Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][N:19]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[Cl:32])=[O:21])[CH:7]=1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42](B(O)O)[CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:23]1[C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:20]([N:19]([CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][C:6]1[CH:7]=[C:2]([C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)[CH:3]=[CH:4][C:5]=1[O:38][CH3:39])[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:21]
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(Br)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccnc2)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
Temperature: 85 °C
Yield: 89.7 %

Procedure:
A solution of 61 mg (0.1 mmol) N-({3-[(5-bromo-2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in 2 mL toluene is treated with 4 mg (0.003 mmol) tetrakis(triphenylphosphine)palladium(0), 15 mg (0.12 mmol) pyridine-3-boronic acid and 0.2 mL 2M potassium carbonate. The solution is heated to 85° C. for 18 hr and cooled to room temperature. The solution is diluted with 10 mL dichloromethane, washed with 10 mL brine, dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 55 mg (89%) (2-chloro-3,4-dimethoxyphenyl)-N-({3-[(2-methoxy-5-(3-pyridyl)phenyl)methyl](imidazol[1,2-a]pyridin-2-yl)}methyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 613.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si](C(C)(C)C)(C)C)=[N:7][C:6]([O:20][Si](C(C)(C)C)(C)C)=[CH:5]2.C([Li])(C)(C)C.[I:33]I.Cl>O1CCCC1.CS(C)=O.CO.O>[I:33][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2cc(Br)ccc2c(O[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: O=C1Cc2cc(I)ccc2C(=O)N1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
An amount of 6-bromo-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}isoquinoline (15.0 g, 32.0 mmol) in 100 mL of anhydrous tetrahydrofuran is cooled to −78° C. and then 47 mL (80.0 mmol) of tert-butyllithium (1.7 M in pentane) is added slowly with stirring. After stirring at this temperature for 2 hr, 12.0 g (48 mmol) of fresh iodine crystal is quickly add into the mixture, and stirred at this temperature for additional 5 h. The dry-ice bath is removed, and the reaction mixture is allowed to warm up to room temperature and stirred over weekend. Evaporating the brown solution yielded brown oil. The reaction mixture is acidified with 48 mL of 2 M HCl solution and stirred at room temperature for 1 h. The mixture is filtered to give light tan solid. The solid is dissolved in hot DMSO, then 20% MeOH/H2O solution is added to give a precipitate. The precipitate is collected and washed successively with water, methanol, ether and hexane to afford 5.1 g (55.6% yield) of off-white solid: MS (ESI) m/z 286.08 (M−H)−1
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:4][C:3](=[O:6])[NH:2]1.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]2[NH:25][C:26]([C@@H:28]([NH2:30])[CH3:29])=[N:27][C:23]=2[CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]2[NH:25][C:26]([C@@H:28]([NH:30][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:1]4[CH2:5][CH2:4][C:3](=[O:6])[NH:2]4)=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=3)[CH3:29])=[N:27][C:23]=2[CH:22]=1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2C(F)(F)F)N1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCC(=O)N2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from the 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA in DMF.
Reaction SMILES: [OH:1][CH:2]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])=[O:4].[C:39](Cl)(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:36][CH2:35][C:34]([CH3:37])([CH3:38])[CH:2]([OH:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])=[O:4])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C(O)C(C)(C)CO
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C(O)C(C)(C)COCc1ccccc1
Yield: 50.6 %

Procedure:
3-(N-Oleoylamino]propyl 3-[N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)amino]propionate (540 mg) and 140 mg of benzoyl chloride were reacted in the same manner as in Example 36 to obtain 318 mg of the title compound (yield: 51%).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:33])[C:26]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:4]([C:3]([OH:34])=[O:2])[NH:5][C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 42.5 °C
Reaction time: 3.5 h
Yield: 95 %

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (166 mmol, 86.2 g) in ethanol (350 mL) was added aqueous 1.0 N sodium hydroxide (250 mL) at room temperature. The mixture was heated to 40-45° C. and the resulting clear solution was stirred for 3-4 h. Then, the mixture was cooled to room temperature and the ethanol was removed on a rotary evaporator. The residue was diluted with 100 mL of water. The neutral impurities was extracted into ether (2×100 mL) and the basic aqueous layer was neutralized with 1 N HCl. The precipitated solid was collected by filtration and the solid cake was washed with water (1 L) and dried at air over weekend. The crude solid was dissolved in hot acetontile (2 L) and the resulting solution was stored in the refrigerator for 15 h. The white crystalline solids were collected by filtration and washed with cold acetonitrile (100 mL). After air drying, 79.76 g (95%) of a white solid, mp 212-215° C. was obtained. 1H NMR, DMSO-d6 (400 MHz) δ10.66 (s, 1H), 8.85 (d, 1H, J=19 Hz), 7.47-7.6 (m, 5H), 7.15-7.29 (m, 5H), 4.58-4.68 (m, 1H), 3.12 (dd, 1H, J=17, 13 Hz), 2.87 (dd, 1H, J=17, 11 Hz), 2.09 (s, 3H). HR MS: Obs. mass, 505.0483. Calcd. mass. 505.0488 (M+).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2c(F)cccc2F)n1
Yield: 46 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2,6-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.116 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.083 g (44%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,6-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [CH:1]1[C:9](C(OC)=O)=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:17][CH2:16][CH2:15][CH2:14][N:5]12.C1C=CC=C2C=1C=C1CCCCN12.[C:31](Cl)([Cl:33])=[O:32]>>[Cl:33][C:31]([C:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:17][CH2:16][CH2:15][CH2:14][N:5]12)=[O:32]
Reactant: COC(=O)c1ccc2c(c1)cc1n2CCCC1
Reactant: O=C(Cl)Cl
Agent: c1ccc2c(c1)cc1n2CCCC1
Product: O=C(Cl)c1cccc2c1cc1n2CCCC1

Procedure:
The methyl ester of Formula III wherein Z is --N(R2)-- and R1 and R2 are together --(CH2)3 --, namely methyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-2-carboxylate, is prepared by reacting 6,7,8,9-tetrahydropyrido[1,2-a]indole with phosgene to form 1-chloroformyl-6,7,8,9-tetrahydropyrido[1,2-a]indole and subsequently converting this product to the methyl ester. A more detailed description of this procedure is set forth in Example 1 of this application. The 6,7,8,9-tetrahydropyrido[1,2-a]indole may be prepared via an intramolecular Wittig reaction (M. D. Crenshaw and H. Zimmer, J. Heterocyclic Chem., (1984) 21, 623).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)c(F)c2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(F)c(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A mixture of 1,1-dimethylethyl N-((7,8-difluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.4 g, 1 mmol) in 3 mL TFA was stirred at room temperature for 30 minutes, M+1=325, M−1=324. The mixture was concentrated and then triturated in DCM/hexane (5:10). The solid was filtered, washed with 10 mL DCM/hexane (5:10), and dried under high vacuum to give 0.24 g of the product as a pale yellow solid. MS (m/z)=326 (M+H)+. Calculated for C15H13F2NO5 325.07.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[K+].[K+].C1(=O)[O:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.C(OCC)(=O)C.O>[OH:18][CH2:19][CH2:20][O:21][C:4]1[C:3]([CH3:10])=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OCCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
To a stirred solution of 4-hydroxy-3-methyl-benzaldehyde (0.545 g, 4.00 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.97 mmol). The reaction mixture was stirred at RT for 5 minutes and then a solution of ethylene carbonate (0.705 g, 8.00 mmol) in DMF (2 mL) was added. The resultant mixture was heated at 80° C. for 90 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate and water. The organic phase was removed, washed with brine (×2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (0.677 g, 94%).
Reaction SMILES: [S:1]1[C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.[Br:27][C:28]1C(Cl)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1>C(Cl)Cl>[Br:27][C:28]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[S:1][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:11]2)=[C:30]([N+:35]([O-:37])=[O:36])[C:31]([NH2:34])=[N:32][CH:33]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)c(N2CCN(Cc3cncs3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 73.8 %

Procedure:
tert-Butyl 4-(thiazol-5-ylmethyl)piperazine-1-carboxylate (0.350 g, 1.23 mmol, 1.1 eq) was dissolved in DCM (3.9 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (3.9 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. The resulting 5-(piperazin-1-ylmethyl)thiazole (supposedly 0.230 g, 1.23 mmol, 1 eq) was suspended in iPrOH (2.4 mL) and DIPEA (0.70 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.280 g, 1.12 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.330 g, 67%); 1H-NMR (500 MHz, DMSO-d6): δ 2.51-2.58 (br s, 4H, piperazine N(CH2)2), 3.01-3.10 (m, 4H, piperazine N(CH2)2), 3.82 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.78 (s, 1H, thiazole 4-H), 8.16 (s, 1H, pyridine 6-H), 9.03 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=2.17 min—399/401 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]([C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH3:19])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:20])[C:8]2[C:9](=[C:4]([NH:3][C:12]([C:14]3[CH:18]=[CH:17][O:16][C:15]=3[CH3:19])=[O:13])[CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: Cc1occc1C(=O)N1c2ccccc2CCC1(C)C
Agent: O=S(=O)(O)O
Product: Cc1occc1C(=O)Nc1cccc2c1CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
20 ml of 85% sulfuric acid solution was added to 2.5 g (9.3 mmols) of 2,2-dimethyl-N-(2-methyl-3-furan carbonyl)-1,2,3,4-tetrahydroquinoline under water cooling. The mixture was stirred at room temperature for 1 hour and then left standing overnight. Then, the reaction solution was poured into ice water and extracted from ethyl acetate. The resultant organic layer was sequentially washed with water, aqueous sodium hydrogen carbonate solution, water, and brine and then dried with magnesium sulfate. The dried mixture was concentrated. The concentrated residue was purified by being recrystallized with ethyl acetate/n-hexane, to obtain 2.1 g of white crystals (Compound No. 18 shown in Table 6). The yield was 84%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.CCCCCC>[CH3:17][N:18]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:20]=[N:19]1
Reactant: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn(C)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To a solution of methyl 3-bromo-5-(trifluoromethyl)benzoate (21.8 g, 77 mmol) in 1,4-dioxane (218 mL), and water (131 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24 g, 116 mmol), sodium carbonate (27.7 g, 261 mmol) and tetrakis(triphenyphosphine)palladium(0) (4.4 g, 3.8 mmol). The reaction mixture was heated at 80° C. for 3 h after which time TLC (20% EtOAc/hexane) showed consumption of the starting material. The reaction mixture was cooled to room temperature and precipitated solids were removed by filtration. The filtrate was diluted with water and extracted twice with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by filtration through silica, eluting with 0% to 40% ethyl acetate in hexanes to provide methyl 3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)benzoate as a pale yellow solid (22.3 g, 100%). LC-MS (FA): ES+ 285; 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>ClCCl.[O-]S([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]([S:29]([CH3:30])=[O:40])=[CH:27][N:28]=3)=[CH:18][CH:17]=2)[CH2:4][O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc(Nc2ccc(CC[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cnc(Nc2ccc(CC[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 0.67 h
Yield: 111.5 %

Procedure:
To a stirred solution of (5)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylthio)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (393 mg) in dichloromethane (5 ml) was added m-CPBA (218 mg) and stirring was continued at RT for 40 min. The reaction mixture was then diluted with aq. Na2SO3 solution and extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated in vacuo to give (4S)-tert-butyl 2,2-dimethyl-4-(4-(5-(methylsulfinyl)pyrimidin-2-ylamino)phenethyl)oxazolidine-3-carboxylate (454 mg, 85% purity, 95% yield) as a yellow oil. MS (ISP): 461.4 ([M+H]+), 405.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].[CH2:11](I)[CH3:12]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH2:11][CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)nc(C)c1Br
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOc1cc(C)c(Br)c(C)n1

Procedure:
A mixture of 5-bromo-4,6-dimethylpyridin-2-ol obtained in Preparation Example 23(1) (50 mg), ethyl iodide (2.0 mL) and silver carbonate (1.4 g) was stirred in a chloroform solvent (10 mL) at room temperature for 36 hours. The reaction mixture was subjected to silica gel pad and eluted with a mixed solvent of (ethyl acetate/n-heptane, 10%). The resulting solution was concentrated under reduced pressure to give the title compound (550 mg).
Reaction SMILES: C(OCCN(C)C)(=O)C(C)=C.[C:12]([O:17][CH3:18])(=[O:16])[C:13](C)=[CH2:14].[CH2:19]=[CH:20][C:21]1C=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])[CH:28]=[CH2:29].C(OCCCC)(=O)C(C)=C.C(S)CCCCCCCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C(O)C(C)C.C1(C)C=CC=CC=1>[CH3:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:18][O:17][C:12]([CH:13]=[CH2:14])=[O:16])[CH2:24][CH3:25].[CH3:35][CH2:34][CH2:33][CH2:32][O:31][C:27]([CH:28]=[CH2:29])=[O:30]
Reactant: C=C(C)C(=O)OC
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)OCCCC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: C=CC(=O)OCCCC
Solvent: Cc1ccccc1
Solvent: CC(C)CO
Product: C=CC(=O)OCC(CC)CCCC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a reactor were charged 80 parts of toluene, 20 parts of isobutanol, 6 parts of dimethylaminoethyl methacrylate, 40 parts of methyl methacrylate, 20 parts of styrene, 20 parts of butyl acrylate, 20 parts of butyl methacrylate, 14 parts of n-butyl methacrylate, 1 part of n-dodecylmercaptan and 1 part of azobisisobutyronitrile. They were stirred at 80° C. for 2 hours. Then, 0.2 part of azobisisobutyronitrile was added 5 times at 2-hour intervals, and polymerization was completed in 16 hours. Thus, there was produced an acrylic copolymer resin solution for rigid product grade which had a glass transition temperature (Tg) of 70° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)c1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Temperature: 70 °C
Yield: 99.8 %

Procedure:
Add manganese dioxide (1.32 g) to a stirred solution of 2-(tert-butyldimethylsilyloxymethyl)-5-(1-hydroxy-3-methyl-butyl)-pyridine (330 mg, 1.066 mmol) in anhydrous 1,4-dioxane (30 mL). Heat the mixture to 70° C. overnight. Cool the reaction mixture to room temperature, filter through Celite® and wash with EtOAc. Concentrate the filtrate in vacuo to provide the desired intermediate as oil (327 mg, 100%). GC-MS m/z: 307 (M+.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][I:43])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCI)CC1
Yield: 61.9 %

Procedure:
A mixture of 4-2 (3.4 g, 13.2 mmol), Ph3P (5.2 g, 19.8 mmol), imidazole (2.7 g, 39.6 mmol), and THF (30 mL) at ambient temperature was treated with iodine (5.0 g, 19.8 mmol) in three portions. After 1 h most of the THF was evaporated and the residue partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, 10% Na2S2O3, and brine, dried (MgSO4) and concentrated to give a solid. Flash chromatography (silica, 10% EtOAc/hexanes) gave 4-3 (3.0 g) as a light yellow oil. Rf 0.27 (silica, 10% EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C[Al](C)C.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCNc1ccc(N)cc1F
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCCCCNc1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a solution of 2-fluoro-N1-hexylbenzene-1,4-diamine (3.36 g, 16 mmol) in CH2Cl2 (20 mL) was added trimethylaluminium (40 mL, 80 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (3.02 g, 19.2 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (150 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as pale yellow oil (1.57 g, 31%). The compound was characterized by the following spectroscopic data: