Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[NH2:17][C:18]1[C:19]2[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[S:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1>O1CCCC1>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(Br)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Temperature: 25 °C
Yield: 10 %

Procedure:
169 mg (1.22 mmol) of potassium carbonate, followed by 191 mg (0.87 mmol) of 4-bromobenzoyl chloride, are added to a solution of 0.27 g (0.70 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 20 mL of tetrahydrofuran under argon. The reaction mixture is stirred at reflux for 2 hours. The reaction mixture is then cooled to a temperature in the region of 25° C. and treated with 40 mL of ice-cold water. The mixture is extracted successively with 60 mL and then with twice 40 mL of ethyl acetate. The organic phases are combined, washed twice with 40 mL of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 35° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with dichloromethane/methanol mixtures (99/1 by volume, and then 98/2) at a flow rate of 13 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 0.04 g of tert-butyl 3-(4-bromobenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate is thus obtained in the form of a white solid melting at 192° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10]N=2)[CH:5]=[CH:4][N:3]=1.[ClH:14].O.[CH:16](O)(C)C>[Pd]>[ClH:14].[N:11]1[CH:12]=[CH:13][C:8]([CH:6]2[NH:7][C:2]([NH2:1])=[N:3][CH2:4][CH2:5]2)=[CH:16][CH:10]=1
Reactant: CC(C)O
Reactant: Nc1nccc(-c2ccncn2)n1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: NC1=NCCC(c2ccncc2)N1
Yield: 27 %

Procedure:
To a solution of 5 g (29.2 mmoles) of 2-amino-4-(4-pyrimidyl)-pyrimidine (Journal of Medicinal Chemistry (1978), 21(7), 623-8) in 30 ml of a 6N solution of hydrochloric acid in isopropanol was added 5 ml of water and 0.2 g of palladium on carbon catalyst (10% wt/wt). The suspension was hydrogenated under 40 psi pressure at 50° C. temperature during 8 h. The catalyst was removed by filtration and the solvent evaporated under reduced pressure. Isopropanol was added and the resulting solution was refiltered and the solvent removed by evaporation under reduced pressure to give 2.0 g (27%) of compound as a white powder which was used as such.
Reaction SMILES: [OH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]1([CH2:14][O:1][C:2]2[C:12]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCOc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCOc2c(OCc3ccccc3)cccc21
Yield: 67.4 %

Procedure:
A mixture of 9-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (7.46 g, 41.6 mmol), benzyl bromide (Preparation 58) (5.45 ml, 45.8 mmol) and potassium carbonate (17.26 g, 125 mmol) was stirred and heated at 60° C. in DMF (75 ml) for 2 hours. Cooled, diluted with water (300 ml) and extracted with EtOAc (200 ml and 4×75 ml) and the combined organics washed with 3×100 ml of water. Dried (magnesium sulphate), evaporated, triturated with ether and filtered off to give 7.55 g of white solid. MS (ES): C16H15NO3 requires 269; found 270 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:38])/[CH:4]=[CH:5]/[C:6]1[C:10]([C:11](=[O:30])[C:12](=[O:29])[N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:15][CH2:14]2)=[C:9]([CH3:31])[NH:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+].O>C(O)C>[CH3:31][C:9]1[NH:8][C:7]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:38])=[O:2])[C:10]=1[C:11](=[O:30])[C:12](=[O:29])[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)/C=C/c1c(-c2ccccc2)[nH]c(C)c1C(=O)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)c(/C=C/C(=O)O)c1C(=O)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To a solution of 155 mg (0.295 mmol) (E)-3-(5-methyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-acetyl}-2-phenyl-1H-pyrrol-3-yl)-acrylic acid methyl ester in 2 ml ethanol 12 mg ((0.295 mmol) sodium hydroxide and 0.5 ml water were added. The mixture was stirred for 24 h at RT. The solvent was evaporated and the residue was treated with 1N HCl. The precipitate was filtered off and dried to give 120 mg (80%) of the title compound. MS 512.17 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:17](=[O:32])(=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=O)(C)(C)C.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C.CCOCC>[ClH:33].[N:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][S:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)(=[O:32])=[O:31])=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2)cc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccc(-c2ccncc2)cc1)c1cc2ccccc2[nH]1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-pyridin-4-yl-phenylsulfamoyl)-indole-1-carboxylic acid tert-butyl ester (0.030 g) in ethyl acetate (1.0 ml) was added 3.5 N HCl/ethyl acetate (2.0 ml). The reaction mixture was stirred at 45° C. for 8 h, then diluted with ether (40 ml). The precipitate was collected, washed with ether and dried under high vacuum over P2O5 to obtain the title compound (0.025 g) as a colorless amorphous powder. MS (ISP): 350.4 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:36][Mg]Br.S([O-])(O)(=O)=O.[K+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([OH:22])[CH3:36])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: C[Mg]Br
Reactant: COC(=O)c1c(-c2cccc(C=O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2cccc(C(C)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2.6 ml) of 6-chloro-4-(3-formylphenyl)-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (130 mg) in THF was added a solution (3 mol/l, 0.10 ml) of methyl magnesium bromide in THF at room temperature with stirring, and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 5% aqueous potassium hydrogensulfate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (69 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][N:17]([CH2:18][CH3:19])[CH2:15][CH3:16]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: CCNCC
Solvent: O
Product: CCN(CC)Cc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
24.6 parts of 3,7-dichloro-8-chloromethylquinoline and 30 parts of diethylamine were stirred at 55° C. for 6 hours. Water was added and the solid was filtered off with suction and dried. 25 parts of 3,7-dichloro-8-diethylaminomethylquinoline of melting point 54° C. were obtained. The yield corresponds to 89% of theory.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[S:9]1(=[O:20])(=[O:19])[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH2:11][NH:10]1>C(#N)C.O>[CH3:8][N:10]1[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[S:9]1(=[O:20])=[O:19]
Reactant: CI
Reactant: O=S1(=O)NCNc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CNc2cccnc2S1(=O)=O
Temperature: 50 °C

Procedure:
0.52 g of potassium carbonate and 0.94 g of iodomethane are added to a solution of 0.25 g of 2,3- dihydro-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 1) in 10 cm3 of acetonitrile. The suspension is heated at 50° C. for 3 hours. The acetonitrile is then removed by evaporation under partial vacuum and the residue obtained is taken up in 10 cm3 of water. The suspension is extracted with chloroform (5 times 100 cm3). The extraction solvent is dried over MgSO4 and then concentrated to dryness. The solid obtained is purified by chromatography on a silica column (elution solvent: 1/9 MeOH/CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12]CCO2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][S:14]SC>>[CH3:13][S:14][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:12]
Reactant: CSSC
Reactant: Brc1cccc(C2OCCO2)c1
Product: CSc1cccc(C=O)c1

Procedure:
2-(3-Bromophenyl)-1,3-dioxolane and dimethyl disulfide were processed as described in Example 71A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCCCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 85.3 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pentanoyl chloride (0.48 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (85%) of product as an off-white solid: mp 178-179° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 5.18 (dd, J=5.0 and 12.4 Hz, 1H), 2.99-2.89 (m, 1H), 2.68-2.45 (m, 4H), 2.13-2.09 (m, 1H), 1.69-1.57 (m, 2H), 1.44-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) δ 172.72, 171.99, 169.73, 167.83, 166.64, 136.64, 136.07, 131.36, 125.96, 118.15, 116.68, 48.97, 36.32, 30.97, 26.88, 22.03, 21.70, 13.64; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.10; H, 5.37; N, 11.58.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.CN(C)C([N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1)=O.[I-].[Na+].N>C(#N)C>[CH3:20][C:18]1[NH:17][C:16]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:15][CH:19]=1
Reactant: Cc1cn(C(=O)N(C)C)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: N
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(Cc2ccc(C#N)cc2)[nH]1

Procedure:
A solution containing alpha-bromo-4-tolunitrile (11.0 g), 1-(dimethylcarbamoyl)-4-methylimidazole (8.6 g) and sodium iodide (8.4 g) in acetonitrile (75 mL) is heated and stirred at reflux for 15 hours. The mixture is cooled to 0° (ice-bath) and ammonia gas is bubbled through the solution for 15 minutes. The volatiles are then evaporated and the residue is partitioned between water (150 mL) and ethyl acetate (150 mL). The organic solution is washed with water (2×50 mL) and is then extracted with 3N hydrochloric acid. The combined acidic extracts are made basic (pH 9) with 6N sodium hydroxide and the product is extracted into ethyl acetate (3×60 mL). After drying (MgSO4), solvent evaporation affords crude 4-[1-(5-methylimidazolyl)methyl]-benzonitrile which forms a hydrochloride salt, m.p. 203°-205°, when its solution in acetone is treated with ethereal HCl.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:21][CH2:22][CH3:23])=[O:6])[CH:8]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncc[nH]2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-(1H-imidazol-2-yl)benzoic acid (250 mg, 0.79 mmol), diisopropylethylamine (103 mg, 0.8 mmol), and HBTU (330 mg, 0.87 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (322 mg, 0.79 mmol) and diisopropylethylamine (206 mg, 1.6 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 4 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound in pure form. APCI MS m/z 632.3 [M+H]+.
Reaction SMILES: C([C:5](C)=[O:6])C(C)C.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:8]([CH:13]([CH2:12][CH2:11][CH2:10][CH3:9])[CH2:5][OH:6])[CH3:14]
Reactant: Cc1ccccc1
Reactant: CC(=O)CC(C)C
Product: CCCCC(CC)CO
Yield: 0 %

Procedure:
A similar four-necked flask was charged with 120 g of the allyl group-bearing epoxy resin produced above, 100 g of methyl isobutyl ketone, 200 g of toluene and 0.04 g of a 2-ethylhexanol-modified chloroplatinic acid solution having a platinum concentration of 2%. After one hour of azeotroping off water, 80 g of an organopolysiloxane blocked with hydrogen atoms at both ends represented by the following formula (7) was added dropwise over 30 minutes at the reflux temperature. Stirring was continued at the temperature for a further 4 hours for reaction. The resulting contents were washed with water and the solvent was distilled off in vacuum. The reaction product was a silicone-modified epoxy resin of the above formula (6) serving as Silicone stress-reducing agent 2.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[H][H]>CCO.O=[Pt]=O>[CH2:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC#Cc1cccc(NCc2ccc(OC)cc2)n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Yield: 94.5 %

Procedure:
A mixture of 14-5 (6.54 g, 17.8 mmol), Et3N (1.85 mL, 13.3 mmol), and PtO2 (0.405 g, 1.78) in EtOH (150 mL) was stirred under a balloon of hydrogen for 6 h. Filtration through celite and evaporative removal of the solvent afforded 6.23 g of 14-6 as a colorless oil. The crude product was used directly in the next step without purification.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:46]=[CH:45][C:44](F)=[CH:43][CH:42]=3)[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>CS(C)=O>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:42]=[CH:43][C:44]([N:6]4[CH2:7][CH2:8][N:3]([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:4][CH2:5]4)=[CH:45][CH:46]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: CC(CO)N1CCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)CO)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
2-(Piperazin-1-yl)propan-1-ol 2HCl (0.274 g, 1.26 mmol) was added to N-ethyl-N-propan-2-ylpropan-2-amine (0.330 mL, 1.89 mmol) in DMSO (5 mL). The reaction mixture was stirred at room temperature for 10 mins. N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.233 g, 0.63 mmol) was added and the mixture heated at 110° C. for 18 h under nitrogen. Heating was continued for 12 additional days. The reaction was cooled and the crude mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.048 g, 15.44%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCCC1>[OH:19][CH:18]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:20]=[CH2:21]
Reactant: C=CC=O
Reactant: C#CC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 741.3 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under the stream of a nitrogen gas, 81.13 ml (0.122 mole) of a 1.5M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After ageing the reaction solution at -50° C. for 30 minutes, 6.84 g (0.122 mole) of acrolein was added dropwise at -50° C. or less. After the reaction solution was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 125 g of 3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 80° C.).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C.O.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[NH2:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:22]([CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Yield: 48.9 %

Procedure:
A solution of Intermediate 110 (0.38 mmol) in methanol (9 mL) was treated with iron (III) chloride hexahydrate (10 mg) and decolorizing charcoal (100 mg). While the mixture was being heated to reflux, hydrazine monohydrate (1.0 mL) was added dropwise via syringe. After two hours of heating at reflux, the mixture was allowed to cool and was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and the residue was purified via automated flash silica gel chromatography, using a 12 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound (0.14 g, 56%) as a black foam. ES/MS calcd. for C36H56N3O6Si+ 654.4. Found m/z=654.5 (M+H)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1([CH2:31][CH2:32][N:33]2[CH:41]=[C:40]3[C:35]([CH:36]=[C:37]([NH2:42])[CH:38]=[CH:39]3)=[N:34]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.N1(CCN2C=C3C(C=CC(N)=C3)=N2)CCOCC1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:42][C:37]4[CH:38]=[CH:39][C:40]5[C:35]([CH:36]=4)=[N:34][N:33]([CH2:32][CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:41]=5)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc2cn(CCN3CCOCC3)nc2c1
Agent: Nc1ccc2nn(CCN3CCOCC3)cc2c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5cn(CCN6CCOCC6)nc5c4)nn23)c1

Procedure:
Following the procedure of Example 1315, N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (114 mg, 0.330 mmol) was coupled in parallel fashion to 2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-ylamine (57 mg, 0.23 mmol) and 2-(2-morpholin-4-yl-ethyl)-2H-indazol-5-ylamine (57 mg, 0.23 mmol). Products were purified by RP pHPLC as described in Example 1291c. Yield of TFA salt: 71 mg (62%); LC/MS: 575 (M+H); HPLC: 97% pure, RT=2.73 min; 1H NMR: (DMSO, δ) 9.68 (s, 1H), 9.08 (s, 1H), 8.73 (d, J=7.9, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.87 (d, J=7.8, 1H), 7.77 (t, J=7.7, 1H), 7.72 (s, 1H), 7.69 (d, J=9.0, 1H), 7.36 (d, J=9.0, 1H), 7.25 (d, J=4.8, 1H), 7.04 (d, J=4.8, 1H), 4.85 (t, J=5.7, 2H), 3.85 (m, 4H), 3.80 (m, 2H), 3.30 (m, 4H), 1.13 (s, 9H).