Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C2C=CC(C(F)(F)F)=CC=2)C=CC=1CO.C[O:21][C:22](=[O:53])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)=[CH:37][C:36]=2[CH3:51])=[CH:27][C:26]=1[CH3:52]>>[CH3:32][O:31][C:29]1[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[CH:37][C:36]=2[CH3:51])=[CH:27][C:26]([CH3:52])=[C:25]([CH:30]=1)[O:24][CH2:23][C:22]([OH:53])=[O:21]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Agent: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C

Procedure:
Preparation of (3-Methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (compound 39A) The title compound was prepared in the manner analogous to Example 3A using (4-bromo-2-methyl-phenyl)-methanol and 4-(trifluoromethyl)benzeneboronic acid. MS m/z 249 (M-OH). Step 2. Preparation of 4chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (compound 39B) The title compound was prepared in the manner analogous to Example 3B using 39A. 400 MHz 1H NMR (DMSO-d6) δ 7.84 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.57 (s, 1H), 7.48 (m, 2H), 4.80 (s, 2H), 2.41 (s, 3H). Step 3. Preparation of [5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 39C) The title compound was prepared in the manner analogous to Example 1F using 1D and 39B. MS m/z 491 (M+1). Step 4. Preparation of [5-Methoxy-2-methyl-4-(methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid (compound 39) The title compound was prepared in the manner analogous to Example 1 using 39C. IR cm−1: 1740, 1322; 400 MHz 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=8.1 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.51 (s, 1H), 7.39 (d, 1H, J=7.8 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.04 (s, 1H), 6.53 (s, 1H), 4.71 (s, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H); MS m/z 477 (M+1). Anal. Calc'd for C25H23F3O4S.0.1 H2O; C, 62.78; H, 4.89; found: C, 62.57; H, 4.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH2:24])=[S:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH:26]=[C:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:24]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(N)=S)cc3)CC2)cc1
Reactant: O=C(CCl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N2CCN(c3ccc(Nc4nc(-c5ccccc5)cs4)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
A mixture of 5 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea, 3 parts of 2-chloro-1-phenylethanone, 1.7 parts of sodium acetate and 100 parts of acetic acid was stirred for 4 hours at 80° C. After cooling, the reaction mixture was evaporated and the residue was stirred in 130 parts of dichloromethane. The whole was neutralised with a sodium hydrogen carbonate solution. The precipitated product was filtered off, washed with water and dichloromethane and crystallized from 1,4-dioxane. The product was filtered off and dried, yielding 4.5 parts (69.6%) of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-phenyl-2-thiazolamine; mp. 269.7° C. (int. 2).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:6].[CH3:24][N:25]([CH3:36])[C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31].C1(C)C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH3:23][N:2]([CH3:1])[C:3]1[CH:19]=[C:18]([N:20]([CH3:21])[CH3:22])[CH:17]=[CH:16][C:4]=1[C:5]1([C:33]2[CH:34]=[CH:35][C:26]([N:25]([CH3:36])[CH3:24])=[CH:27][C:28]=2[NH:29][C:30](=[O:32])[CH3:31])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Reactant: CC(=O)Nc1cccc(N(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1cc(N(C)C)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
In a manner similar to that of part B of Example 3 condensation of 2-(2,4-bis(dimethylamino)benzoyl)benzoic acid (2.4 g.) and m-(dimethylamino)acetanilide (1.42 g.) and recrystallization of part of the product from a mixture of toluene, ligroin and hexane and part from a mixture of ethyl acetate and hexane afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-acetamido-4-(dimethylamino)phenyl)phthalide (I: X = Y4 = (CH3)2N, Y2 = CH3CONH, Z4 = Z5 = Z6 = Z7 = H) (m.p. 97°-136° C.).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:18]([NH:20][C:21]2[S:22][C:23]([Cl:37])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)[N:25]=2)=[O:19])=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:37][C:23]1[S:22][C:21]([NH:20][C:18](=[O:19])[N:17]([CH2:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:8])=[CH:16][CH:15]=2)=[N:25][C:24]=1[C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(-c2nc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)c3ccc(CCO)cc3)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-(2-(tert-butyldimethylsilyloxy)ethyl)phenyl)-3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)urea (0.289 g, 0.373 mmol) in THF (2 mL) at room temperature was added TBAF (1 M in THF, 1.5 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated. Purification by flash column chromatography on silica gel (eluted with 3% to 10% MeOH in DCM) gave N-(4-(5-chloro-2-(((3,3-diphenylpropyl)(4-(2-hydroxyethyl)phenyl)carbamoyl)amino)-1,3-thiazol-4-yl)phenyl)methanesulfonamide 68. Mass spectrum, calculated for C34H33ClN4O4S2 660.2; found 661.2 (M++1).
Reaction SMILES: [CH2:1]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:17])[CH:11]=1)[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH:19](Cl)[C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH3:17][C:12]1[CH:13]=[CH:14][C:15]2[O:16][CH:19]([C:20]([OH:22])=[O:21])[O:8][C:7]3[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=3[CH2:1][C:10]=2[CH:11]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: Cc1ccc(O)c(Cc2cc(C)ccc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1ccc2c(c1)Cc1cc(C)ccc1OC(C(=O)O)O2

Procedure:
A mixture of 27.4 g (0.120 mole) of 2,2'-methylene bis-p-cresol, 15.5 g (0.120 mole) of dichloroacetic acid, 66.5 g (0.480 mole) of potassium carbonate and 500 ml of isopropyl alcohol was refluxed for 24 hours with vigorous stirring after which 15.5 g. (0.120 mole) of dichloroacetic acid was added and the mixture was refluxed with stirring for 64 hours. The isopropyl alcohol was removed by distillation and replaced with 500 ml of water. The precipitate was collected, washed with 2% aqueous potassium hydroxide, suspended in 1 liter of water, and the suspension was acidified to litmus with 10% aqueous HCl. The resulting precipitate was collected and dried affording 2,10-dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid, m.p. 200°-205°C (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14]>C(OC)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)([C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=2[F:10])[OH:14])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccccc1F
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: COC(C)(C)C
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C

Procedure:
p-Fluorophenylmagnesium bromide (124 mL, 0.12 mol) was added dropwise to a stirring solution of 2,4′-difluorobenzophenone (24.5 g, 0.11 mol) in t-butylmethyl ether (100 mL) at rt. After the addition was complete the reaction was heated at reflux for 3 h. The solution was then cooled to rt and was poured in to ice cold 1.0 M HCl (aq) (100 mL). The organics were extracted with EtOAc (3×70 mL) and dried (Na2SO4). Concentration under reduced pressure gave the desired product bis(4-fluorophenyl)-2-fluorophenylmethanol as a pale yellow oil which was used in the next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.C([Li])CCC.[I:23]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([I:23])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: II
Reactant: Clc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccnc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.1 %

Procedure:
To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and DIPEA (3.911 g, 38.651 mmol) in dry THF (40 ml) cooled at −78° C. under a nitrogen atmosphere, was added n-butyllithium (24.157 ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at −78° C. for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise. The mixture was stirred at −78° C. for 1 h. The mixture was allowed to warm to room temperature, diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The combined organic extracts were separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D5 (7.8 g, 81%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=O.C(#N)C.P(Cl)(Cl)(Cl)=O.C(OC(C)C)(=O)C>O>[F:11][C:8]([F:9])([F:10])[C:7]1[O:12][C:3]([CH2:2][Cl:1])=[N:5][N:6]=1
Reactant: O=C(CCl)NNC(=O)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)C
Solvent: CC#N
Product: FC(F)(F)c1nnc(CCl)o1
Temperature: 0 °C
Reaction time: 28 h
Yield: 82.2 %

Procedure:
N′-(2-chloroacetyl)-trifluoroacetohydrazide (60 g) and acetonitrile (120 mL) are charged into a round-bottom flask and cooled to about 0° C. Phosphorus oxychloride (27.1 g) is added to the solution for about 15 minutes. The reaction mixture is heated to about 80° C. and stirred for about 28 hours. In a separate vessel, isopropyl acetate (180 mL) and water (180 mL) are mixed and cooled to 0° C. The reaction slurry is added to this solution slowly. The organic layer is separated and washed with 5% sodium bicarbonate solution (180 mL) and finally with 20% sodium chloride solution (180 mL). The organic layer is dried over sodium sulfate. The solvent is completely distilled off under vacuum to afford the title compound. (Yield: 82.2%)
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@@:3]([CH2:18]SC1C=CC(C)=CC=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].F[B-](F)(F)F.C[O+](C)C.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>ClCCl.O>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C@:3]2([C:2]([F:28])([F:27])[F:1])[CH2:18][O:17]2)[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CSc1ccc(C)cc1)C(F)(F)F
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94.9 %

Procedure:
To a solution of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol (42.7 g, 102 mmol) in 250 mL of anhydrous dichloromethane was added trimethyloxonium tetrafluoroborate (22.7 g, 153 mmol). The resulting suspension was stirred at room temperature for 4.5 hours. A solution of potassium carbonate (42.4 g, 307 mmol) in 250 mL of water was then added. After 16 hours, the reaction mixture was poured into 200 mL of saturated aqueous sodium bicarbonate solution and extracted with three 400 mL portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 0%-2% EtOAc/hexanes) afforded the title compound as a pale yellow oil (28.3 g, 95%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=O)=[CH:5]2)[CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(OCC)C>ClCCl>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:22]([C:6]2[C:7](=[O:21])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([CH2:14][N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[CH:9]=3)[N:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 165 °C

Procedure:
To a flask containing ethyl 1-cyclopropyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.38 g) from Preparation No. 25 is added 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 165° C. overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 1% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give a solid which is dissolved in a minimal amount of dichloromethane. The solution is added to 1:1 diethyl ether:pentane to precipitate the title compound as a white solid. This solid is collected by filtration and dried in vacuo to afford 0.36 g of the title compound.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Temperature: 40 °C
Yield: 98 %

Procedure:
To a suspension of methyl (3S,4R)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 20 (15 g, 45 mmol) in ethanol (225 mL) at room temperature under dry nitrogen was added 10% palladium on carbon (Degussa type) (1.5 g), and the reaction mixture placed under 50 psi pressure of hydrogen, and heated to 40° C. overnight. After cooling to room temperature, the reaction mixture was filtered through Celite® and concentrated in vacuo to afford the title compound as an orange oil (10.8 g, 98%).
Reaction SMILES: C(N(CC)[C:4]1[CH:9]=CC=C[CH:5]=1)C.[Cl:12][C:13]1[CH:18]=[C:17]([O:19]CC#C)[C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:18]2[CH:5]=[C:4]([CH3:9])[O:19][C:17]=2[C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1
Reactant: C#CCOc1cc(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
100 ml of N,N-diethylaniline was added to 5.2 g (14 mmol) of 3-(4-chloro-2-fluoro-6-propargyloxyphenyl)-1-methyl-6-trifluoromethyluracil and 6.4 g (42 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.4 g (yield: 26.9%) of the desired product as white powder. Melting point: 196-197° C.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:15])[N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2.Cl>>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OC(F)F)cc(F)c2C1=O
Agent: Cl
Product: O=C1NCCc2cc(OC(F)F)cc(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.2 %

Procedure:
To a mixture of 144i (2.0 g, 6.0 mmol) in EtOAC (10 mL) was added HCl in EtOAC (20 mL, 4 M) at RT. See FIG. 3. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude residue was triturated with MTBE (20 mL) to give 2.0 g (85.9%) of 6-(difluoromethoxy)-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one 144j. 1H NMR (400 MHz, CDCl3) δ 6.80-6.85 (m, 2H), 6.40-6.76 (m, 1H), 6.19 (s, 1H), 3.51-3.55 (m, 2H), 2.98-3.01 (m, 2H); MS-ESI [M+H]+=232.0.
Reaction SMILES: [C:1]([O-])(=O)[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])(C([O-])=O)O.[Cl-].[Cl-].[Ca+2].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>OCC(CO)O>[C:9]([OH:11])(=[O:10])[CH2:8][CH2:3][CH2:2][CH2:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:1][CH2:2][CH2:3][CH3:8]
Reactant: CCCCCC
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: OCC(O)CO
Product: CCCCCCCCCCCCCCC(=O)O

Procedure:
Lipase (Lipase D10 manufactured by Amano Pharmaceutical Co., Ltd.) (60 mg) was dispersed in 15 ml of glycerol containing 8% v/v of 20 mM citrate buffer (pH 5.5) and 100 mM CaCl2 to form a lower layer, a solution of 375 mg of n-pentadecanoic acid in 50 ml of n-hexane (concentration 7.5 mg/ml) was provided thereon as the upper layer, and the two layers were stirred at 40° C. to carry out an esterification reaction at the interface between the two layers. The crystallizing bottle was maintained at 4° C. to obtain pentadecanoic acid monoglyceride. As a result, it was confirmed that pentadecanoic acid of 95% purity was synthesized.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[CH2:15]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=[CH2:15]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(C(=O)OC)cc1
Reaction time: 0.67 h
Yield: 83.5 %

Procedure:
To a three-neck, round-bottom flask equipped with an overhead stirrer, addition funnel, and a nitrogen inlet was added sodium hydride as a 60 percent dispersion (58.5 g, 1.46 mole). The sodium hydride was washed with THF (300 mL) then fresh THF (2000 mL) added. To the well-stirred suspension at room temperature was added methyltriphenyl-phosphonium bromide (500.1 g, 1.40 mole) over 35 minutes. After another 40 minutes of stirring, a solution of methyl p-formylbenzoate (218.9 g, 1.33 mole) in THF (600 mL) was added over 20-25 minutes. The mixture was then stirred at room temperature overnight for a total of 18 hours. The mixture was then filtered and the filtrate concentrated in vacuo. The residue was then treated with a 50 percent solution of ethyl acetate in hexanes (1400 mL) and filtered again. This filtrate was then concentrated in vacuo and placed on a large chromatography column (1400 mL of silica gel 60, 35-70 mesh packed with a 5 percent solution of ethyl acetate in hexanes) and eluted with a 5 percent solution of ethyl acetate in hexanes. The desired fractions were combined and concentrated in vacuo to provide 180.67 g (83.5 percent) of oil which slowly solidified to a white waxy solid. Proton NMR (Gemini 300 MHz in deuterochloroform): delta 7.98 (2H), 7.42 (2H), 6.72 (1H), 5.82 (1H), 5.37 (1H), 3.88 (3H). FDMS confirmed a mass of 162.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)[CH:6]=[N:7][CH:8]=1)#[N:2].Cl.[NH2:17][C:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21]>>[C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21])=[O:13])[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CC#CC(C)(C)N
Reactant: CCC(Oc1cncc(C#N)c1)C(=O)O
Agent: Cl
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C#N)c1

Procedure:
The product from Step 2 was condensed with 4-amino-4-methylpent-2-yne hydrochloride in a similar procedure to that described in Example 1 Stage 3 to give the required product as a colourless solid, m.p. 112–113° C.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:12])=[O:11]>O>[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:4])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:11])=[O:12]
Reactant: C1COCCO1
Reactant: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NS(C)(=O)=O)n1
Reaction time: 0.25 h

Procedure:
A mixture of selenium dioxide (11.1 g.), dioxane (250 ml.) and water (5 ml.) was stirred for 15 minutes at 110° to 115° C. to give yellow solution. Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate (26.4 g) was added thereto with stirring at the same temperature. After stirring for 1 hour, the reaction mixture was decanted with heating and cooled to precipitate yellow crystals. The crystals were collected by filtration, washed with dioxane and ether and dried to give ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (23.5 g.).