Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].C(O)(=O)C.[CH3:16][S-:17].[Na+].[Cl-].[Na+]>O.C(#N)C>[C:6]1([S:3]([CH2:1][CH2:2][S:17][CH3:16])(=[O:4])=[O:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CSCCS(=O)(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 6.5 h
Yield: 90 %

Procedure:
To a three-neck 50 mL round bottom flask equipped with a temperature probe, magnetic stirring, and bleach scrubber was charged in sequence 3.43 g (20.39 mmol) phenyl vinyl sulfone followed by 5 mL of acetonitrile, and the mixture was then cooled in an ice-water bath. To this mixture was then added 2.53 g (42.13 mmol) of glacial acetic acid in one portion. To this mixture was con-added 10 g (21.40 mmol) of a 15 wt % sodium thiomethoxide in water solution over a 17 min period. The internal reaction temperature rose from 14° C. to 17° C. during the sodium thiomethoxide addition. The ice-water bath was removed and the reaction mixture was heated to 50-60° C. for 3.5 h at which time liquid chromatography (LC) analysis indicated about 42% (relative area) of starting phenyl vinyl sulfone in the reaction mixture. Another 4.76 g (10.19 mmol) of a 15 wt % sodium thiomethoxide in water solution was added over a 9 min period. The reaction mixture was then stirred an additional 6.5 h at 50-60° C., and then cooled to ambient temperature and allowed to stir overnight. At this time LC analysis indicated about 7% (relative area) of starting phenyl vinyl sulfone in the reaction mixture. To the reaction mixture was added 1.37 g (23.44 mmol) of sodium chloride and the reaction phases were allowed to separate. The organic layer was concentrated on a rotary evaporator to give 3.96 g of methyl 2-phenylsulfonylethyl sulfide as a yellow oil (yield was ˜90% based on theoretical yield). 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 3H), 2.78 (m, 2H), 3.35 (m 2H), 7.1 (m, 2H), 7.7 (m, 1H), 7.9 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 15.5, 26.4, 56.0, 127.9, 129.4, 134.1, 138.6.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.CC#N.C([O-])([O-])=O.[K+].[K+].[F:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[C:43]=1O.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>CC(O)=O.O>[F:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[C:43]=1[O:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: Oc1c(F)cc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)OCc2ccccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Fc1cc(F)c(OCc2ccccc2C2CCNCC2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (2.1 g, 4.7 mmol, 1.0 eq.) was dissolved in MeCN (46 mL, 890 mmol) and added to K2CO3 (1.9 g, 14 mmol, 3.0 eq.) and 2,4,6-trifluorophenol (1.0 g, 7.0 mmol, 1.5 eq.). The mixture was shaken at 50° C. overnight, then cooled to room temperature. The supernatant was separated from the K2CO3 and other solids. TFA (7 mL, 90 mmol, 20.0 eq.) was added to the supernatant and the mixture was shaken overnight at room temperature. The solution was then concentrated to yield a crude residue. The residue was dissolved in 5.0 mL 1:1 AcOH/H2O, then in an additional 2.0 mL AcOH, filtered and purified by preparative HPLC to yield the title compound as a TFA salt (1.3 g, 97.5% purity). MS m/z: [M+H]+ calcd for C18H18F3NO, 322.13. found 322.2.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].Br[CH2:10][CH2:11][CH2:12][Cl:13]>ClC1C=CC=CC=1>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][CH2:11][CH2:12][Cl:13])[CH2:5][CH2:4]1)=[O:2]
Reactant: ClCCCBr
Reactant: O=CN1CCNCC1
Solvent: Clc1ccccc1
Product: O=CN1CCN(CCCCl)CC1
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 1-formylpiperazine (5.7 g, 50 mmol),1-bromo-3-chloropropane (7.2 ml, 11.8 g, 75 mmol) and chlorobenzene (30 ml) was stirred at 100°-105° C. for 3 hours. After cooling the separated 1-formylpiperazine hydrochloride (4.58 g, yield: 94.4%) was filtered off and the filtrate concentrated. The residue was chromatographed on a silica gel column eluting with a 8:2 mixture of ethyl acetate and methanol to afford 2.46 g of the oily title compound, yield: 51.6%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[H-].[Na+].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[N:13]=1>C(O)C>[OH:1][CH2:2][CH2:3][S:4][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[N:13]=1
Reactant: OCCS
Reactant: Clc1ccc2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: OCCSc1ccc2nccn2n1
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
In 30 ml of ethanol is suspended 1.46 g of 2-hydroxyethylmercaptan. With ice-cooling, 897 mg of sodium hydride (oily, 60 wt.%) is added and the mixture is stirred for 10 minutes. Then, 1.91 g of 6-chloroimidazo[1,2-b]pyridazine is added and the mixture is stirred at room temperature for 6 hours. The solvent is distilled off under reduced pressure and the residue is shaken well with dichloromethane and water. The dichloromethane layer is separated and dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel (200 g) column chromatography and after the column is washed with ethyl acetate, elution is carried out with acetone. The fractions rich in the desired compound are pooled and the solvent is distilled off under reduced pressure. To the residue are added dichloromethane and isopropyl ether and the resulting pale-brown powder is collected by filtration. This procedure gives 500 mg of 6-(2-hydroxyethylthio)imidazo[1,2-b]pyridazine.
Reaction SMILES: CC1C=CC(S([NH:11][NH2:12])(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:27]=[CH:26][C:25]3[C@:28]4([CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=5)[CH2:40][CH2:39][C:34]5([O:38][CH2:37][CH2:36][O:35]5)[CH2:33][C@H:29]4[CH2:30][CH2:31][CH2:32][C:24]=3[CH:23]=2)=O)=[CH:16][CH:15]=1>CO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:11]=[N:12][N:27]3[CH:26]=[C:25]4[C@:28]5([CH2:41][C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=6)[CH2:40][CH2:39][C:34]6([O:35][CH2:36][CH2:37][O:38]6)[CH2:33][C@H:29]5[CH2:30][CH2:31][CH2:32][C:24]4=[CH:23][C:22]=23)=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CO
Product: Fc1ccc(-c2nnn3cc4c(cc23)CCC[C@@H]2CC3(CC[C@@]42Cc2ccccn2)OCCO3)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 100.1 %

Procedure:
4-Methylbenzenesulfonohydrazide (0.177 g, 0.948 mmol) in MeOH (4 mL) was combined with (4-fluorophenyl)((7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl)methanone (0.224 g, 0.474 mmol) and the mixture was stirred at about 50° C. for about 48 h. The reaction mixture was cooled to rt and was washed with sat. aq. NaHCO3 and extracted with DCM (10 mL). The organics were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel (12 g) using a gradient of 10-100% EtOAc in heptane to afford (4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-1,2,4,4a,5,6,7,13b-octahydrospiro[benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridine-3,2′-[1,3]dioxolane] (156, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.230 g, 56%); LC/MS, method 3, Rt=2.52 min, MS m/z 485 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.28-8.23 (m, 1H), 8.10-8.02 (m, 3H), 7.80-7.72 (m, 1H), 7.41-7.30 (m, 2H), 7.02-6.97 (m, 1H), 6.57-6.53 (m, 1H), 3.96-3.80 (m, 4H), 3.63-3.54 (m, 1H), 3.52-3.40 (m, 1H), 3.25-3.17 (m, 2H), 2.39-2.34 (m, 1H), 2.21-2.05 (m, 2H), 1.95-1.55 (m, 7H), 1.50-1.37 (m, 1H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[N:19][C:18]=3[C:17]([O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34].CO>>[ClH:34].[CH3:33][O:32][C:17]1[C:18]2[N:19]=[C:20]([NH:23][C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[S:21][C:22]=2[C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2=CCNCC2)c2sc(NC(=O)N3CCOCC3)nc12
Yield: 84 %

Procedure:
0.130 g (0.27 mMol) 4-{4-methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 3 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 95 mg (84%) morpholine-4-carboxylic acid [4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-amide hydrochloride (1:1) as an off-white solid. ES-MS m/e (%): 375 ([M+H]+, 100).
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:13][O:12][C:8]1[C:9]([O:10][CH3:11])=[CH:2][C:3]([CH:4]=[O:5])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: COc1ccc(C=O)c(Br)c1OC
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cc(C=O)c(-c2ccc(SC)cc2)cc1OC
Temperature: 25 °C
Yield: 71.5 %

Procedure:
2-Bromoveratraldehyde (25 g, 103.3 mmol) and 4-(methylthio)benzeneboronic acid (19.66 g, 118.5 mmol) were dissolved in toluene (550 mL) and sodium carbonate (2M, 103 mL, 206 mmol) was added. To this reaction mixture was added ethanol (50 mL) followed by tetrakis (triphenylphosphine)palladium (3.4 g, 2.5 mmol) and the reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (250 mL) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were washed with water (4×250 mL), brine (1×250 mL), dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give the crude product. The product was purified by trituration with ethyl acetate/hexane to give the title compound as a white solid (21.3 g, 85% yield), mp 114-115° C. 1H NMR (CDCl3, 300 MHz) δ9.83 (s, 1H), 7.64 (s, 1H), 7.43-7.23 (m, 4H), 6.83 (s, 1H), 3.98 (d, J=2.4 Hz, 6H), 2.55 (s, 3H). 13C NMR (CDCl3, 75.45 MHz) δ190.9, 153.4, 148.7, 1408, 138.9, 134.5, 134.1, 130.5, 130.1, 128.0, 128.0, 126.9, 126.1, 112.5, 108.7, 56.2, 56.1, 15.6. LRMS (APIMS) m/z 289 (M+H)+.
Reaction SMILES: [Na].[F:2][CH:3]([F:9])[C:4](OCC)=[O:5].[O-]CC.[Na+].Cl.[CH3:15][CH2:16][O:17][C:18]([CH3:20])=[O:19]>CCO>[F:2][CH:3]([F:9])[C:4](=[O:5])[CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19]
Reactant: CCOC(=O)C(F)F
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Add sodium metal (7 kg, 300 mol) in portions to EtOH (53.6 kg) while maintaining the temperature below 60° C. Stir the reaction mixture until the sodium dissolves, then cool the mixture to 20-30° C. Add a solution of ethyl difluoroacetate (34 kg, 274 mol) in EtOAc (63 kg) to the sodium ethoxide at a temperature of 25-40° C. Heat the reaction mixture to 65° C. while stirring. After 2 h cool the mixture to room temperature. Add 10% HCl (30 kg HCl and 204 kg water) to the mixture until the pH of the mixture is 6-7. Extract the mixture with EtOAc (64 kg); separate; and extract the aqueous layer again with EtOAc (60 kg). Combine organic phases, and wash with brine (NaCl (48 kg) in water (136 kg)). Dry the organic phase with 4 A molecular sieve powder (15 kg), and concentrate to give the title compound as a brown-yellow oil (33 kg, 73% yield, 96% GC purity). 1H NMR (500 MHz, CDCl3,) δ 5.91 (t, J=54 Hz, 1H), 4.23 (m, 2H), 3.70 (s, 2H), 1.27 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:21]C(=O)C(F)(F)F)[CH2:16]3)[CH:10]=2)=[N:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO.COOOC>[NH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:6]3[S:7][C:3]([C:1]#[N:2])=[CH:4][N:5]=3)[CH:10]=2)[CH2:16]1
Reactant: N#Cc1cnc(Nc2cc(N3CCCC(NC(=O)C(F)(F)F)C3)ncn2)s1
Agent: COOOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cnc(Nc2cc(N3CCCC(N)C3)ncn2)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Crude N-(1-{6-[(5-cyano-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}piperidin-3-yl)-2,2,2-trifluoroacetamide 9-5 (0.9 mmol) was suspended/dissolved in methanol/dimethoxyether (5 mL/2 mL) and potassium carbonate (1.8 mmol). This was warmed to 75° C. and stirred overnight. The product was purified on a preparative hplc and isolated via lyophilization from dioxane/water to produce 9-6. Hi-Res MS: calc: 302.1183 found: 302.1190. 1NMR(CD3OD): 8.31 ppm (s, 1H); 7.87 ppm (s, 1H); 6.09 ppm (s, 1H); 4.21 ppm (d, 1H); 4.07 ppm (d, 1H); 3.60 ppm (m, 1H); 2.95 ppm (m, 1H); 2.75 ppm (m, 1H); 2.00 ppm (m, 1H); 1.77 ppm (m, 1H); 1.54 ppm (m, 1H); 1.37 ppm (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6][CH2:5]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29])([O-:21])=[O:20]>C(Cl)Cl>[O:10]=[S:7]1(=[O:11])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N+:19]([O-:21])=[O:20])(=[O:29])=[O:30])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCN1CCS(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A mixture of 4-(2-aminoethyl)thiomorpholine 1,1-dioxide (2.00 g, 11.2 mmol) and triethylamine (1.42 g, 14.0 mmol) in DCM (100 mL) was cooled in an ice bath and treated slowly with 2-nitrobenzene-1-sulfonyl chloride (2.49 g, 11.2 mmol). The mixture was removed from the ice bath and stirred at rt for 18 h. The resulting mixture was washed with water (2×50 mL) and the combined aqueous washes were extracted with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow solid. Purification by silica gel chromatography (linear gradient 100% DCM to 100:1 DCM:MeOH) gave the title compound as a pale yellow solid (3.47 g, 85% yield). LCMS: m/z 364 (M+H+), retention time 0.98 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.71 (t, J=5.49 Hz, 2H) 2.96 (br. s., 4H) 3.05 (br. s., 4H) 3.20 (q, J=5.49 Hz, 2H) 5.93 (br. s., 1H) 7.73-7.84 (m, 2H) 7.84-7.93 (m, 1H) 8.11-8.23 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[S:8][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[NH:6][C:4]1=[O:5].FC(F)(F)C(O)=[O:18].OO>O>[CH2:2]([CH:3]1[C:4](=[O:5])[NH:6][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S@:8]1=[O:18])[CH3:1]
Reactant: CC[C@@H]1SC2(CCN(C)CC2)NC1=O
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: O
Product: CCC1C(=O)NC2(CCN(C)CC2)[S@]1=O
Temperature: 0 °C

Procedure:
A solution of AF267B (1.72 gr, 0.008 mol) in water (2.5 ml) was cooled (ice-water bath) and trifluoroacetic acid (3.5 ml) was added. To the cold stirred obtained mixture was added hydrogen peroxide (30%, 0.57 ml, 0.008 mol), the cooling bath was removed and the reaction mixture was stirred at room temperature over night. Sodium sulfite was added and the pH of the solution was adjusted to 9 with a saturated solution of sodium carbonate. The aqueous phase was extracted with dichloromethan (2×100 ml) and then with ethyl acetate (1×50 ml). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated. Flash chromatography (silica-gel 60, 230–400 mesh, Merck 1.09385, elution with methanol/chloroform/ammonium hydroxide 10:89:1 v/v) gave AF300. 1H NMR (CDCl3) δ 1.19 (t, j=7.3 Hz, 3H, CH3), 1.85–2.0 (m, 5H), 2.17 (m, 1H), 2.27 (m, 1H), 2.34 (s, 3H, NCH3), 2.26 (m, 2H), 3,30 (dd, j=3.56, 11.13 Hz, CH3CH2CH), 6.37 (br NH) ppm; MS (EI) m/e 230 (M+).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>O1CCCC1>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[NH:35][C:36]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:37]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2ccccc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-naphthyl isocyanate (206 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 176 mg (52.2%) of the desired product as a solid.
Reaction SMILES: N1C=CC=CC=1C([O:9][CH:10]1[C:14]2=[N:15][C:16]3[C:17](=[N:18][CH:19]=[C:20]([NH:22][C:23]([C:25]4[N:26]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=5)[C:27]5[C:32]([CH:33]=4)=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=5)=[O:24])[CH:21]=3)[N:13]2[CH2:12][CH2:11]1)=O.CO>C(Cl)(Cl)Cl.ClCCl.N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:9][CH:10]1[C:14]2=[N:15][C:16]3[C:17](=[N:18][CH:19]=[C:20]([NH:22][C:23]([C:25]4[N:26]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=5)[C:27]5[C:32]([CH:33]=4)=[CH:31][C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][CH:28]=5)=[O:24])[CH:21]=3)[N:13]2[CH2:12][CH2:11]1
Reactant: O=C(OC1CCn2c1nc1cc(NC(=O)c3cc4cc(C(F)(F)F)ccc4n3Cc3cccc(F)c3)cnc12)c1ccccn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cnc2c(c1)nc1n2CCC1O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 0.065 g (0.07 mmol) of 3-[[[1-(3-fluorobenzyl)-5-trifluoromethyl-1H-indol-2-yl]carbonyl]amino]-7,8-dihydro-6H-pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridin-6-yl pyridine-2-carboxylate, prepared in Example 8.1, in 10 ml of chloroform is admixed with 0.022 g (0.7 mmol) of methanol and 0.0127 g (0.07 mmol) of copper acetate. After seven hours of stirring at ambient temperature, the reaction mixture is diluted with 10 ml of dichloromethane and 10 ml of aqueous ammonia, with stirring. The organic phase is separated, washed with 10 ml of water, dried over sodium sulfate and concentrated under reduced pressure. The resulting product is subsequently purified by successive chromatography on a silica column and then on a neutral alumina column. This gives 0.012 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32]Cl)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32][N:14]2[C:13](=[O:16])[CH:12]=[C:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:28][CH:27]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2cc(=O)n(CC=Cc3ccc(Cl)cc3)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 72.5 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 72.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH3:18])[CH3:2]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:9][CH2:4][CH2:5][CH2:6][CH2:7][CH2:10][CH2:11][CH2:12][OH:13])=[O:13])=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH3:18])[CH3:2]
Reactant: CCCOc1cc(/C=C/C(=O)O)ccc1OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCOc1cc(/C=C/C(=O)OCCCCCCCCO)ccc1OCC

Procedure:
The preparation is carried out analogously to Example 1 from 1.0 g (4.00 mmol) of 3(E)-[4-ethoxy-3-propoxyphenyl]acrylic acid and 0.92 g (4.39 mmol) of 8-bromo-1-hexanol and, according to chromatography over 150 g of silica gel using toluene/ethyl acetate, gives 8-hydroxyoctyl 3(E)-[4-ethoxy-3-propoxyphenyl]acrylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C1(P(=[CH:35][C:36]([O:38][CH3:39])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:39][O:38][C:36](=[O:37])[CH:35]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 52 %

Procedure:
2-Ethoxy-4-trifluoromethyl-benzaldehyde (729 mg, 3.34 mmol) was reacted with methyl (triphenylphosphoranylidene)acetate (1.45 g, 4.34 mmol) at 110° C. overnight as described above to yield title compound (476.5 mg, 52%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:11]=[C:12]([NH:20]C(=O)C3C=CC(C)=C(C#C[Si](C)(C)C)C=3)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].CN(CC1N(C2C=C(NC(=O)C3C=CC(C)=C(I)C=3)C=C(C(F)(F)F)C=2)C=CN=1)C.N#N.C(N(CC)C(C)C)(C)C.C[Si](C#C)(C)C>[Cu]I.CCOC(C)=O.O.CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=2)[NH2:20])[CH:7]=[CH:8][N:9]=1)[CH3:1]
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Agent: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Potential synthesis of N-[3-{2-[(dimethylamino)methyl]-1H-imidazol-1-yl}-5-(trifluoromethyl)phenyl]-4-methyl-3-[(trimethylsilyl)ethynyl]benzamide: N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (5 mmol), Pd[(PPh3)]4 (289 mg, 0.25 mmol). CuI (71 mg, 0.375 mmol) are placed in a schlenk flask. The flask is subjected to 3 cycles of vacuum refilling with N2. To this mixture is added anhydrous N,N-diisopropylethylamine (1.1 mL, 6 mmol), DMF (5 mL), and trimethylsilylacetylene (0.92 mL, 6.5 mmol). This solution is stirred at rt for 24 h. Water and EtOAc are added to the reaction mixture to facilitate the extraction. The combined organic layers are dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue is purified on a silica gel column (eluent: 5% MeOH in CH2Cl2, MeOH was pre-saturated with ammonia gas) to give the desired product.