Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CCOCC>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
Synthesis of these compounds was begun by suspending 4-carboxybenzaldehyde (34.5 mmol) in 50 mL CH2Cl2, adding 5 mL triethylamine and, after 5 minutes, 4.25 mL pivaloyl chloride. After 1.5 hours, 3.42 mL piperidine was added to the stirred reaction and, after 2 hours, the solution was diluted with ether and washed two times with 5% NaHCO3, three times with dilute HCl, and finally a saturated solution of NaCl. The organic solution was dried over Na2SO4 and the solvents were removed on a rotary evaporator to yield 7.38 g of 1-(4'-formylbenzoyl)piperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1.CCOC(C)=O.CCCCCC>C(#N)C>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([CH2:31][N:11]([CH:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH:8]([CH3:10])[CH3:9])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:33][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(C(C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(4-Methoxy-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (140 mg, 0.41 mmol) in acetonitrile (5 ml) at ambient temperature was added cesium carbonate (1.33 g, 4.10 mmol). Then methyl 4-(bromomethyl)benzoate (115 mg, 0.60 mmol) was added to the suspension and the reaction mixture was stirred at 70° C. for 1 hour by which time TLC (EtOAc/Hexane 1:1) monitoring showed the reaction to be completed. After cooling to ambient temperature, the mixture was filtered to remove excess cesium carbonate and evaporated to dryness. The residue was purified by flash chromatography (EtOAc/Hexane 1:1) to furnish the pure product as slightly yellow oil. Yield 153 mg (76%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[OH:1][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])=[O:20]
Reactant: CC(C)CC(=O)Cl
Reactant: Oc1cc(O)c(O)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)CC(=O)c1c(O)cc(O)c(O)c1O
Reaction time: 5 h
Yield: 27.2 %

Procedure:
Under an atmosphere of argon, 4.28 g (30.14 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved by stirring in 70 ml of nitrobenzene. The solution was cooled with water. To the cold solution, 16.1 g (120.56 mmol, 4.00 equivalents) of granular aluminum chloride was added piecemeal and stirred. To the stirred mixture, 3.67 ml (30.1 mmol, 1.00 equivalent) of isovaleryl chloride was added dropwise. After 5 hours, the reaction solution was poured into 100 ml of a cold.2 M hydrochloric acid solution, stirred for 20 minutes, and extracted from ether. The organic layer was washed with water, distilled to remove ether, combined with a large volume of water, and distilled under reduced pressure to remove nitrobenzene. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to obtain a crude reaction product. By purifying the crude product by silica gel column chromatography (300 g of Wako Gel C-200, hexane:ethyl acetate=2:1), 1.85 g (yield 27.2%) of the product (9) was obtained in the form of yellow powder crystals.
Reaction SMILES: ClN1C(=O)CCC1=O.CSC.[CH2:12]([OH:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:12](=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC/C=C/C=C\CCCCCCCCO
Agent: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CSC
Product: CCCC/C=C/C=C\CCCCCCCC=O
Reaction time: 0.5 h

Procedure:
A mixture of 27.8 g (207.9 mmol) N-chlorosuccinimide and 450 ml of toluene is cooled to -20° to -25° and 20.4 ml of dimethylsulfide (277.3 mmol) is added all at once. The mixture is stirred at -20° for 30 min. A solution of 33 g (138.6 mmol) of (9Z, 11E)-9,11-hexadecadien-1-ol in 10 ml of toluene is added over a period of 20 min. at -15°, with occasional warming to -5°. After addition is complete, the mixture is stirred at -15° for 20 min., then warmed to -5°, and then cooled to -50° as 38.7 ml (277.3 mmol) of triethylamine is added in one portion. The suspension is allowed to warm to 0° and is then quenched with water. The phases are separated and the aqueous layer is extracted with ether (2X). The combined organic phases are washed with 2 N sulfuric acid, water, saturated sodium bicarbonate and brine and dried over sodium sulfate. Purification by chromatography on a column of silica gel, eluting with hexane, then 10% ether/hexane, followed by recrystallization from hexane at -78° yields pure (9Z,11E)-9,11-hexadecadienal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:20][O:21][CH3:22])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: OCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1.0 g) and diisopropylethylamine (1.3 mL) in dichloromethane (5 mL) was added chloromethyl methyl ether (0.75 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=15/1–10/1) to give 1-bromo-4-[2-(methoxymethyloxy)ethyl]-benzene (1.2 g).
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)(=[O:6])=[O:5].CCN(CC)CC.C(Cl)[Cl:22]>CN(C1C=CN=CC=1)C>[Cl:22][CH2:12][C:10]1[O:11][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CO)o1
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-methanesulfonyl-furan-2-yl)-methanol (692 mg, 3.93 mmol) in dry CH2Cl2 (7.0 mL) was treated at 0° C. with Et3N (0.71 mL, 5.11 mmol) followed by DMAP (50 mg, 0.39 mmol) and Ms-C1 (0.37 mL, 4.71 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 868 mg of crude 2-chloromethyl-5-methanesulfonyl-furan as a yellow oil. 183 mg of this crude material in DMF (0.7 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (90 mg, 0.79 mmol) in DMF (0.7 mL) pre-treated for 1 h with DIPEA (0.27 mL, 1.59 mmol) and the reaction mixture was stirred for 48 h at rt. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a yellow oil: TLC:rf (4:6 hept-EA)=0.36. LC-MS-conditions 02: tR=0.85 min.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][C:28]([F:31])([F:30])[F:29]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[O:27][C:28]([F:29])([F:31])[F:30]
Reactant: Nc1ccc(F)c(OC(F)(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(OC(F)(F)F)c1
Yield: 67.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 4-fluoro-3-(trifluoromethoxy)-aniline in place of the 2,4-difluoroaniline. 270 mg of N-[4-fluoro-3-(trifluoromethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[C:20]([C:19]1[CH:22]=[C:23]([CH3:24])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)#[N:21]
Reactant: O=C1NCCO1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (200 mg) described in Preparation Example 131 and oxazolidin-2-one (68 mg), the title compound (167 mg) was obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[O:10]([CH2:15][CH:16]1[CH2:18][O:17]1)[CH2:11][CH:12]1[CH2:14][O:13]1>O>[C:2]1([CH2:1][O:8][CH2:18][CH:16]2[O:17][CH:12]([CH2:14][OH:13])[CH2:11][O:10][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(OCC1CO1)C1CO1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: OCC1COCC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
108 g of benzyl alcohol (1.0 mole) is stirred under a nitrogen atmosphere at room temperature and 0.4 g of sodium is added to the mixture and stirring continued for 2-1/2 hours. Then 13.1 g of 2,2'-(oxybismethylene)bisoxirane (0.1 mole) is added and the mixture then heated to reflux for 18 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the resulting yellow oil then vacuum distilled through a 10 cm vigreux column. The fraction distilling at 150°-154° @0.4 mm is collected yielding 4.8 g (20%) of the above compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O.[Cl:25][C:26]1[CH:31]=[C:30]([C:32](=O)[CH2:33][C:34](=O)[C:35]([F:38])([F:37])[F:36])[CH:29]=[CH:28][N:27]=1.[OH-].[Na+]>C(O)(C)C.O>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[N:10]=[C:34]([C:35]([F:36])([F:37])[F:38])[CH:33]=2)[CH:29]=[CH:28][N:27]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccnc(Cl)c1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-n2nc(C(F)(F)F)cc2-c2ccnc(Cl)c2)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
(4-Fluoro-phenyl)-hydrazine hydrochloride (95 mg, 0.57 mmol) is dissolved in isopropanol (3.0 mL) and triethylamine (0.08 mL, 0.57 mmol) is added. After the mixture is stirred for 5 min, trifluoroacetic acid (0.09 mL, 1.19 mmol) is added and the mixture is again stirred for 5 min Then 1-(2-Chloro-pyridin-4-yl)-4,4,4-trifluoro-butane-1,3-dione (130 mg, 0.52 mmol) is added and the reaction mixture is heated at 85° C. for 40 hrs and stirred at room temperature for another 48 hrs. Water (20 mL) is added and 1.0 M NaOH solution is used to adjust the pH to about 6. The reaction mixture is then extracted with EtOAc (3×20 ml) and the organic layers are combined and concentrated to give the crude product, which is used without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.CCO[C:19](/[CH:21]=[CH:22]/[CH2:23]P(OCC)(OCC)=O)=[O:20]>>[CH2:4]([NH:3][C:19](=[O:20])/[CH:21]=[CH:22]/[CH:23]=[CH:5]/[CH2:6][CH2:7][CH2:12][CH2:23][CH2:22][CH2:21][CH2:19][O:20][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1)[CH:9]([CH3:10])[CH3:8]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Product: CC(C)CNC(=O)/C=C/C=C/CCCCCCCOc1ccc2cc(C(F)(F)F)ccc2n1

Procedure:
Starting from 2-chloro-6-trifluoromethylquinoline (prepared as for Compound 23 starting from 4-trifluoromethyl aniline (ex. Aldrich)), and using triethyl 4-phosphonocrotonate.
Reaction SMILES: [CH:1]1([CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]=[C:18]=[S:19]>C(#N)C>[CH:1]1([CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:18](=[S:19])[NH:17][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN=C=S
Reactant: c1nc2c([nH]1)CCNC2C1CCCCC1
Solvent: CC#N
Product: CNC(=S)N1CCc2[nH]cnc2C1C1CCCCC1

Procedure:
Operating as in Example 14, 15.5 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 150°, are obtained from 18.4 g of histamine dihydrochloride and 24.4 ml of hexahydrobenzaldehyde. A solution of 2.05 g of 4-cyclohexyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.1 g of methyl isothiocyanate in 30 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered, and 2.50 g of the title compound, m.p. 232°, are collected.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CSc1cccc(C=O)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: CSc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 74A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=c1cc(O)cc[nH]1
Product: CCCCCCCCCC(=O)Oc1cc[nH]c(=O)c1
Yield: 15.5 %

Procedure:
The general procedure of Example 12 was repeated using 1.00 g of 4-hydroxy-2-pyridone and 2.05 g of n-decanoyl chloride to produce 370 mg of the title compound in a yield of 15%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][NH2:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][NH:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(CN)CCOCC2)cc1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Yield: 55.6 %

Procedure:
1-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-yl]methanamine (3.65 g, 11.4 mmol), 2-bromopyridine (910 μl, 9.48 mmol), tris(dibenzylideneacetone)dipalladium(0) (471 mg, 0.455 mmol), 2,2′-bis(diphenylphosphino)1,1′-binaphyl (567 mg, 0.910 mmol) and sodium tert-butoxide (1.29 g, 13.0 mmol) were stirred in toluene (50 ml) at 70° C. under nitrogen for 24 hours. The toluene was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and saturated sodium bicarbonate solution (50 ml). The organic layer was separated and dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ether:pentane (80:20 by volume) to provide the title compound (2.10 g, 46%) as a yellow solid. LRMS APCI+ m/z 399 [MH]+.
Reaction SMILES: Br[CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[C:14]([OH:20])(=[S:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[C:14]([S:19][CH2:2]/[C:3](=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5])(=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(O)=S
Reactant: O=C(O)/C(=C/c1ccccc1)CBr
Product: CC(C)(C)C(=O)SC/C(=C\c1ccccc1)C(=O)O
Yield: 93 %

Procedure:
The (Z)-2-bromomethyl-3-phenylpropenoic acid described in Example 1 (step A) is reacted with thiopivaloic acid according to the experimental procedure described in Example 1 (step B). Yield: 93% 1H NMR (CDCl3): 9.10 (broad s, 1H); 7.90 (s, 1H); 7.35 (s, 5H); 4.00 (s, 2H); 1.20 (s, 9H)
Reaction SMILES: [CH2:1](Cl)[CH3:2].[OH-].[Na+].[OH:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1>CS(C)=O>[CH2:1]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCl
Reactant: Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1ccc(N)cc1
Reaction time: 5 h
Yield: 81.8 %

Procedure:
In accordance with the process of Example 1, 150 ml of dimethyl sulfoxide, 19.4 g (0.3 mole) of ethyl chloride, 8.8 g (0.22 mole) of sodium hydroxide and 21.8 g (0.22 mole) of p-hydroxyaniline were charged in the autoclave and the reaction was carried out at 80° C. for 5 hours with stirring to obtain 24.7 g of p-ethoxyaniline having a boiling point of 123.5° to 124.5° C./10 mmHg. (yield: 90.1%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][NH:18][NH2:19]>CO>[Cl:16][C:4]1[N:3]=[C:2]2[N:18]([CH3:17])[N:19]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1Cl
Reactant: CNN
Solvent: CO
Product: Cn1nc(-c2ccccc2)c2ccc(Cl)nc21
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of (2,6-dichloropyridin-3-yl)(phenyl)methanone (0.7 g, 2.776 mmol) and methyl hydrazine (0.256 g, 5.553) in methanol (7 mL) was heated at 90° C. in a sealed tube for 4 h. The reaction mixture was concentrated under reduced pressure and diethyl ether was added. The organic layer was washed with an excess of water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as a pale yellow solid. The product was purified by column chromatography (5% EtOAc in hexane) to yield the title compound (0.455 g, 68%) as a white solid. [1H-NMR (CDCl3, 300 MHz) δ 8.26 (d, 2H), 7.91 (m, 2H), 7.56-7.39 (m, 3H), 7.18 (d, 1H), 4.18 (s, 3H); HPLC RtA=5.880 min. (97%); LCMS RtC=1.990 min; [M+H]+=244.0; Mp=94-96° C.]
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])=[CH:8][CH:9]=1)=[O:4].COC(C1SC(C[C@H](C(OC(C)(C)C)=O)C)=CC=1)=O.[OH-].[Li+].Cl>CO.O1CCCC1>[C:16]([O:15][C:13]([C@H:11]([CH3:12])[CH2:10][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(CC(C)C(=O)OC(C)(C)C)s1
Agent: COC(=O)c1ccc(C[C@@H](C)C(=O)OC(C)(C)C)s1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Cc1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Using 5-(2-tert-butoxycarbonylpropyl)thiophene-2-carboxylic acid methyl ester obtained as an intermediate of Example 13, and in the same manner as in Example 31, optical resolution was performed. The obtained (2R)-5-(2-tert-butoxycarbonylpropyl)thiophene-2-carboxylic acid methyl ester (0.18 g, 0.63 mmol) was suspended in methanol (1.6 mL) and tetrahydrofuran (1.6 mL), 1N aqueous lithium hydroxide solution (1.6 mL) was added, and the mixture was stirred overnight. 1N Hydrochloric acid (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.17 g).
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+]>C1COCC1.CO.O>[OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)CCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCc4cc(C(=O)O)ccc43)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of methyl 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate (900 mg, 1.709 mmol) in THF (8.6 mL) was added aqueous potassium hydroxide (1.82 mL, 17.09 mmol) and the mixture was stirred at rt overnight. The reaction was diluted with MeOH (10 mL) and water (10 mL) and the organic solvents were removed under reduced pressure. The pH was adjusted to ˜3 by addition of 1 M HCl, during which time the product precipitated. Collection of the precipitate by filtration furnished racemic 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (749 mg, 85%) as a white solid. The racemic mixture was resolved by chiral SFC using a Chiral Technologies IA-H 3.0×25 cm, 5 uM column and a solvent system of 50% MeOH/CO2, running at 70 mL/min. Under these conditions, the two enantiomers eluted at 5.5 min and 10.5 min.