Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[N:29]1([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:25])[F:26])(=[O:16])=[O:15])[CH2:11][N:10]2[C:38]([C:35]2([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:36][CH2:37]2)=[O:39])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: O=C(O)C1(N2CCCCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3OC(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3OC(F)(F)F)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 61 %

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)pyrrolidine-2-carboxamide 7D with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)pyrrolidine-2-carboxamide as a light yellow solid (61%). MS ISP (m/e): 555.3 (100) [(M+H)]+.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH2:16][CH2:17][CH3:18].[Cl:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClS(O)(=O)=O.C1C(=C(C#N)C#N)C=CC(=C(C#N)C#N)C=1>[Cl:21][CH: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][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Agent: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(Cl)C(=O)O
Temperature: 220 °C
Yield: 69.8 %

Procedure:
Into a 50 ml 3-neck round bottom flask fitted with a condenser, thermometer, and magnetic stirrer were placed 11.4 g (0.04 mole) stearic acid, 8.0 g (0.06 mole) N-chlorosuccinimide, 0.1 ml (0.0015 mole) chlorosulfonic acid, and 0.04 g (0.0002 mole) TCNQ. The flask was placed in a heating bath set at 150° C. The mixture was stirred during heating, and a homogeneous liquid phase was formed. The solution temperature continued to rise above that of the heating bath, and a sudden exothermic reaction occurred in which the reaction temperature increased to ca. 220° C. The reaction mixture was cooled and dissolved in chloroform, and the resulting solution was washed thoroughly with dilute aqueous sodium chloride solution. After drying and removal of the chloroform, the residue was recrystallized from acetonitrile to afford 8.9 g (70%) of 2-chlorostearic acid which was equivalent in purity to the product of Example I.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CCN(CC)CC.COC(C)(C)C>[CH3:12][N:13](/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cnccn1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CN(C)/C=C/C(=O)c1cnccn1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of acetylpyrazine (5 g, 40.9 mmol) in N,N-dimethylformamide dimethyl acetal (10.9 mL, 81.8 mmol) and Et3N (5.7 mL) was heated at 110° C. for 16 h. The heating was stopped and a precipitate was formed while it was allowed to cool down to room temperature. The suspension was diluted with tert-butyl methyl ether; the solid was separated by filtration and washed with tert-butyl methyl ether. This material was triturated with the same solvent, filtered off and dried to afford the title compound 23a as a yellow solid (5.9 g, 33.3 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.66 (dd, J=2.4, 1.6 Hz, 1H), 7.84 (d, J=12.4 Hz, 1H), 6.30-6.20 (m, 1H), 3.19 (s, 3H), 2.93 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a stirred solution of (3SR,4RS)-1-benzyl-3-(4-chloro-3-fluoro-phenyl)-4-nitro-pyrrolidine (0.78 g, 2.33 mmol) in EtOAc (15 ml) was added portion wise SnCl2.2H2O (2.63 g, 11.6 mmol). The reaction mixture was then heated at reflux for 4 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (500 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum. A column chromatography (CH2Cl2/MeOH 95/5) gave 0.46 g (65%) of the title compound as a light brown oil. ES-MS m/e: 305.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COc1cc(NC(=O)Nc2cccc([N+](=O)[O-])c2)ccc1-c1cnco1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 1D in 20 ml of methylene chloride was added, as a solid, 525 mg (3.2 mmol) of m-nitrophenylisocyanate. A voluminous precipitate was obtained. Stirring was continued overnight. The precipitate was filtered and washed with methylene chloride to afford 1.1 g (3.1 mmol, 97%) of compound 17A as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH3:59])[CH2:56][CH2:57]O.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:54][N:55]([CH3:59])[CH2:56][CH2:57][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.130 mmol) was dissolved in THF (3.6 mL), and the solution was added with triphenylphosphine (68 mg, 0.26 mmol), 2-dimethylaminoethanol (0.026 mL, 0.26 mmol) and 40% DEAD-toluene solution (0.118 mL) under ice-cooling, followed by stirring for 20 minutes. The reaction mixture was warmed to room temperature and stirred for 14 hours. The mixture was added with triphenylphosphine (68 mg, 0.26 mmol), 2-dimethylaminoethanol (0.026 mL, 0.26 mmol) and 40% DEAD-toluene solution (0.118 mL) and stirred for 1.7 hours. Then, the mixture was further added with triphenylphosphine (34 mg, 0.13 mmol), 2-dimethylaminoethanol (0.026 mL, 0.26 mmol) and 40% DEAD-toluene solution (0.059 mL), followed by stirring for 1.3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=12/0.5/0.5, chloroform/methanol=3/1) to obtain 4-[2-(dimethylamino)ethoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.9 mg, yield 53%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:28][CH:29]=[CH2:30])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: C=CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: C=CCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), prop-2-en-1-amine (0.5 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. MS m/z (rel. intensity, 70 eV) 317 (M+, 2), 113 (3), 71 (5), 70 (bp), 68 (3) 63 (3).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([NH:33][NH2:34])=[O:32])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36].C(=O)(O)[O-].[Na+].O>O1CCCC1>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]4[O:32][C:35](=[O:36])[NH:34][N:33]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(c2n[nH]c(=O)o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 378 mg of tert-butyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-4-(hydrazinocarbonyl)piperidine-1-carboxylate in 10 ml of tetrahydrofuran was added 130 mg of 1,1′-carbonyldiimidazole at room temperature. After stirring at room temperature for 3 hours, 100 mg of 1,1′-carbonyldiimidazole was added at room temperature, followed by stirring at room temperature for 5 days. To the reaction mixture was added 10 ml of saturated aqueous sodium bicarbonate solution, followed by stirring the reaction mixture at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−1/2) to give the title compound as a pale yellow oil.
Reaction SMILES: C(OB([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)O)(C)(C)C.[C:14]([OH:18])(=[O:17])[CH:15]=O.[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][CH:15]([C:8]2[CH:9]=[CH:10][C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:13]=2)[C:14]([OH:18])=[O:17])=[CH:29][CH:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OB(O)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(C(=O)O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, t-butyl phenyl boronic acid (850 mg, 4.4 mmol), glyoxylic acid (404 mg, 4.4 mmol) and 4-Amino-benzoic acid tert-butyl ester (780 mg, 4.4 mmol) were dissolved in 25 mL of dichloromethane and allowed to stir at RT. After 30 min the reaction turned cloudy, but was allowed to stir an additional 2 h. Upon completion, the reaction was quenched with 20 mL water and the organic layer was separated, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give 1.6 g (95%). of a light yellow powder. 1H NMR (CDCl3): δ 1.29 (9H, s), 1.55 (9H, s), 5.17 (1H, s), 6.57 (2H, d, J=8.4 Hz), 7.39 (4H, s), 7.78 (2H, d, J=8.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][CH3:15].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of 3-bromo-5-Iodo-benzoic acid (4.0 g, 12.2 mmol) in 100 mL of thionyl chloride was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was then dissolved in 80 mL of CH2Cl2. Dimethylamine hydrochloride (1.5 g, 18.3 mmol) and DIPEA (4.3 mL, 24.5 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure and the crude material was purified by column chromatography (Isco™ 330 g) using 50% hexanes/EtOAc as eluting solvent to afford 3.8 g (88%) of 3-bromo-5-iodo-N,N-dimethyl-benzamide as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][C:16]([NH:28][C:29](=[O:33])[NH:30][CH2:31][CH3:32])=[CH:17][C:18]=3[C:19]3[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=3)=[CH:10][N:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37][CH2:38][CH2:39][CH2:40][O:41][P:42]([O:52]CC2C=CC=CC=2)([O:44]CC2C=CC=CC=2)=[O:43])=[O:36])=[CH:4]1)[CH3:2].C[Si](Br)(C)C.O>ClCCl.CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][C:16]([NH:28][C:29](=[O:33])[NH:30][CH2:31][CH3:32])=[CH:17][C:18]=3[C:19]3[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=3)=[CH:10][N:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37][CH2:38][CH2:39][CH2:40][O:41][P:42]([OH:44])([OH:52])=[O:43])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn3CC)cn1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCCOP(=O)(O)O)cn3CC)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
3-{[Bis(benzyloxy)phosphoryl]oxy}propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 21, 700 mg, 0.82 mM) was dissolved in dry dichloromethane (40 mL), and the reaction mixture was cooled to 0° C. Trimethylsilyl bromide (251 mg, 1.64 mmol) was added and the mixture was stirred for 16 h at room temperature. A solid formed on the walls of round bottom flask. The solvent was decanted and the solid was washed with ethyl acetate (30 mL) to give crude compound. The crude compound was dissolved in methanol (20 mL) and water (30 mL) was added to precipitate the product which was filtered and dried to afford 230 mg (35%) of 3-(phosphonooxy)propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:13])[CH2:11][CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:13])[C:11](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12]
Reactant: CCC(=O)c1cc(C)ccc1OC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C)cc1C(=O)C(C)=Cc1ccccc1
Yield: 101.3 %

Procedure:
To a mixture of 140 g of 2'-methoxy-5'-methylpropiophenone, 83.4 g of benzaldehyde and 1.5 lilers of ethanol was added 154 ml of 20%-sodium hydroxide aquecus solution under stirring. The reaction mixture was stirred overnight at room temperature, then 10%-hydrochloric acid was added to make the reaction mixture acidic, and extracted with benzene. The benzene extract was washed with water and an aqueous solution saturated with sodium chloride in this order, then dried to obtain 212 g of 2'-methoxy-5'-methyl-2-benzylidenepropiophenone. Yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]([F:28])([F:27])[F:26])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Cl-].[OH:35][NH3+:36]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]([F:27])([F:26])[F:28])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[C:16]([CH:19]=2)/[C:17](=[N:36]/[OH:35])/[NH2:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [NH3+]O
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C

Procedure:
A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooled to ambient temperature, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].[NH2:13][NH2:14].Cl.C(Cl)Cl>CCO.O>[F:1][C:2]([F:11])([F:12])[C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[NH:14][N:13]=1)([CH3:10])[CH3:9]
Reactant: NN
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(c1cc(N)[nH]n1)C(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (2 g, 11.16 mmol) in EtOH (10 mL) was added hydrazine (1.263 g, 33.5 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL), and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (100% EA, 12 g silica column). All fractions found to contain product by TLC (EA, Rf=0.3) were combined and concentrated to yield an off-white oil of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.459 mmol, 22.03% yield): 1H NMR (400 MHz, CD3OD) δ 5.58 (s, 1H), 1.47 (s, 6H). ES-LCMS m/z 194 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:35](=[O:36])[N:34]([CH3:38])[CH3:33]
Reactant: CN(C)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: [N+:1]([C:4](=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)C(=O)CCC)([O-:3])=[O:2].[H-].[Na+].[C:18](Cl)(=[O:20])[CH3:19]>C(COC)OC.C(Cl)(Cl)Cl>[C:18]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:4][N+:1]([O-:3])=[O:2])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCCC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 23 g of 1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-yl-idene)-2-pentanone in 200 ml of monoglyme was added dropwise at 0° C. to a suspension of 4.65 g of a 57% sodium hydride/mineral oil dispersion in 100 ml of monoglyme. The stirred mixture was allowed to warm to room temperature and stirred overnight. A solution of 8.2 g of acetyl chloride in 50 ml of monoglyme was added dropwise to the reaction at 0° C. The resulting mixture was stirred for one hour at 0° C., then allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with chloroform and extracted with 10% sodium hydroxide solution. The organic phase was separated, washed with water, then with saturated sodium chloride solution, and dried Na2SO4), and the solvent was evaporated under reduced pressure. The resulting liquid was chromatographed, using a wet column with silica gel. As eluent, there was first used 2 litres of a 98/2 chloroform/acetone mixture, then a 95/5 chloroform/acetone mixture was used. Three fractions were obtained. The last fraction was triturated with ether, then cooled, to give a solid yellow product, 3-acetyl-2-nitromethylene-tetrahydro-2-H-1,3-thiazine, m.p. 91°-92.5° C.