Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].O.C(=O)([O-])O.[Na+].[NH2:12]OS(O)(=O)=O.[CH3:18][O:19][C:20]([C:22]([C:27]([O:29]C)=O)=[C:23]([S:25][CH3:26])[SH:24])=[O:21]>O>[CH3:18][O:19][C:20]([C:22]1[C:27]([OH:29])=[N:12][S:24][C:23]=1[S:25][CH3:26])=[O:21]
Reactant: NOS(=O)(=O)O
Reactant: COC(=O)C(C(=O)OC)=C(S)SC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(O)nsc1SC
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 73 %

Procedure:
A separate reaction vessel was charged with water (280 mL, 7 volumes) and sodium hydrogencarbonate (1.5 equiv, 38.2 g). The water/sodium hydrogencarbonate mixture was cooled to 5° C. under nitrogen atmosphere. Hydroxylamine-O-sulfonic acid (1.2 equiv, 41.1 g) was added over 5 minutes, and the mixture was stirred 15-30 minutes. The 2,2-Bis-methoxycarbonyl-1-methylsulfanyl-ethenethiol anion/acetonitrile solution from Example 1 was added over 60-70 minutes. The mixture was warmed to 25° C. over 1 hour, then held for 16 hours at 25° C. Most of the acetonitrile was removed by vacuum distillation (130 Torr, 50° C.). The residue was cooled to room temperature, acidified to pH ˜1 by addition of 37% hydrochloric acid (32 mL). The solids were granulated for 16 hours at 25° C. The slurry was filtered, and the filter cake was washed 3×100 mL with water, once with 200 mL 1:3 ethyl acetate:hexanes (v/v), and once with 100 mL 1:3 ethyl acetate:hexanes (v/v). The wet cake (50.5 g) was dried in a vacuum oven for 16 hours to give 3-Hydroxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl ester, providing 45.4 grams (73% yield). 1H NMR: (DMSO-d6) δ 11.92 (s, 1H); 3.74 (s, 3H); 2.53 (s, 3H). MS: (API-ES pos) 206 (M+H)+, base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH:18](O)[CH2:19][CH2:20][C:15]2=[N:14]1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH:18]([F:30])[CH2:19][CH2:20][C:15]2=[N:14]1
Reactant: CCN(CC)S(F)(F)F
Reactant: C#CCOc1cc(-n2nc3n(c2=O)CC(O)CC3)c(Cl)cc1Cl
Solvent: ClCCl
Product: C#CCOc1cc(-n2nc3n(c2=O)CC(F)CC3)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 169 mg (0.477 mmol) of 5,6,7,8-tetrahydro-2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-6-hydroxy-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one in 5 mL of dichloromethane was added 76 μl (0.573 mmol) of diethylaminosulfur trifluoride (DAST) at 0° C. The reaction mixture was stirred at 0° C. for 1h. The mixture was then quenched with ice and extracted with dichloromethane. The organic extracts were dried (MgSO4), and then concentrated in vacuo to give a pale red solid. The crude product was purified by flash chromatography over silica gel, eluting with a 95:5 v:v mixture of dichloromethane and methanol to give 64 mg of the title product as a pale yellow foam. 19F NMR (CDCl3, 400 MHz) δ-188 ppm, 1H NMR (CDCl3, 400 MHz) δ 7.5 (s,1H), 7.1 (s,1H), 5.2 (m,1H), 4.8 (s,2H), 4.2-3.6 (m,2H), 3.2-3.0 (m,1H), 3.0-2.6 (m,1H), 2.5 (s,1H), 2.3-1.8 (m,2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH:10]2[CH2:12][CH2:11]2)=O)=[CH:6][N:5]=[C:4]([CH:13]([F:15])[F:14])[N:3]=1.C([OH:18])C>CC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:10]2([OH:18])[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH:13]([F:15])[F:14])[N:3]=1
Reactant: O=C(c1cnc(C(F)F)nc1Cl)C1CC1
Reactant: CCO
Solvent: CC(C)=O
Product: OC1(Cc2cnc(C(F)F)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 g of 4-chlorodifluoromethyl-5-cyclopropylcarbonylpyrimidine was added to 100 ml of ethanol, then, 15 g of a t-butylamine borane complex was further added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. After addition of 30 ml of acetone, the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. 100 ml of water was added to the residue, and extraction with ethyl acetate was carried out. The extract layer was washed with water, and the solvent was distilled off under reduced pressure. The residue was dried in vacuum to obtain 45 g of the desired product. nD20.5 1.5020
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])[CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[ClH:1].[CH2:2]([N:5]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:24])[NH2:25])=[CH:19][CH:18]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])[CH2:3][CH3:4]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(CCC(=O)O)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.52 g (1.0 mMol) of 1-Methyl-2-[(4-amidinophenyl)-thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in 15 ml ethanol, mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then 5 ml of water were added, the alcohol was distilled off, and it was acidified with concentrated hydrochloric acid. The water was distilled off in vacuo, and the crude product was taken up in 5 ml of ethanol and filtered to remove the insoluble sodium chloride. After the solvent had been distilled off the title compound was obtained as a white solid. Yield: 0.43 g (88% of theory), Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5) C23H27N5O3S (453.57) ##EQU10##
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[CH3:23][Mg]Br>C1COCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([CH:21]([OH:22])[CH3:23])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:3])=[O:4]
Reactant: C[Mg]Br
Reactant: CS(=O)(=O)c1ccccc1-c1nc2cccnc2cc1C=O
Solvent: C1CCOC1
Product: CC(O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reaction time: 2 h

Procedure:
To a solution of crude of 2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carbaldehyde (1.0 g, 3.2 mmol) in THF (25 mL) was added methyl magnesium bromide (3.2 mL, 9.6 mmol) at 0° C. The reaction mixture was stirred for 2 h at same temperature. The reaction mixture was quenched with satd solution of ammonium chloride and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 1-(2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanol: LC-MS (ESI) m/z 329.0 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 67 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 67%). 1H NMR (300 MHz, CDCl3) δ 3.30 (m, 4H), 3.76 (m, 4H), 4.15 (s, 3H), 6.80-6.82 (m, 1H), 6.87-6.91 (m, 2H), 7.19-7.22 (m, 1H), 7.29 (br s, 1H), 7.49-7.51 (m, 1H), 7.60 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:29])C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-:29])=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.15 g (0.423 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline) was dissolved in a mixed solvent of 5 ml of ethyl acetate and 5 ml of chloroform and 0.11 ml (0.508 mmol) of 32% peracetic acid was added thereto. The mixture was heated at 50° C. and stirred for 3 hours. After the reaction mixture was poured into a sodium hydrogencarbonate aqueous solution, the resulting solution was extracted with chloroform, dried (Na2SO4), then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1 (v/v)) to obtain 0.13 g (0.351 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5-oxide shown below as a white solid. ##STR59## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3230, 2980, 1710, 1540, 1440, 1370, 1280, 1170, 880, 770.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH2:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([Si:34]([CH3:40])([CH3:39])[O:35][CH2:36][CH:37]=O)([CH3:33])([CH3:32])[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:37][CH2:36][O:35][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:40])[CH3:39])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO[Si](C)(C)C(C)(C)C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1

Procedure:
3-Amino-5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-1-carboxylic acid tert-butyl ester (16.1 g, 41.23 mmol), from Synthetic Example 18, was reacted with (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (CAS 102191-92-4, obtained from Aldrich, 10.06 g, 58 mmol), according to the procedure detailed in Synthetic Example 19. The crude 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-indazole-1-carboxylic acid tert-butyl ester thus obtained was used without further purification in the next step.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18](OC)=[O:19])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[NH:26][N:25]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: COC(=O)c1ccncc1C(=O)c1ccc(-n2ccnc2)cc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2cnccc12

Procedure:
A solution of 0.43 g (1.4 mmol) of 3-[4-(1H-imidazol-1-yl)benzoyl]-4-carbomethoxypyridine in 50 mL of EtOH is treated with hydrazine monohydrate (0.08 g, 1.54 mmol) and heated to reflux for 1 day. The mixture is allowed to cool and the white solid precipitate filtered and dried to produce 4-[4-(1H-imidazol-1-yl)phenyl]-1-oxo-1,2-dihydropyrido[3,4-d]pyridazine. M.P. 377° C. dec.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC(=O)c1ccc(CCBr)s1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ccc(CCN=[N+]=[N-])s1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
Sodium azide (697 mg, 10.7 mmol) was added to a solution of the bromide from step 2 (2.7 g, 9.7 mmol) in DMF (39 mL) at room temperature. After 18 h at room temperature, the reaction mixture was diluted with EtOAc (300 mL) and washed with water (3×100 mL) and brine (50 mL). The organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford 2.24 g (96%) of isopropyl 5-(2-azidoethyl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.CCO>[Pd].O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Temperature: 50 °C
Yield: 88 %

Procedure:
A mixture of 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (D87) (1.5 g, 4.9 mmol, 1 equiv), NH4COOH (3.0 g, 49 mmol, 10 equiv), 10% Pd on charcoal (50% wet, 250 mg, 0.082 equiv w/w), EtOH (20 ml) and H2O (10 ml) was heated at 50° C. for 90 min. The mixture was cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with saturated NaHCO3 solution (100 ml), dried over MgSO4 and concentrated in vacuo to give 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.2 g, 88%) as a white waxy solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]1([C:22]([NH:24][NH2:25])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:25]/[NH:24][C:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:23])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)c1cccc2ccccc12
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2cccc3ccccc23)c2ccccc21
Yield: 58 %

Procedure:
The title compound was prepared using isatin 3 and 1-naphthhydrazide according to the synthetic method E. The product was purified by flash chromatography (eluent: AcOEt/Heptane: 3/7) to afford a yellow oil which crystalized. Yield: 58%. 1H NMR (DMSO-d6): δ 0.83 (t, J=6.9 Hz, 3H), 1.26 (m, 6H), 1.59-1.62 (m, 2H), 3.73 (t, J=6.9 Hz, 2H), 7.17-7.23 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 7.63-7.70 (m, 3H), 7.90 (d, J=6.6 Hz, 1H), 8.07 (t, J=6.6 Hz, 1H), 8.19 (d, J=8.7 Hz, 1H), 8.35 (br s, 1H), 13.51 (br s, 1H). 13C NMR (DMSO-d6): δ 14.29 (CH3), 22.39 (CH2), 26.32 (CH2), 27.34 (CH2), 31.27 (CH2), 39.50 (CH2), 110.61 (CH), 119.61 (C), 121.22 (C), 123.65 (CH), 125.36 (CH), 125.51 (CH), 126.83 (CH), 127.20 (CH), 128.03 (CH), 129.04 (CH), 130.34 (C), 131.26 (C), 132.26 (CH), 133.82 (C), 143.49 (C═N), 161.34 (C═O). HRMS (ES+) calcd for C25H26N3O2 (M+H+), m/e, 400.2033; found, 400.2020.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[O:13]([C:15]#[N:16])[K]>O>[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:15]([NH2:16])=[O:13])[CH2:5][CH2:4]1
Reactant: NC1CCC(=O)c2sccc21
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21
Temperature: 70 °C

Procedure:
The aqueous solution (280 ml.) of (+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride from Example 53 is stirred while 40 grams of KOCN in 95 ml. of water is added dropwise. The mixture is warmed to 70° C. for 1.5 hour and cooled to 10° C. The light brown solid is collected and washed well with 700 ml. of water. The product is then stirred with 110 ml. of cold methanol, collected, and washed with 50 ml. of cold methanol to afford 48 grams of the title compound, m.p. 247°-249.5° C. (dec.), [α]D24 = - 97.16° (c, 0.14 in methanol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH:10]([CH3:12])[CH3:11].O>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:10]([CH3:12])[CH3:11])[C:6]=1[CH:7]=[O:8]
Reactant: CC(C)I
Reactant: Cc1nc[nH]c1C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncn(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol) and 2-iodopropane (4.5 mL, 45.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-2% MeOH/DCM), affording 4-methyl-1-(propan-2-yl)-1H-imidazole-5-carbaldehyde (691 mg, 10% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8]N1C(=O)CCC1=O.[NH2:16][C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=2[Cl:41])=[O:22])=[CH:19][CH:18]=1>O>[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]2[C:25]([Cl:41])=[CH:26][C:27]([C:31]([F:40])([C:36]([F:37])([F:38])[F:39])[C:32]([F:33])([F:34])[F:35])=[CH:28][C:29]=2[Cl:30])=[O:22])=[CH:42][C:43]=1[Cl:8]
Reactant: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
To the toluene (30 ml) solution in which 4-amino-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)phenyl]benzamide (2.80 g) is dissolved, N-chlorosuccinimide (0.87 g) was added. The reaction solution was stirred for 6 hours at 80° C. under heating. The solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The organic phases were combined, and then dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to give 4-amino-3-chloro-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl] benzamide (2.03 g, yield 67.3%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][CH:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:28]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCOC(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C2CCN(CCCOC(c3ccccc3)c3ccccc3)C2)c1
Temperature: 80 °C
Yield: 51.3 %

Procedure:
A solution of 5.3 g (50 mmole) of 1-(diphenylmethoxy)-3-bromopropane in 50 cm3 of dimethylformamide was added to a mixture of 8.8 g (50 mmole) of 3-(3-methoxyphenyl)pyrrolidine, 13.8 g (100 mmole) of potassium carbonate, a few potassium iodide crystals and 250 cm3 of dimethylformamide. The reactive medium was heated to 80° C. for 12 hours and then filtered after it returned to room temperature. The filtrate was concentrated to dryness under reduced pressure. The residue was taken up with ether and extracted with 500 cm3 of N hydrochloric acid. The aqueous phase was separated, basified with 10N sodium hydroxide solution and extracted with methylene chloride. The organic solution was dried on sodium sulfate. Evaporation of the solvent yielded an oily residue, which was purified by silica gel column filtration (eluent, hexane-ethyl acetate, 1/1). There was obtained 10.3 g (yield: 51.3%) of 1-[3-(diphenylmethoxy)propyl] 3-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[CH:5]=1)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Product: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Yield: 94.7 %

Procedure:
A mixture of 3-acetamidoacetophenone (30 g, 169 mmol) and dimethylformamide dimethyl acetal (50 mL, 376 mmol) is refluxed under nitrogen for 8 hours. The reaction mixture is cooled and the solid collected by filtration to yield product (5) as an orange solid (37.2 g, 160 mmol, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])C(OC(C)(C)C)=O)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:3])=[O:2]
Reactant: COC(=O)CCC(=O)C(C(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 6-methyl 2-(2-nitrophenyl)-3-oxohexanedioate (6.0 g, 17.08 mmol) in DCM (60 mL) were added trifluoroacetic acid (22 ml, 286 mmol) and triethylsilane (8 ml, 50.1 mmol). The mixture was stirred at room temperature for 2 h. Concentration in vacuo then afforded the title compound (8.7 g, 17.08 mmol, 99% yield). LCMS: rt=2.55 min, [M+H+]=252.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C:3]([O:5][CH:6]([O:10][C:11]([O:13]C1C=CC(S(C)(=O)=O)=CC=1)=[O:12])[CH:7]([CH3:9])[CH3:8])=[O:4].O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32]>ClCCl>[CH3:24][CH:2]([CH3:1])[C:3]([O:5][CH:6]([O:10][C:11]([O:13][N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])=[O:12])[CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)C(=O)OC(OC(=O)Oc1ccc(S(C)(=O)=O)cc1)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C

Procedure:
2-Methyl-1-[4-(methylsulfonyl)phenoxycarbonyloxy]propyl 2-methylpropanoate D6 is dissolved in dichloromethane at a concentration of 10% (w/vol). N-hydroxysuccinimide (1.1 equivalents) is added to the solution. The reaction mixture is warmed to reflux and stirred until the reaction is complete. The organic phase is extracted twice with a 10% potassium carbonate solution followed by a wash with water (2×). Drying over sodium sulfate is followed by solvent evaporation to provide the title compound E2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][NH2:34])[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: NCc1ccccc1C1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 48 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.00 g, 4.0 mmol) and 2-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.65 g, 48%) as a bright yellow solid, mp 164°-165° C.