Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
At room temperature, p-aminophenol (0.51 g, 4.70 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). To the resulted solution, potassium tert-butoxide (0.53 g, 4.70 mmol, 1 eq) was added in portions and the resulted mixture was stirred for 0.5 hours. Tert-butyl 4-chloropicolinate (1 g, 4.70 mmol, 1 eq) and potassium carbonate (45 mg, 0.33 mmol, 0.07 eq) were added, and the mixture was heated to 80° C. and stirred for 2 hours. The mixture was cooled to room temperature and ethyl acetate (50 mL) was added. The mixture was filtered to remove the undissolved material and the filtrate was washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (dichloromethane:ethyl acetate=30:1) to give the title compound (805 mg, purity 96%, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC.[Cl-].C(N(CC)CC)C>CN(C)C=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:34]1[S:35][CH:36]=[CH:37][N:38]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc(N)c1-c1nccs1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 13.3 %

Procedure:
60 mg (0.07 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, 43 mg (0.11 mmol) of 2-(tributylstannyl)thiazole, 2.0 mg (0.01 mmol) of bis-triphenylphosphinepalladium(II) chloride, 4.4 mg (0.02 mmol) of copper (I) iodide and 32 μl (0.23 mmol) of triethylamine in dimethylformamide (1.5 mL) were heated to 120° C. for 20 minutes with microwave irradiation under nitrogen atmosphere. The reaction mixture was filtered through Celite® and washed with methanol. The solvent of the filtrates were evaporated in vacuum and the residue was dissolved in ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) and then by preparative HPLC (Waters XBridge C18 OBD column, mixture of eluents NB from 50% B to 65% B, in a 10 min. gradient) to give 4 mg (13% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].[N:25]1[N:26](C2C=CC=CC=2C(O)=O)[N:27]=[CH:28][CH:29]=1>>[N:25]1[N:26]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH2:1])=[O:11])[N:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1ccccc1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 300 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7](O)=[O:8])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH:15]([CH3:17])[CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1.C(C1NN=NN=1)(=O)N>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:37][C:38]2[NH:42][N:41]=[N:40][N:39]=2)=[O:8])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: Nc1nnn[nH]1
Reactant: Cc1oc(C(=O)O)c(OC(C)C)c1OC(C)C
Agent: NC(=O)c1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1oc(C(=O)Nc2nnn[nH]2)c(OC(C)C)c1OC(C)C
Yield: 27.4 %

Procedure:
Following the procedure described in Example 120, 2.00 g (8.84 mmol) of the above carboxylic acid, 1.65 g (10.18 mmol, 1.15 equiv) of 1,1'-carbonyl diimidazole, 2.2 g (21.5 mmol, 2.4 equiv) of triethylamine, and 0.89 g (10.46 mmol, 1.18 equiv) of 5-aminotetrazole in refluxing (2.5 hours) acetonitrile (46 mL) is converted to the carbamoyltetrazole. Recrystallization from toluene afforded 0.75 g (2.73 g theo., 27%) of 5-methyl-3,4-diisopropoxy-N-1H-tetrazol-5-yl-2-furancarboxamide; mp 190°-192° C. (dec).
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:29]=[C:30]([F:32])[CH:31]=1)[O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:16][CH:15]=1.Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]1([S:7][N:21]([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[C:30]([F:32])[CH:31]=[C:10]([F:9])[CH:11]=3)=[CH:28][CH:27]=2)[C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1

Procedure:
5.7 g of freshly distilled phenylsulfenyl chloride in 10 ml of toluene are added dropwise at 0° to +5° C. in the course of 30 minutes to a solution of 12 g of ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 40 ml of pyridine, with stirring. After this, the mixture is stirred for 4 more hours at room temperature. The reaction mixture is poured into 300 ml of 2N hydrochloric acid and ice, and the mixture is extracted twice using diethyl ether. The combined organic phases are washed to neutrality with water and sodium chloride solution and dried over sodium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography on silica gel (eluent: hexane/diethyl ether, 20:1), which gives pure ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, nD20 : 1.5700.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[C:12]1([C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]3[N:29]=[CH:30][N:31]=[CH:32][C:21]=3[CH2:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:33](OCCC(C)C)=[O:34]>O1CCCC1>[N:33](=[C:20]1[C:21]2[CH:32]=[N:31][CH:30]=[N:29][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:19]1)[OH:34]
Reactant: c1ccc(C2=NCc3cncnc3-c3ccccc32)cc1
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: ON=c1nc(-c2ccccc2)c2ccccc2c2ncncc12
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a suspension of potassium tert-butoxide (24.9 g, 222 mmole) in 600 ml of dry tetrahydrofuran is added 200 ml of dry tert-butylalcohol at -20° C. under nitrogen. To this solution is then added, via addition funnel, 7-phenyl-5H-pyrimido[5,4-d][2]-benzazepine (25 g) in 260 ml of tetrahydrofuran. The resulting solution is stirred for about 2 hours at -20° C. and treated with 17.4 ml (130 mmole) of isoamyl nitrite. The reaction mixture is warmed to 0° C. over approximately 15 minutes and quenched with the addition of 60 ml of cold water and 20 ml of glacial acetic acid. All solvents are removed under reduced pressure and the residue is partitioned between ethyl acetate (600 ml) and brine (100 ml). The phases are separated and the organic extracts are dried (Na2SO4), concentrated, and triturated with ether.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36](Br)[CH:37]=1)[C:33]#[N:34].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:29][C:30]1[CH:37]=[C:36]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:22]=2)[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1
Reactant: CC(C)(C)[Si](OCc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCc1ccc(-c2cc(Br)cc(C#N)c2)cc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.49 g (3.83 mmoles) of boronic acid derivative from Example 4, 2.0 g (7.67 mmoles) of 3,5-dibromobenzonitrile, and 133 mg (0.1 mmoles) of tetrakistriphenylphosphine in 16 mL toluene and 3.4 mL 95% ethanol with 3.47 mL (6.97 mmoles) of 2 N sodium carbonate was stirred vigorously at 80° C. under nitrogen for 3.5 hours.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.N([O-])=[O:14].[Na+]>O.S(=O)(=O)(O)O.[Cl-].[Na+].O>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([OH:14])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: Nc1ccc(-n2ncnn2)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-n2ncnn2)cc1
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
A suspension of 4-tetrazol-2-yl-phenylamine (5.4 g) in water (42 ml ) and conc sulphuric acid (10 ml) was added slowly to a solution of sodium nitrite (2.3 g) in water (8.5 ml) at 5°. The resulting green solution was stirred at this temperature for ca. 30 min, treated with a mixture of water (50 ml) and conc. sulphuric acid (67 ml) and heated to 120° for 1 h. Water (170 ml) was added, the reaction mixture cooled, saturated with brine (100 ml) and extracted with dichloromethane (3×100 ml), dried (Na2SO4) and evaporated to give the title compound as an orange solid (1.6 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>C(#N)C>[CH3:33][N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]2=3)=[O:3])[CH2:28][CH2:29]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(NC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
Amounts of 3.2 gm (0.012 mol) of 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.1 gm (0.02 mol) of sodium carbonate were refluxed in 100 ml of acetonitrile together with 2.3 ml (0.02 mol) of 4-amino-1-methyl-piperidine for 15 minutes under stirring. The mixture was filtered while hot, and the filtrate was purified over a silica gel column [eluant: acetonitrile; followed by methylene chloride/ethyl acetate/cyclohexane/methanol/ammonia (175:75:23:23:3)]. The desired fraction was concentrated by evaporation in vacuo, and the residue was recrystallized from 50% aqueous acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:53][C:51]5[N:52]=[C:48]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[S:49][CH:50]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: -50 °C
Reaction time: 5 h
Yield: 113.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.800 g, 2.52 mmol), triphenylphosphine (0.992 g, 3.78 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.555 g, 2.90 mmol) in a 200 mL flask fitted with an addition funnel was maintained under vacuum for ten minutes. The mixture was then flushed with nitrogen and charged with dry tetrahydrofuran (60 mL, distilled over lithium aluminum hydride). The solution was warmed to −50° C. and then sonicated for 5 min. The cooled heterogeneous mixture was then treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.663 g, 3.28 mmol) in tetrahydrofuran (15 mL), added dropwise over 2.5 h. The reaction was homogeneous (pale yellow) at the end of the addition. The mixture was then stirred for another 2.5 h (total 5 h). The reaction mixture was then diluted with dichloromethane (400 mL), washed with saturated sodium bicarbonate (20 mL), brine and dried (anhydrous magnesium sulfate). Evaporation gave a white solid which was chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3). The fractions were collected and evaporated to give the desired compound (1.40 g) as a white solid, contaminated with hydrazide by tlc. Crystallization in ethyl acetate (40 mL) gave the pure title material (0.838 g, 68%) as a white solid. The mother liquors (0.475 g) were chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3) to give after crystallization from ethyl acetate (30 mL) to provide additional desired compound (0.160 g, 13%, total 81%) as a white solid. LC (Method C): 2.480 min. HRMS (ESI) calcd for C24H19N4O4S2 [M+H]+ m/z 491.0842, found 491.0865. 1H NMR (CDCl3, 400 MHz) 3.85 (s, 3H) 4.21 (s, 3H) 5.33-5.55 (m, 2H) 6.48 (d, J=1.96 Hz, 1H) 6.72 (dd, J=1.96, 0.78 Hz, 1H) 7.12 (s, 1H) 7.36-7.39 (m, 1H) 7.41-7.50 (m, 3H) 7.86 (s, 1H) 7.95-8.02 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:29][C:26]([F:27])([F:28])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:31][CH2:30][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CNCC3)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
6-Benzyl-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[4,3-d]pyrimidin-4-amine (270 mg, 0.55 mmol) was dissolved in anhydrous chloroform (10 mL) and 1-chloroethylchloroformate was added (0.18 mL, 1.65 mmol). After stirring for 30 min, N,N-diisopropylethylamine was added (0.24 mL, 1.65 mmol) and the mixture was stirred for an additional 2 h. The chloroform was removed under vacuum and 30 ml of methanol was added and the mixture was heated for 30 min. Upon reaction completion, the methanol was removed and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product (163 mg, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:30])[C:22]1[C:23]([O:28][CH3:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(#N)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])=[O:30]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
30.0 g (0.15 mol) of 4-nitrobenzenesulfonamide are treated with 30.0 g (0.3 mol) of triethylamine in 300 ml of acetonitrile and, at 50° C., treated with 27.8 g (0.16 mol) of o-anisoyl chloride, dissolved in 20 ml of acetonitrile. After 3 hours at 50° C., the mixture is stirred into 80 ml of ice-water, and the precipitate is filtered off with suction and dried. More product can be obtained by acidifying the mother liquor;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:20]=[C:17]([CH3:18])[N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Yield: 87.6 %

Procedure:
8.7 kg of ethyl 3-(4-fluorophenyl)-3-oxopropionate, 11.7 kg of acetoamidine hydrochloride and 28.6 kg of potassium carbonate were stirred for 5 hours at about 50° C. in 34.5 kg of methanol. Insolubles were separated from the reaction mixture and washed with methanol, and the mother liquor and the washing were combined with water and neutralized with an 18% aqueous solution of hydrochloric acid. After neutralization, the crystal was ripened by stirring under reflux for 4 hours, and the precipitated crystal was isolated by centrifugation, washed with water, dried to obtain 7.4 kg of the target compound as a white crystal.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H-].[Na+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br.[Na+].[I-]>CN(C=O)C.O>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][O:18][C:15]2[CH:14]=[CH:13][C:12]([C:2]([OH:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:17][CH:16]=2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
Into a 100 mL-3 neck flask fitted with a stirrer and thermometer, 200 mg of [2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF (5 mL) was added dropwise to 35 mg of NaH in DMF (20 mL) while stirring at room temperature under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 153 mg of 3,5-difluorobenzyl bromide in DMF (5 mL) was added dropwise followed by the addition of 92 mg of NaI portion wise. The reaction was then heated at 100° C. for 2 hours. The mixture was cooled to room temperature and poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 410 mg of a brown oil. This two spot material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1. Collection of the bottom spot provided the intermediate title compound (70 mg, 24%) as an oil. Ion spray M.S. 398.1 (M*−1).
Reaction SMILES: CCCCCCCC.[F:9][C:10]([F:24])([F:23])[C:11]([F:22])(Br)[C:12](=[O:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].[F:25]C(F)(F)C(=O)C(F)(Br)C(F)(F)C(F)(F)F>>[F:9][C:10]([F:24])([F:23])[C:11]1([F:22])[O:20][C:12]1([F:25])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C(C(F)(F)F)C(F)(Br)C(F)(F)C(F)(F)F
Reactant: O=C(C(F)(F)C(F)(F)F)C(F)(Br)C(F)(F)F
Solvent: CCCCCCCC
Product: FC(F)(F)C(F)(F)C1(F)OC1(F)C(F)(F)F

Procedure:
The distillate was subjected to flash chromatography on silica gel using octane as an eluant. The column effluent containing primarily octane and the mixture of perfluoro-2-bromo-3-pentanone and perfluoro-3-bromo-2-pentanone was then subjected to two vacuum distillations at a pressure of 56 and 100 torr, respectively, to separate the bromoperfluoroketones from the bulk of the octane. The low-boiling fractions from the vacuum distillations were then re-distilled at atmospheric pressure. The fractions collected at a head temperature of 71.2-72.8° C. were combined. The product was a mixture of perfluoro-2-bromo-3-pentanone and perfluoro-3-bromo-2-pentanone in molar ratio of 1.0 to 1.12 with overall purity of >98 GC area %.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:14][CH3:15])=[C:9]([CH3:13])[C:10]=1[CH2:11][CH3:12])(OCC)=O.[CH:16](=O)[CH2:17]C>>[CH2:1]([C:6]1[NH:7][C:8]([CH2:14][CH3:15])=[C:9]([CH3:13])[C:10]=1[CH2:11][CH3:12])[CH2:16][CH3:17]
Reactant: CCC=O
Reactant: CCOC(=O)c1[nH]c(CC)c(C)c1CC
Product: CCCc1[nH]c(CC)c(C)c1CC

Procedure:
2-Carbethoxy-3,5-diethyl-4-methyl-pyrrole was reductively alkylated with propionaldehyde to yield 2-n-propyl-3,5-diethyl-4-methylpyrrole. ##STR90##
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:20]([F:22])([F:21])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1.0 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde and 0.55 ml (trifluoromethyl)trimethylsilane in 10 ml tetrahydrofuran were added 100 mg tetrabutylammoniumfluoride. The reaction mixture was stirred at room temperature for thirty minutes. Then 20 ml 2NHCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo to obtain 2,2,2-Trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(C2C=CC3N(C(C)C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)C=1.C([CH:52]1[O:54][CH2:53]1)Br>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][CH:53]4[O:54][CH2:52]4)[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: BrCC1CO1
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Product: CC(C)n1c(=O)n(CC2CO2)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Yield: 83 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethyl-pyridin-2yl)-1-(1-methylethyl)benzimidazol-2-one and 1.0 g of epibromohydrin gave 2.4 g of colorless crystals. Yield: 83%; m.p.: 110-111° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:18][CH:17]3[CH2:16][O:12]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: c1ccc2ocnc2c1
Product: Cc1nc2cc(OCC3CO3)ccc2s1

Procedure:
Compound 33 was prepared in the manner of compound 6 substituting 2-methyl-benzothiazol-5-ol for compound 8 in partC-5 of Example 1.