Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][CH2:9]2)=[CH:6][N:7]=1.CO.[Li+].[OH-]>C(O)(C(F)(F)F)=O.C1COCC1.O>[NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(=O)NC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(C2CCC(=O)NC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-(3-amino-6-(6-oxopiperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (144 mg, 0.310 mmol) was dissolved in TFA (Volume: 3 mL) and heated at 150° C. for 30 min in microwave The solvent was evaporated in vacuo and the residue was azeotroped with toluene thrice to afford the crude debenzylated lactam. This crude product was dissolved in THF (Volume: 3 mL, Ratio: 3) and MeOH (Volume: 1.500 mL, Ratio: 1.5) and to the mixture was added LiOH (0.037 g, 1.550 mmol) dissolved in Water (Volume: 1.500 mL, Ratio: 1.5). The mixture was agitated at room temperature for 30 min and concentrated in vacuo and the residue neutralized with 2 mL (4.0 N HCl) and the solvent evaporated. The residue was azeotroped once with THF and once with toluene to afford the crude acid which was taken to the next step (assuming quantitative yield) without any further purification. LCMS (m/z): (MH+), 331.2, 0.44 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:18][CH:17]([C:19](O)=[O:20])[CH:16]([C:22](=[O:34])[NH:23][C:24]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][CH:25]3[CH:27]=[CH2:28])[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:44][NH:45][CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH3:51].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([O:31][C:29]([C:24]1([NH:23][C:22]([CH:16]2[CH2:15][CH:14]([O:13][C:7]3[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:10]=[C:9]([O:11][CH3:12])[N:8]=3)[CH2:18][CH:17]2[C:19](=[O:20])[N:45]([CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51])[CH3:44])=[O:34])[CH2:26][CH:25]1[CH:27]=[CH2:28])=[O:30])[CH3:33]
Reactant: CCCCC=CNC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Yield: 78 %

Procedure:
Compound 3g (583 mg, 1.227 mmol) was dissolved in 15 ml dry DMF. DIEA (0.96 ml, 5.522 mmol), N-methylhexeneamine×HCl (270 mg, 1.779 mmol) and HATU (676 mg, 1.779 mmol) were added at 0° C., and the reaction mixture was stirred at RT over night. The DMF was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3(aq), H2O and brine. The organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography (heptane/EtOAc) gave the pure title compound (550 mg, 78%), MS (M+H)+573.
Reaction SMILES: [NH2:1][C:2]1([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[F:53])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=[C:14]3[C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)=[O:10])[CH2:3]1.[CH:54](OCC(F)(F)F)=[O:55].CCN(C(C)C)C(C)C>C1COCC1>[F:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH2:46][C:2]1([NH:1][CH:54]=[O:55])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:15]=[C:14]3[C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)=[O:10])[CH2:3]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(N)(Cc5ccccc5F)C4)cc23)ccn1
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NC=O)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of N-(3-amino-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (0.01 mmol, 7 mg), 2,2,2-trifluoroethyl formate (0.06 mmol, 6 μL) and DIEA (10 equiv.) in THF was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-formamidocyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [OH:1][CH:2]([CH:43]([CH3:45])[CH3:44])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][CH:42]=[C:12]23)[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:45][CH:43]([CH3:44])[C:2](=[O:1])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][CH:42]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C(C)C)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4-[trans-4-(2-hydroxy-3-methylbutoxy)cyclohexyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.19 g) in methylene chloride (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.26 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.047 g, 25%).
Reaction SMILES: C(OC([N:11]1[CH2:16][C@H:15]([CH3:17])[C@:14]([OH:19])([CH3:18])[C@H:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:13]1[C:14]([OH:19])([CH3:18])[C@@H:15]([CH3:17])[CH2:16][NH:11][CH2:12]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidine-1-carboxylate (414 mg, 1.09 mmol) in a vial was dissolved in MeOH (10 mL) and 10% palladium on carbon (100 mg) was added. The vial was closed with septum and connected to a balloon filled with hydrogen. The reaction mixture was stirred at room temperature overnight. The solution was filtered to remove the palladium on carbon and solvent was evaporated under reduced pressure to give the sub-title compound as a colorless oil (245 mg, 92%), which was used in the next step without further purification. LCMS calc. for C12H25N2O3 (M+H)+ m/z=245.2. found 245.1.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:19]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: C=CCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
2 g of sodium hydroxide, 15 ml of distilled water, 7.6 g of methyl 4-hydroxybenzoate, 0.16 g of tetrabutylammonium bromide and 5.92 ml of 5-bromopent-1-ene are successively placed in a reactor. Vigorous stirring is maintained at ambient temperature for 12 hours. After having added 30 ml of a 2.5M sodium hydroxide solution, the reaction medium is heated at 60–80° C. for 90 minutes. It is subsequently diluted with 120 ml of distilled water and extracted with two times 50 ml of diethylether. The aqueous phase is acidified with 10 ml of concentrated hydrochloric acid in order to make possible the precipitation of the acid. After filtration, washing with distilled water and then drying in a desiccator over P2O5, the acid is obtained with a yield of 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[N:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C@@H:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])=O.O(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[C:7]([C:8]2[O:13][CH2:12][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:10]=2)=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: O=C(N[C@H](CO)c1ccccc1)c1cccnc1Oc1cccc(Cl)c1
Agent: ClOCl
Solvent: Cc1ccccc1
Product: Clc1cccc(Oc2ncccc2C2=N[C@@H](c3ccccc3)CO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
A solution of (S)-2-(3-Chloro-phenoxy)-N-(2-hydroxy-1-phenyl-ethyl)-nicotinamide (0.340 grams, 0.922 mmole) and phosprorus oxychloride (0.7 ml) in toluene (10 ml) was stirred over night. The mixture was concentrated to dryness and dissolved in methanol (10 ml) and potassium carbonate was added. The mixture was stirred for 2 hours at room temperature and refluxed for 30 minutes. The methanol was evaporated, and the residue taken up in ethyl acetate. It was washed with water and brine, dried over Na2SO4, and concentrated to give a product that was purified by chromatography on silica gel eluting with 1/3 ethyl acetate/hexane to give a pale yellow oil (0.013 g); HRMS 351.0917; M.P. 78-80° C.; Anal. calcd. for C20H15N2O2Cl: C, 57.37;H, 3.74; N, 7.42. Found: C, 57.31; H, 3.80; N, 7.39.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]2[CH2:10][CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>C1COCC1>[CH:8]1([C:3]2[C:2]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)=[CH:6][N:5]([CH3:7])[N:4]=2)[CH2:10][CH2:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)c(C2CC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a stirred solution of 4-bromo-3-cyclopropyl-1-methyl-1H-pyrazole (500 mg, 2.5 mmol) in THF (10 mL) was added dropwise a 2.5 M solution of n-BuLi (1.4 mL, 3.5 mmol) at −78° C., and the resulting light yellow solution was stirred for 30 min. To the mixture was added a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 mL, 5.5 mmol) in THF (1 mL), and the mixture was warmed to room temperature over 30 min. The reaction was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (50 mL), washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography on silica gel (5% MeOH—CH2Cl2, Rf=0.35) to provide 3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (294 mg, 48%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1>CO>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Solvent: CO
Product: Cc1ccc(N)c(N)n1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
6-Methyl-3-nitro-pyridin-2-ylamine (1.3 g, 8.5 mmol) was dissolved in methanol (40 ml). The flask was purged of all oxygen, placed under a nitrogen atmosphere, and charged with Pd/C (150 mg of 10% palladium on carbon). The reaction mixture was purged, and placed under a hydrogen atmosphere, maintained with a balloon. It was allowed to stir for 18 h until the reduction was judged complete. It was then filtered through Celite™ to remove the palladium. The solvent was removed under vacuum to yield the title compound (1.01 g, 96%). 1H NMR (DMSO-d6): δ=6.59 (d, 1H, J=7.5 Hz), 6.19 (d, 1H, J=7.5 Hz), 5.23 (bs, 2H), 4.39 (bs, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:11]([CH2:13][CH2:14][CH3:15])[N:12]=1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[C:11]([CH2:13][CH2:14][CH3:15])[N:12]=1)=[O:5])[CH3:2]
Reactant: CCCc1nc(CNC(=O)OCC)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CCCc1nc(CNC(=O)OCC)sc1Cc1ccc(N)cc1
Yield: 46.1 %

Procedure:
4.7 g of 2-ethoxycarbonylaminomethyl-5-(4-nitrobenzyl)-4-propylthiazole (13 mmol) in 100 ml of ethanol are hydrogenated at room temperature under 1 atmosphere in the presence of 5 g of Raney nickel. The reaction mixture is filtered and then concentrated to give 2 g of 2-ethoxycarbonylaminomethyl-5-(4-aminobenzyl)-4-propylthiazole in the form of a beige powder melting at 126° C.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]#[N:36])[C:19](=[O:31])[N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH:21]([CH3:22])[C:15]3=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[OH-:41].[Na+].C(#N)C1C=CC=CC=1.OO>CS(C)=O>[CH3:40][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]([NH2:36])=[O:41])[C:19](=[O:31])[N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH:21]([CH3:22])[C:15]3=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN(C)C)c4)ncc3C2C)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4cccc(CCN(C)C)c4)ncc3C2C)cc1
Reaction time: 4 h

Procedure:
(±)-3-[7-[3-(2-Dimethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (92.7 mg; 0.17 mmol) (from Example 6 supra) was dissolved in dimethyl sulfoxide (1.0 mL) and the resulting solution was cooled in an ice-water bath. Aqueous sodium hydroxide (1 M; 300 μL; 0.30 mmol) was added, resulting in the precipitation of the benzonitrile. Aqueous hydrogen peroxide (30%; 53 μL; 0.52 mmol) was then added. The benzonitrile went back into solution and the product then precipitate out of solution. After 4 hours, the reaction was diluted with water. The solid was collected, washed with water and dried. Recrystallization from dichloromethane-ether gave (±)-3-[7-[3-(2-dimethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide. (Yield 72.9 mg; 76.1%). Melting Point: 215–230° C. HR-MS(ES+) m/z Calculated for C31H33N7O3 ([M+H]+): 552.2718; Found: 552.2722.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>[Cu]I.N(CC)CC>[CH3:16][Si:17]([C:20]#[C:21][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a flask containing a mixture of 4-bromobenzophenone (1.31 g, 5.0 mmol). PdCl2 (PPh3)2 (70 mg. 0.10 mmol), and CuI (10 mg, 0.050 mmol) was added Et2NH (50 mL) and trimethylsilyl-acetylene (0.85 mL, 6.0 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h. The solvent was removed under vacuum, and the residue was extracted with CH2Cl2 /H2O. The organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was recrystallized from CH2Cl2 /hexane to afford pale brown crystalline 4-(trimethylsilylethynyl)benzophenone in 93% yield (1.30 g). 1H NMR (300 MHz, C6D6, 25° C., TMS): δ=0.25 (s, 9 H, CH3) 7.44-7.74 (m 9 H, Ph and C6H4); MS (EI) : m/e 278 (M+ --CH3) To a Et2O solution (100 mL) of 4-(trimethylsilylethynyl)benzophenone (1.39 g, 5.0 mmol) prechilled to -30° C. was slowly added a solution of phenyllithium (3.33 mL, 6.0 mmol, 1.8 M in cyclohexane-ether). The solution was slowly warmed to room temperature and stirred for 4 hours. 1 mL of H2O was added and the solution was stirred for 30 minutes. Additional H2O (>200 mL) was added and the organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was chromatographed using CH2Cl2 /hexane (2:1) as eluent to afford (4-ethynylphenyl)-diphenylmethanol as a pale yellow oil in 81% yield (1.24 g).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[OH-:24].[Na+]>C1(=O)CCCCC1.O.CC(C)=O>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([OH:10])(=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:24])=[O:9]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: C=CC=C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: O
Solvent: O=C1CCCCC1
Solvent: CC(C)=O
Product: O=C(O)/C=C\C(=O)O
Reaction time: 4 h

Procedure:
A polymerization was carried out at 70° C. for 4 hours using 54.1 g. of butadiene, 98.1 g. of maleic anhydride and 1.7 g. of azobisisobutyronitrile in 750 cc. of acetone. There was obtained 106.0 g. of a pale yellow copolymer with an intrinsic viscosity of 0.50 as measured in cyclohexanone at 30° C. (All measurements are done hereinbelow under the same conditions.) A reaction was carried out at 80° C. for 1 hour using 15.2 g. of the copolymer, 6.0 g. of sodium hydroxide and 131 g. of water to form an aqueous solution of butadiene-maleic acid copolymer sodium salt. The aqueous solution, an aqueous calcium-chloride solution at a concentration of 0.1 M/l, 30% aqueous solution of sodium lauryl sulfate (LAS) and water were employed together with THPA in an amount equal to the copolymer salt to prepare compositions shown in Table 1. Whereas aqueous gel was formed with the compositions of Examples 1-5, no aqueous gel was formed or the polymer was precipitated with the compositions of Comparative Examples 1-3, in which one of the essential components was not contained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:12].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)(O)[O-].[Na+]>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:4][C:3]=1[N:12]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(F)c(N)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CS(=O)(=O)c1ccc(F)c(N2CCNCC2)c1
Yield: 39 %

Procedure:
10 mL solution of 432 mg 2-fluoro-5-methylsulfonylphenylamine (compound in Production Example 338) and 490 mg bis(2-chloroethyl)amine hydrochloride in 1,2-dichlorobenzene was stirred at 200° C. for 9 hours. The reaction mixture was neutralized by adding an aqueous saturated sodium bicarbonate solution and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 230 mg of the title compound (dark brown solid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:10])=[N:17][N:16]=[N:15]2)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Cc1nnnn1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A suspension of N-(4-bromo-2-nitro-phenyl)-acetamide (1.18 g, 4.55 mmol) in acetonitrile (25 mL) was cooled to 0° C. and then treated with sodium azide (838 mg, 13.65 mmol). The reaction mixture was then treated with trifluoromethanesulfonic anhydride (2.88 g, 10.25 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (70 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-nitro-phenyl)-5-methyl-1H-tetrazole (1.16 g, 90%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd for C8H6BrN5O2 (M+) 282.9705, found 282.9700.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11])#[N:2].S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[C:7]=1[CH:8]=[CH:9][C:10]([Cl:27])=[O:11])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl

Procedure:
By the method of Example 7, Step A, 0.96 g (0.0026 mole) of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid and 1 mL of thionyl chloride were reacted in 20-30 mL of toluene, yielding 0.56 g of 3-[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]acrylic acid chloride as an oil. The nmr spectrum was consistent with the proposed structure and indicated the product to be primarily the trans acrylic acid derivative.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C(N(CC)[C:9](=[O:12])[CH2:10][CH3:11])C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=O)=[C:18]([OH:31])[CH:17]=1.C([O-])(O)=O.[Na+].Cl>ClC1C=CC=CC=1Cl>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:10]([CH3:11])[C:9](=[O:12])[O:31]2)=[CH:20][CH:21]=1
Reactant: CCC(=O)N(CC)CC
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccc(F)cc2)c2ccc(Br)cc2oc1=O
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychloride (95.0 μL, 1.02 mmol) was added dropwise, at rt to a solution of N,N-diethylpropionamide (146 μL, 1.02 mmol) in 1,2-dichlorobenzene (1 mL). After 30 min. at rt, (4-bromo-2-hydroxyphenyl)(4-fluorophenyl)methanone (300 mg, 1.02 mmol) was added all at once. After 10 min. the reaction mixture was heated at 140° C. for 16 h and allowed to cool to rt. It was poured into 5% NaHCO3 (20 mL) and the resulting mixture stirred at 60° C. for 20 min., cooled to rt, acidified (pH=1) with 6N HCl and extracted with CHCl3. The combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was subjected to chromatography on silica gel (EtOAc/toluene 1:100) affording the title compound as a white solid, contaminated with ˜10% of an impurity. It was used as such in the following step.