Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].COCCOC.[C:13]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=O)[CH3:14].C1(C)C=CC(S([CH2:33][N+:34]#[C-])(=O)=O)=CC=1>C(O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:13][CH2:14][C:33]#[N:34])=[CH:17][CH:18]=1)#[N:21]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
1.40 g (1.25 mmole) of potassium tert-butoxide was added to a 17 ml ethylene glycol dimethyl ether solution containing 0.73 g (5 mmole) of 4-acetylbenzonitrile, 0.5 ml of ethanol and 1.27 g (6.5 mmole) of p-toluenesulfonylmethylisocyanide under ice-cooling; then the mixture was stirred at room temperature for 0.5 hour and then at 40° C. for an additional hour. After the reaction mixture was cooled by allowing to stand at room temperature, it was filtered under reduced pressure and the filtrate was purified by silica gel chromatography to obtain 0.55 g (yield: 70.4 %) of 2-(4-cyanophenyl)ethylcyanide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]2[N:11]([C:12]=1[CH3:13])[CH2:10][CH2:9][CH2:8]2)=[O:4].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>C1COCC1.C(OCC)C>[F:21][C:2]([F:1])([F:20])[C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]2[N:11]([C:12]=1[CH3:13])[CH2:10][CH2:9][CH2:8]2)([OH:4])[C:23]([F:25])([F:24])[F:22]
Reactant: Cc1c(C(=O)C(F)(F)F)c(-c2ccccc2)c2n1CCC2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(C(O)(C(F)(F)F)C(F)(F)F)c(-c2ccccc2)c2n1CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 2,2,2-trifluoro-1-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-ethan-1-one (1.8 g, 6 mmol) in THF (70 ml) is treated successively with trifluoromethyltrimethylsilane (7.5 ml, 2 M in THF, 15 mmol) and tetrabutylammonium fluoride (bound to silica gel, 1.1 mmol/g of SiO2; 0.5 g, 0.55 mmol) and stirred at 40° C. for 2 h (TLC: SiO2/hexane-diethyl ether 1:1; starting material Rf 0.4; product Rf 8.5). The mixture is cooled in an ice bath and treated with NaOH (70 ml, 10% strength solution; 7 g, 175 mmol) and stirred at room temperature for 1 h. The THF phase is treated with diethyl ether (50 ml) and separated in a separating funnel and the aqueous phase is again extracted with diethyl ether (50 ml). The combined organic phases are washed with water (50 ml), dried over Na2SO4 sicc. and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:36])[CH2:34][CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid 5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2.5 hrs with a stream of nitrogen bubbling through it. The n-propylamine (2.06 g, 0.0348 mole) was added dropwise and the reaction mixture was allowed to stir at room temperature under nitrogen atmosphere overnight. The tetrahydrofuran was evaporated and the residue was triturated with water. The solid was collected and dried under high vacuum at 50° C. overnight. The solid was dissolved in isopropyl alcohol, filtered, diluted with water, and placed in the freezer overnight. The crystalline precipitate was collected by filtration, washed with water, and dried at 50° C. under high vacuum overnight to give 3.6 g (63%), m.p. 220°-21° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[S:12][C:13]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:15]=1)=[O:10])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-]>[C:21]([O:20][C:18]([CH2:17][CH2:16][C:13]1[S:12][C:11]([C:9]([OH:10])=[O:8])=[CH:15][CH:14]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCc1ccc(C(=O)OCc2ccccc2)s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (0.5 g, 1.45 mmol) obtained in step 1 was dissolved in methanol (5 mL) and chloroform (0.5 mL), palladium hydroxide (0.1 g) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[I-].C[S+](C)C.[CH:13](=O)[C:14]1C=CC=[N:16][CH:15]=1>CS(C)=O>[O:6]1[CH2:5][CH:7]1[C:3]1[CH:4]=[N:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1
Reactant: C1CCOC1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: c1cncc(C2CO2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Sodium hydride 50% dispersion in oil (1-1.8 equiv.) is taken in DMSO and heated at 65° C. for 1 h. THF is added to at the mixture at the same temperature and heated for 10 min. The reaction mixture is cooled to 0° C. and Trimethylsulfonium iodide (1-1.2 equiv.) is added, followed by nicotinaldehyde (1 equiv.) and the contents are stirred at RT for 1 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product (3-(oxiran-2-yl)pyridine).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc2cc(C(C)=O)oc12
Product: COc1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-Acetyl-7-methoxybenzofuran (5 g) (0.0263 mole) was added to chlorosulfonic acid (18.4 g) (0.158 mole) at -15° C. in portionwise (each 0.5 g) for 30 min. After stirring the reaction mixture at -10° to -5° C. for 1 hour, the resultant was gradually added dropwise to ice. The solution was extracted with ethyl acetate, washed with water and dried, followed by distilling away ethyl acetate under reduced pressure to give 5.8 g of crude 2-acetyl-4-chlorosulfonyl-7-methoxybenzofuran.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[O:5][CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[O:1])[C:3]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[CH:4][O:5]2)=[CH:10][CH:9]=1)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-(4-oxo-7-((trimethylsilyl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide (1.8 g, 4.37 mmol) was dissolved in a 1:1 mixture of methanol/tetrahydrofuran (6 ml), potassium carbonate (121 mg, 0.2 eq) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate in the presence of water. The organic phase was dried over magnesium sulfate, filtered, and solvent removed under reduced pressure to afford N-(4-(7-ethynyl-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12](O)[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][C:16]2([CH3:24])[CH3:23].[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][C:16]2([CH3:24])[CH3:23]
Reactant: c1nc[nH]n1
Reactant: CC1(C)OC(=O)c2ccc(C(O)c3c(F)cc([N+](=O)[O-])cc3F)cc21
Product: CC1(C)OC(=O)c2ccc(C(c3c(F)cc([N+](=O)[O-])cc3F)n3cncn3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.4 %

Procedure:
The diarylcarbinol (5-[(2,6-difluoro-4-nitrophenyl)-hydroxymethyl]-3,3-dimethyl-3H-isobenzofuran-1-one ((Formula I) as prepared in Example 1; 171.3 g, 0.49 moles) and 1,2,4 triazole (85.7 g, 1.24 moles) are charged into a 3L, 4-necked round bottom flask equipped with a mechanical stirrer and a nitrogen inlet. This rapidly stirred mixture is cooled in an ice bath and 680 mL of ice cold concentrated H2SO4 is added in one portion. After 20 min the ice bath is removed and the resultant solution is stirred at room temperature for 20 hr. The dark solution is transferred to an addition funnel and added dropwise over 3 hr to 12L of rapidly stirring ice water in a 22L, 4-necked flask, during which time 5-[(2,6-difluoro-4-nitrophenyl)-[1,2,4]triazol-1-yl-methyl]-3,3-dimethyl-3H-isobenzofuran-1-one precipitates as a fine white solid. After standing for 2 h at 0° C., the solid product is isolated by vacuum filtration, washed with H2O (500 mL), and air dried for 2-12 hr. The resultant solid is transferred to a clean 3L, 4-necked flask equipped with a reflux condenser, mechanical stirrer, and J-Kem thermocouple. 1.5 L of MeOH is added, and the mixture is heated to 55 ° C. to give a dear solution. This solution is filtered while hot into a clean 3L 4-necked flask, equipped with an addition funnel, and mechanical stirrer. H2O (175 mL) is then added dropwise to this rapidly stirred hot solution. As the solution cools, white crystals of 5-[(2,6-difluoro-4-nitrophenyl)-[1,2,4 ]triazol-1-yl-methyl ]-3,3-dimethyl-3H-isobenzofuran-1 -one form. After standing at room temperature for about 2 hr to about 12 hr, the crystals are collected by filtration, air dried for 3 hr, and then dried under vacuum to afford 132.2 g (67 %) of 5-[(2,6-difluoro- 4-nitrophenyl)-[1,2,4]triazol-1-yl-methyl]-3,3-dimethyl-3H-isobenzofuran-1-one which is >98% pure by HPLC analysis.
Reaction SMILES: [CH2:1]([C:3]1[N:13](CC2C=CC3/C(=C(/C)\C#N)/C4C=CC=CC=4CCC=3C=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].OCC1C=CC2/C(=C(/C)\C#N)/C3C=CC=CC=3CCC=2C=1>>[CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C(\C)C#N
Agent: C/C(C#N)=C1\c2ccccc2CCc2cc(CO)ccc21
Product: CCc1nc2c(C)cc(C)nc2[nH]1
Yield: 230.1 %

Procedure:
[step 1] (Z)-2-[2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]propiononitrile (376 mg, 68%) was obtained in the same manner as in step 1 of Example 36, using (Z)-2-(2-hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propiononitrile (350 mg, 1.3 mmol) obtained in Reference Example 6 and 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (349 mg, 2.0 mmol) instead of 5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>>[OH:21][C:18]1([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCC(=O)CC1
Reactant: OCc1ccc(C(F)(F)F)cc1Br
Product: CN1CCC(O)(c2cc(C(F)(F)F)ccc2CO)CC1

Procedure:
Reaction of 2-bromo-4-trifluoromethylbenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-hydroxy-4-(α-hydroxy-4-trifluoromethyl-2-tolyl)-1-methylpiperidine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[CH:60]=[C:59]([S:61](Cl)(=[O:63])=[O:62])[N:58]=[CH:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:59]2[N:58]=[CH:57][N:56]([CH3:55])[CH:60]=2)(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 17 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting materials in 17% yield. LCMS for C28H31ClN9O3S (M+H)+: m/z=608.2.
Reaction SMILES: C(N1CC[C@H](N)C1)(OCC1C=CC=CC=1)=O.C([N:24]1[CH2:29][CH2:28][CH:27]([N:30]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:31](=[O:36])[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:26][CH2:25]1)(OC(C)(C)C)=O>>[CH:37]1([N:30]([C:31](=[O:36])[NH:32][CH:33]([CH3:34])[CH3:35])[CH:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)NC(=O)N(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Product: CC(C)NC(=O)N(C1CCCCC1)C1CCNCC1

Procedure:
The title compound was prepared following the procedure described in Step B of Intermediate 1 using 1-BOC-4-[cyclohexyl(N-isopropylcarbamoyl)amino]piperidine.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][C:6](OCC)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: CCOC(=O)CCCC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CCCCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
Ethyl 5,5-dimethylhexanoate (1.87 g) (prepared in Example 34 with esterification), was dissolved in 30 ml of THF and lithium aluminium hydride (2 g) added portionwise. The reaction was stirred for 2 hours at 0° C. before quenching with 2 ml 15% NaOH and 6 ml water before diluting with dichloromethane and filtering through CELITE (RTM) and the solvent evaporated to give 5,5-dimethylhexanol product (1.1 g) as a slightly volatile liquid. This alcohol was dissolved in 30 ml dichloromethane containing pyridinium chlorochromate and stirred at room temperature to convert it to the corresponding aldehyde, 5,5-dimethylhexanal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[OH:41])=[CH:31][CH:30]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][CH:13]([C:15]([O:17]CC)=[O:16])[CH2:12]3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:28]=1.S(=O)(=O)(O)[O-].[K+]>C(O)=O>[Cl:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[OH:41])=[CH:31][CH:30]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]3)[NH:7][C:6]=2[CH:28]=1
Reactant: CCOC(=O)C1CC(Oc2nc3cc(-c4ccc(-c5ccccc5O)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Product: O=C(O)C1CC(Oc2nc3cc(-c4ccc(-c5ccccc5O)cc4)c(Cl)cc3[nH]2)C1
Temperature: 80 °C

Procedure:
To a solution of ethyl 3-{[6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (153 mg, 0.258 mmol) in formic acid (4 mL) was added saturated aqueous solution of potassium bisulfate (0.8 ml, 0.258 mmol). The reaction mixture was heated at 80° C. overnight. Then the volatiles were removed in vacuo, and the residue acidified with 1 N aqueous HCl, and extracted with EtOAc. The organic phase was separated, washed with water, and concentrated in vacuo. Purification of the resulting residue by reverse phase HPLC (20-100% MeCN: H2O) afforded the title compound as a white solid. LC-MS: calculated for C24H19ClN2O4 434.1, observed m/e: 434.99 (M+H)+ (Rt 1.82/4 min). 1H NMR (500 MHz, CD3OD): δ 7.70-6.90 (m, 10H), 5.25-5.20 (m, 1H), 2.90 (m, 3H) 2.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16][C:17]4[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.Br.CS(C)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][S:16][C:17]4[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCc1cc2c(s1)SCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1cc2c(s1)SCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Yield: 70.4 %

Procedure:
To a solution of 5 g of 2-(4-chlorophenyl)-8-ethyl-4a,5-dihydro-2H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(4H)-one in a 30% solution of hydrogen bromide in acetic acid is added 2 ml of dimethylsulfoxide at room temperature. After the mixture is stirred for an hour at the same temperature, the mixture is poured into ice-cold water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 3.5 g of 2-(4-chlorophenyl)-8-ethyl-5H-thieno[2',3':2,3]thiopyrano[4,5-c]pyridazine-3(2H)-one as yellow needles, melting at 161°-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11]([NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11]([NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)c1cc(C(=O)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(=S)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-piperidin-1-yl-benzamide (F67-02: 198 mg, 0.43 mmol), toluene (5 mL) and Lawesson's reagent (157 mg, added in two portions) were placed in a test tube and heated for 2.5 hours under reflux. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The foam thus obtained was subjected to the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl.CCOCC>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:31]([O:32][CH3:33])=[O:34])=[CH:18][CH:19]=1
Reactant: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Methyl 2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (9.5 g, 31.53 mmol) was dissolved in DIPEA (8.24 mL, 47.29 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (3.58 g, 37.50 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h, diluted with ether and washed with 1 M HCl. The organic layer was washed with Na2CO3 (aq), dried MgSO4, filtered through celite and the solvent was evaporated to yield dimethyl 2-(4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (10.9 g, 96%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c1C
Yield: 37.8 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (0.08 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.1 g) to give 65 mg (38%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([N:34]1[CH2:35][CH2:36][N:31]([C:29]2[S:28][N:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:30]=2)[CH2:32][CH2:33]1)=[O:19]
Reactant: Cn1c(NC(=O)OCC(Cl)(Cl)Cl)nc2ccccc21
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)nc2ccccc21
Yield: 46.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (1-methyl-1H-benzimidazol-2-yl)carbamate (238 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and 145 mg (46.8%) of the desired product as a solid was separated by filtration.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].CN1CCCC1=[O:19]>O>[OH:19][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CN1CCCC1=O
Solvent: O
Product: COc1ccc(C(=O)CO)cc1

Procedure:
It is used in the synthesis of MOPMN, above, and was synthesized from 2-bromo-4'-methoxyacetophenone (Aldrich). The 2-bromo-4'-methoxyacetophenone was refluxed in 20% water and N-methyl-2-pyrrolidinone for 10 hours at 105° C. The product was extracted with ethylether, dried over MgSO4, the ether evaporated and the dry solid recrystallized before use. Melting point 98.5°-100.5° C. and the NMR corresponds to the product.