cl:8])([Cl:10])[Cl:9]
Reactant: C#C
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Yield: 50.3 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pd(PPh3)4. Into the same apparatus as described in Example 1 were added 1.01 g of bis(dichlorosilyl)trichlorosilylmethane, 0.103 g of Pd(PPh3)4, and 25 ml of dried benzene to form a mixture. Acetylene gas was blown into the mixture at a rate of 90 ml per minute for 3 hours. The resulting mixture was vacuum distilled at 67 Pa to yield a mixture comprising 0.89 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC area 50.3%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].FC1C(F)=CC=C([N+]([O-])=O)C=1C(C(OCC)=O)C(OCC)=O.Cl>>[F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1F
Agent: CCOC(=O)C(C(=O)OCC)c1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(F)c1F

Procedure:
The mixture of diethyl 2-(2,3-difluoro-4-nitrophenyl)malonate and diethyl 2-(2,3-difluoro-6-nitrophenyl)malonate from D15 (0.5 g) was heated with 11M hydrochloric acid (5 ml) at reflux overnight then evaporated to give 320 mg of the title compound (pale yellow solid) as a 1:1 mixture with 2,3-difluoro-6-nitrophenylacetic acid. M−—CO2H=172.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C:11](=[CH:23][CH2:24]P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:44][C@@H:45]([C@H:57]1[CH2:66][CH2:65][CH2:64][C@@H:63]2[C@:58]1([CH3:68])[CH2:59][CH2:60][CH2:61][C:62]2=O)[CH2:46][C:47]#[C:48][C:49]([CH3:56])([O:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH3:50]>C1COCC1>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][C@H:9]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:17])[CH3:18])[CH2:12][C:11](=[CH:23]/[CH:24]=[C:62]2\[CH2:61][CH2:60][CH2:59][C@@:58]3([CH3:68])[C@H:63]\2[CH2:64][CH2:65][CH2:66][C@@H:57]3[C@H:45]([CH3:44])[CH2:46][C:47]#[C:48][C:49]([CH3:56])([O:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[CH3:50])[CH2:10]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=CCP(=O)(c2ccccc2)c2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2/C(=C/C=C3C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C3)CCC[C@]12C
Reaction time: 0.5 h

Procedure:
590 mg (1.03 mmol) of carefully dried (3R,5R)-[2-[3,5-bis-(t-butyldimethylsilanyloxy)-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) was dissolved in 5 ml of abs. THF and treated at -78° with 0.644 ml of nBuLi (1.6M, hexane). 15 Minutes later, 187 mg (5.15 mmol) of (4aR,5R,8aR)-5-((R)-1,5-dimethyl-5-trimethylsilanyloxy-hex-3-ynyl)-4a-methyl-octahydro-naphthalen-1-one, dissolved in 0.5 ml of abs. THF, was added to the deep red solution and kept for 0.5 h at -78° and for 0.5 h at 0°. The reaction mixture was then poured onto crushed ice/KH2PO4, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and the solvents carefully removed i.V. Flash chromatography (SiO2, hexane/AcOEt=95/5) afforded in the less polar fractions 129 mg of the title compound as colorless oil and in the more polar ones 67 mg of recovered ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl>[CH2:46]([NH:53][C:23]([CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17]1)=[O:24])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)NCc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.15 mmol) was added to the solution at 0° C. After 1 h, benzylamine (12 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(2-benzylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (19 mg, 32%) as a white solid: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.2, found 557.4 [M+H+]; 1H NMR (400 MHz, CDCl3), δ ppm 1.04-1.22 (m, 2H, CH2), 1.42-1.93 (m, 8H, 4×CH2), 2.13-2.29 (m, 1H, CH), 2.67 (t, J=6.2 Hz, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.2 Hz, 2H, NCH2), 4.36 (d, J=5.5 Hz, 2H, NCH2Ar), 5.91 (t, J=5.5 Hz, 1H, NH), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.06-7.13 (m, 2H, Ar), 7.21-7.26 (m, 3H, Ar), 7.28 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1 h, Ar), 8.67 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C1C2C(=NC=CC=2)NN=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.[Li+].CC([N-]C(C)C)C.[CH:35](N1CCCCC1)=[O:36]>>[Br:19][C:20]1[CH:25]=[N:24][C:23]([F:26])=[C:22]([CH:21]=1)[CH:35]=[O:36]
Reactant: O=CN1CCCCC1
Reactant: Fc1ccc(Br)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: c1ccc2[nH]c(-c3n[nH]c4ncccc34)cc2c1
Product: O=Cc1cc(Br)cnc1F

Procedure:
Scheme 3 describes a method for preparation of 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-b]pyridine derivatives (XXVII) by first selective deprotonation at position-3 of 5-bromo-2-fluoropyridine (XVII) with LDA followed by N-formylpiperidine quench to produce 5-bromo-2-fluoronicotinaldehyde (XVIII). Aldehyde XVIII was condensed with pinacol followed by nucleophilic aromatic substitution by hydrazine to give 5-bromo-2-hydrazinyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine (XIX). XIX was then cyclized under acidic conditions to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine (XX). The 1H-pyrazolo[3,4-b]pyridine NH was THP protection followed by reaction of the bromide (XXI) with bis(pinacolato)diboron to form the borate ester (XXII). Suzuki coupling with various bromides (XVIII) or chlorides yields 1H-pyrazolo[3,4-b]pyridine derivatives (XXIII). Iodization of position-3 of 1H-pyrazolo[3,4-b]pyridine (XXIII) with N-iodosuccinimide followed by Suzuki Coupling with various Boc-protected 1H-indol-2-ylboronic acids (XXV) to produce (XXVI). Final deprotection of the pyrazole and indole nitrogens yields the desired 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-b]pyridine derivatives (XXVII).