Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:13]1=[O:27]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:16]2[CH:15]=[CH:14][C:13](=[O:27])[N:12]([CH3:11])[CH:17]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cc(-c2ccc(=O)n(C)c2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.05 min; Mass spectrum (ESI+): m/z=292, 294 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=[O:20])[CH2:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]=2[O:13][CH2:14]C(C)C)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:20])[CH2:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]=2[O:13][CH3:14])=[CH:21][CH:22]=1
Reactant: CC(C)COC1=C(Cc2ccc(Cl)cc2)C(=O)CC(C)(C)C1
Solvent: CO
Product: COC1=C(Cc2ccc(Cl)cc2)C(=O)CC(C)(C)C1
Yield: 73.2 %

Procedure:
A solution of 154 g of the 2-(4-chlorobenzyl)-3-(2-methylpropoxy)-5,5-dimethylcyclohex-2-en-1-one obtained in Example 1 in 1200 ml methanol containing 3 g p-toluenesulphonic acid was refluxed for 2 hours. The reaction mixture was then extracted with 3 liters water and 1 liter diethyl ether and re-extracted with a further 1 liter diethyl ether. The organic phases were then back-washed first with 200 ml 10% aqueous sodium hydroxide and then with 100 ml saturated sodium chloride solution, dried over anhydrous magnesium sulphate and flashed. The residue was then crystallized in 60/80 petroleum, filtered and air-dried to give 98 g 2-(4-chlorobenzyl)-3-methoxy-5,5-dimethylcyclohex-2-en-1-one as a white solid, m.pt 62°-63° C. Yield: 73%.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH:6][OH:7].[S:8]([CH2:15][C:16]([OH:18])=[O:17])([CH2:11][C:12](O)=[O:13])(=[O:10])=[O:9].C(Cl)Cl>O>[S:8]([CH2:15][C:16]([O:18][OH:2])=[O:17])([CH2:11][C:12](=[O:13])[O:6][OH:7])(=[O:10])=[O:9]
Reactant: OO
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CS(=O)(=O)CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C(CS(=O)(=O)CC(=O)OO)OO
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A mixture of 16.32 mL of 90% aqueous hydrogen peroxide (0.6 mole), 2.3 mL of deionized water and 18.17 mL of 95.5% sulfuric acid was formed in a 150 mL beaker equipped with an ice bath, alcohol thermometer and mechanical stirrer. The water and sulfuric acid were added sequentially to the H2O2 with cooling and stirring to hold the temperature of the mixture to about 25° C. This mixture was added to 18.215 g (0.1 mole) of sulfonyldiacetic acid in admixture with 100 mL of methylene chloride without cooling over a period of about 8 minutes with agitation. The resulting combination formed two liquid phases and one solid phase. Agitation of this mixture was continued for three hours with the temperature in the range of 20°-22° C. under cover to reduce loss of methylene chloride. The mixture was then cooled to about 5° C. and diluted with 18 mL of deionized water added gradually with stirring and cooling. The solids were collected, reslurried with methylene chloride and treated with 80 mL of 6% aqueous sodium bicarbonate. The solids were collected and similarly treated with another 40 mL of 6% NaHCO3 resulting in a final pH of about 4. The recovered solids appeared reduced by the reslurry operations and were combined with 2.91 g of dry powdered boric acid. The mixed solids were dried to constant weight (5.24 g) and found to have an active oxygen content of 5.03%.
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.Cl[CH2:48][CH2:49][C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:51]>>[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][N:44]([CH2:48][CH2:49][C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:51])[CH2:43][CH2:42]1
Reactant: O=C(CCCl)c1ccccc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCC(=O)c3ccccc3)CC2)cc1F
Yield: 101.4 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-chloro-1-phenylpropan-1-one (169 mg), to provide crude 3-[4-(2,5-difluoro-4-methoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-one (365 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](Cl)=[O:26])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2].[N+:29](=[CH2:31])=[N-:30]>>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:26])[CH:31]=[N+:29]=[N-:30])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O

Procedure:
In step 13, compound (19) is reacted with diazomethane at room temperature without being separated from the reaction solution, so that the 4-chlorocarbonyl group of compound (19) is converted into diazoacetyl group, affording 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-ribofuranosyl)-4-diazoacetyl-5-(dimethylaminomethyleneamino)imidazole [compound (20)].
Reaction SMILES: [I:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.C(Cl)Cl>C(Cl)Cl.CO>[I:1][C:2]1[CH:26]=[CH:25][C:5]([CH:6]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCN(C(=O)c2ccc(I)cc2)c2ccccc2)c1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(I)cc1

Procedure:
The title compound was prepared by analogy to Preparation 65 except that 4-iodo-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide was used instead of 4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and the final residue was subjected to flash chromatography using a gradient from neat CH2Cl2 to CH2Cl2:MeOH 60:1.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH2:8][O:7][CH2:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:17]=[CH:16]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cccc2cc[nH]c12
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Sodium hydride in mineral oil (60% by wt., 0.62 g; 15.5 mmol) was washed with hexanes and suspended in DMF (40 mL). SEM-Cl (2.0 mL, 11.3 mmol) was added followed by a solution of 7-bromoindole in DMF (15 mL) dropwise over 5 min. The resultant white suspension was stirred overnight at room temperature and then the reaction was quenched with saturated aqueous NaHCO3. The mixture was poured into EtOAc and the organic layer was separated and washed with pH 7 buffer, saturated aqueous NaHCO3, brine dried (MgSO4) and concentrated to a light yellow oil. Flash chromatography (2 to 5% EtOAc/hexanes) afforded the title compound as a colorless oil (2.58 g, 79%). 1H NMR (400 MHz, DMSO-d6) 7.58–7.61 (m, 2H), 7.36 (d, J=8 Hz, 1H), 6.70 (dd, J=8, 8 Hz, 1H), 6.55 (d, J=3 Hz, 1H), 5.80 (2, 2H), 3.45 (t, J=8 Hz, 2H), 0.80 (t, J=8 Hz, 2H), 0.01 (s, 9H). 13C NMR (75.7 MHz, DMSO-d6) 132.58, 132.31, 131.92, 126.69, 121.19, 120.26, 103.50, 102.03, 75.69, 64.45, 17.18, −1.46. MS (FD+, m/z) 327, 325 (M+). HRMS 326.0570 (M++1, calcd for C14H21NOSiBr 326.0576).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:22](Br)[CH:23]=[CH2:24].[CH2:26](O)[CH3:27]>>[CH2:26]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([NH:1][CH2:22][CH:23]=[CH2:24])[CH:3]=1)[CH3:27]
Reactant: C=CCBr
Reactant: CCO
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: C=CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (3.08 g), allyl bromide (7.25 g), and dry ethanol was refluxed for 24 hours. After cooling, the precipitated ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate was filtered off and recrystallized from ethanol. The melting point of the ester was 153°-154°C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23](=O)[C:24]([Cl:27])([CH3:26])[CH3:25])=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:2].[NH:29]([C:31]([O:33]CC)=[S:32])[NH2:30]>C(#N)C>[CH2:1]([N:3]=[C:4]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[C:24]([CH3:26])([CH3:25])[S:32][C:31](=[O:33])[NH:29][N:30]=3)=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:2].[ClH:27]
Reactant: CCN=C(c1ccc(OC)cc1)N1CCCc2cc(C(=O)C(C)(C)Cl)ccc21
Reactant: CCOC(=S)NN
Solvent: CC#N
Product: CCN=C(c1ccc(OC)cc1)N1CCCc2cc(C3=NNC(=O)SC3(C)C)ccc21
Product: Cl
Reaction time: 2 h

Procedure:
A solution of 1.7 g of 1-(N-ethyl-p-methoxybenzimidoyl)-6-(2-chloro-2-methylpropionyl)-1,2,3,4-tetrahydroquinoline in 40 ml of acetonitrile is treated with 1 equivalent of O-ethyl hydrazinothioformate and the mixture is boiled for 2 hours. After customary working up, 5-[1-(N-ethyl-p-methoxybenzimidoyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6,6-dimethyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, m.p. 244° (hydrochloride), is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-methoxyphenylacetic acid (1.16 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 163° C.
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:12])(=[O:11])[CH2:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26](=[N:56]O)[C:27]1[CH:55]=[CH:54][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([NH2:51])=[O:50])=[CH:47][CH:46]=3)[CH2:37][CH2:36]2)=[CH:29][CH:28]=1>O.C(Cl)(Cl)Cl>[NH2:56][C:26](=[N:25][O:11][C:8](=[O:12])[CH2:9][CH3:10])[C:27]1[CH:55]=[CH:54][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:46]=[CH:47][C:48]([C:49]([NH2:51])=[O:50])=[CH:52][CH:53]=3)[CH2:37][CH2:36]2)=[CH:29][CH:28]=1
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reactant: CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To an N-methyl-2-pyrrolidone (10 mL) solution of 0.35 g of propionic acid was added 0.76 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for one hour. An N-methyl-2-pyrrolidone (10 mL) solution of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred for 15 hours. The reaction mixture was added to a mixture of chloroform and water. The precipitate was collected by filtration and washed with ethyl acetate to provide 0.58 g of 4-{3-[4-(3-{4-[amino(propionyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(propionyl)oxime as white solid form.
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:14][N:15]([CH:17]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24])[CH3:16].[Cl-:30].[NH4+]>CCOCC>[ClH:30].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][C:19]2([OH:24])[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[CH:17]([N:15]([CH3:14])[CH3:16])[C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: [Cl-]
Reactant: CN(C)C(c1cccs1)C1CCCCC1=O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1cccs1)C1CCCCC1(O)Cc1ccc(C(C)(C)C)cc1
Product: Cl
Temperature: 25 °C
Yield: 26.2 %

Procedure:
0.31 g (12.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.30 g (12.6 mmole) of 4-tert.-butylbenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.50 g (10.5 mmole) of the 2-(dimethylaminothiophen-2-ylmethyl)cyclohexanone prepared according to Example 70 were dissolved in 10 ml of ether, added dropwise to the Grigiard reagent while cooling in all ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.69 g of crude base (90.7% of theory) were obtained, from which 1.16 g of 1-(4-tert.-butylbenzyl)-2-[dimethylaminothiophen-2-ylmethyl]cyclo-hexanol, hydrochloride (26.2% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 210° C.
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[C:13]([O:17][CH2:18][CH2:19][OH:20])(=[O:16])[CH:14]=[CH2:15].C1C=CC=CC=1>[Zn](OC(C)=O)OC(C)=O.O>[C:13]([O:17][CH2:18][CH2:19][O:20][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)OCCO
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: C=CC(=O)OCCO[Si]1(C)O[SiH](C)O[SiH](C)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution containing 1M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01 g of (CH3CO2)2Zn was slowly added 1M of 2-hydroxyethyl acrylate. The resulting mixture was stirred for 12 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH:35]([CH3:37])[CH3:36]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=3[O:34][CH:35]([CH3:37])[CH3:36])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccccc3)cc2-c2ccccc2)c(OC(C)C)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 3,5-diphenyl-1H-pyrazole (0.36 g, 1.65 mmol) in N,N-dimethylformamide (8.6 mL) was added sodium hydride (60% in oil, 66 mg, 1.65 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added sodium iodide (22 mg, 0.15 mmol) and a solution of methyl 4-(bromomethyl)-3-isopropoxybenzoate (0.43 g, 1.50 mmol) in N,N-dimethylformamide (4.3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.59 g, yield 92%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)=[CH:7][C:6]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])=[C:6]([C:25]([F:26])([F:27])[F:28])[CH:7]=2)=[CH:12][C:13]=1[C:21]([F:22])([F:23])[F:24])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(-c2ccc(CCCO)c(C(F)(F)F)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(CCCOS(C)(=O)=O)c(C(F)(F)F)c2)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 3-[4′-(3-hydroxy-propyl)-3,3′-bis-trifluoromethyl-biphenyl-4-yl]-propan-1-ol (intermediate 6) (5.4 g, 13.3 mmol) in dichloromethane (40 mL) triethylamine (2.5 g, 24.7 mmol) and methanesulfonyl chloride (2.7g, 23.6 mmol) were added dropwise. The mixture was stirred overnight, diluted with dichloromethane (50 mL) and washed with water (2×15 mL). Evaporation of the organic solution gave 3,3′-bistrifluoromethyl-4,4′-biphenyl-dipropanol bismethanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)[CH3:2].C(O)(=O)C.O.[NH2:30][NH2:31].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:31][N:30]=1)=[O:24])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Yield: 100 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>CS(C)=O.CCOC(C)=O>[N+:32]([C:29]1[CH:30]=[CH:31][C:22]([NH:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25])([O-:34])=[O:33]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 17 h
Yield: 42 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methylamine (1.13 g, 5.92 mmol) and potassium carbonate (816 mg, 5.92 mmol) in dimethyl sulfoxide (12 mL) was treated with methyl 2-fluoro-5-nitrobenzoate (1.18 g, 5.92 mmol). After 17 h, the mixture was cooled, diluted with EtOAc, and filtered. The filtrate was concentrated and partitioned between EtOAc and 10% HCl. The aqueous layer was washed with EtOAc (1×), pH adjusted (>10) by addition of NaOH, and washed with EtOAC (3×). The combined extracts were washed with H2O (5×), brine, dried (sodium sulfate), and concentrated. The residue was purified by column chromatography (SiO2, 1 to 3% [2 N NH3 in MeOH]:chloroform) yielding 920 mg (42%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1cc(C)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and o-anisidine (27 μl, 0.243 mmol) similar to Example 13 and isolated as a pale white solid (40 mg, 56%). 1H NMR (CDCl3): 8.82–8.80 (m, 1H), 8.46 (d, J=8.1 Hz, 1H), 7.90 (dd, J=1.4, 7.7 Hz, 1H), 7.84–7.78 (m, 1H), 7.36–7.32 (m, 1H), 7.28 (s, 1H), 7.18–6.98 (m, 2H), 6.92 (dd, J=1.8, 8.0 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 2.50 (s, 3H).