Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[CH2:31]([S:35](Cl)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]>>[CH2:31]([S:35]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: CCCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCCCS(=O)(=O)N1CC(C(=O)N2CCN(c3cc(C)ccc3C)CC2)N(c2ccccc2)C1=O

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 1-butanesulfonyl chloride to give the title compound as an off-white solid. MS: 499.0 ([M+H]+)
Reaction SMILES: [Li][CH3:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:35])([C:21]4[CH:28]=[CH:27][C:24]([CH:25]([OH:26])[CH3:2])=[CH:23][CH:22]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:37])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
MeLi (0.00258 mol) was added dropwise at −70° C. to a solution of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5yl)methyl]benzaldehyde (described in Example B6) (0.001 mol) in THF (5 ml) under N2 flow. The mixture was stirred at −70° C. for 2 hours. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.9 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (58%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1-hydroxyethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 181° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:10])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(O)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(N)n1
Reaction time: 4 h
Yield: 12.1 %

Procedure:
Under an argon atmosphere 6-amino-5-bromo-pyridin-2-ol (23 g, 122 mmol) was dissolved in DMF (300 mL). K2CO3 (50.6 g, 366 mmol) was added followed by the addition of methyl iodide (11.4 mL, 183 mmol). The mixture was stirred for 4 h while keeping the temperature at 20-25° C. The suspension was poured onto H2O (1 L) and the aqueous phase was extracted with EtOAc (×2). The combined organic phases washed with H2O (0.5 L) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluent toluene:heptane 2:1->100:0 followed by toluene:EtOAc 95:5 to afford 3-bromo-6-methoxy-pyridin-2-ylamine as a solid (3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19]C)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(=O)O)c(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 75 °C
Yield: 90 %

Procedure:
Methyl N-(benzyloxycarbonyl)-4-aminomethyl-2-O-benzylsalicylate (6.81 g, 16.8 mmoles) was dissolved in tetrahydrofuran (50 mL). A solution of lithium hydroxide monohydrate (0.78 g, 18.5 mmoles) in water (25 mL) was added, and the reaction mixture was stirred and heated at 75° C. for 24 hours. The solution was cooled, and 1N aqueous hydrochloric acid (50 mL) was added. The reaction mixture was extracted twice with ethyl acetate (150 mL then 50 mL). The combined ethyl acetate extracts were washed with water (75 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to 150 mL. The ethyl acetate solution was heated to boiling, and hexanes (150 mL) was added. The solution was cooled in ice, and crystals formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford 5.92 g (90% yield) of N-(benzyloxy-carbonyl)-4-aminomethyl-2-O-benzylsalicylic acid (m.p. 139°-140° C., open capillary, uncorrected).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[O:34]1[CH2:35][CH2:36][N:31]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:10]4[C:3]5[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=5[N:8]([CH:26]5[CH2:30][CH2:29][O:28][CH2:27]5)[CH:9]=4)=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[CH2:32][CH2:33]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccc(C=O)cc3)cc1)cn2C1CCOC1
Reactant: C1COCCN1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccc(CN4CCOCC4)cc3)cc1)cn2C1CCOC1

Procedure:
In a similar manner to Example 10 a mixture of 4-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde (336 mg), and morpholine (146 mg) were reacted to give 5-[4-(4-morpholinomethylphenoxy)-phenyl]-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p 142-144° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[O:11][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]([F:19])([F:18])[F:20])[O:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1oc(C(F)(F)F)nc1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1oc(C(F)(F)F)nc1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of Methyl 4-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-5-carboxylate (49 mg, 0.17 mmol) in THF (1.5 mL) was added LiOH (21 mg, 0.51 mmol) in water (0.4 mL). After 2 hours, the THF was evaporated, and the aqueous layer was acidified with 1N HCl and then extracted in EtOAc (3×15 mL). The organic fractions were dried over Na2SO4 and concentrated. 1HNMR (400 MHz, MeOD/CDCl3): d 7.99 (m, 2H), 7.03 (t, 2H, J=8.4 Hz). MS (ESI): m/z 274.0 [M−H]− (S-41)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([NH2:19])=[N:15][NH:16][C:17]=1[NH2:18].[C:20](OC)(=[O:26])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+]>CO>[NH2:18][C:17]1[C:13]([CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[CH3:1])=[C:14]2[NH:19][C:20](=[O:26])[CH2:21][C:22](=[O:23])[N:15]2[N:16]=1
Reactant: Cc1c(Cc2c(N)n[nH]c2N)cccc1C(F)(F)F
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cc2c(N)nn3c2NC(=O)CC3=O)cccc1C(F)(F)F
Temperature: 65 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a solution of 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-3,5-diamine (1 g, 3.70 mmol), dimethyl propanedioate (1.467 g, 11.10 mmol) in methanol (30 mL) was added sodium methoxide (0.680 g, 12.58 mmol). The reaction mixture was stirred at 65° C. for 18 h. After the reaction mixture was cooled to room temperature, the solvent was evaporated. Water (10 mL) was added in. The mixture was neutralized with 1 N HCl. Filtration gave the product (1.2 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H) 3.59-3.67 (s, 2H) 3.73 (s, 2H) 5.64 (br. s., 2H) 7.14 (d, J=7.83 Hz, 1H) 7.30 (m, 1H) 7.54 (d, J=7.83 Hz, 1H) 11.26 (s, 1H); LC/MS: MS (ES+) m/e 339.1 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=2)[NH:3]1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[S:29][CH:30]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:27]=4)[CH2:32][CH2:33]3)=[O:19])[CH:8]=2)[NH:3]1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C1Cc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C1Cc2cc(NC(=O)N3CCN(c4nc(-c5ccccc5)cs4)CC3)ccc2N1

Procedure:
A solution of 2,2,2-trichloroethyl (2-oxo-2,3-dihydro-1H-indol-5-yl)carbamate (200 mg, 0.618 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (152 mg, 0.618 mmol), diisopropylethylamine (0.108 ml, 0.618 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (18.0 mg, 6.9%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>>[CH2:21]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)CBr
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCC(=O)Cn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Yield: 56 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-bromo-2-butanone were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 56%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.OP(O)(O)=O.CC(O)=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:28]([NH2:30])=[O:29])[C:26]=1[F:27])[NH:23][CH:22]=[CH:21]2.[NH4+].[OH-]>CO.C(Cl)Cl.CCOC(C)=O>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:28]([NH2:30])=[O:29])[C:26]=1[F:27])[NH:23][CH:22]=[C:21]2[CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: NC(=O)c1c(F)c(Br)cc2cc[nH]c12
Reactant: O=C1CCSCC1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1c(F)c(Br)cc2c(C3CCSCC3)c[nH]c12
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 18.2 %

Procedure:
Tetrahydro-4H-thiopyran-4-one (285 mg, 2.451 mmol) was added to a 2 dram vial containing H3PO4 (2 g, 20.41 mmol) and AcOH (3 mL, 52.5 mmol). The reaction was heated to 90° C. (bath temp), and 5-Bromo-6-fluoro-1H-indole-7-carboxamide (210 mg, 0.817 mmol) was added in 3 portions over 3 min. The reaction was heated at 90° C. for 17. The reaction mixture was cooled to room temperature and was then added slowly to a mixture of ice and saturated NH4OH (10 mL) with stirring. EtOAc (10 mL) was then added, the mixture was filtered, and the precipitate was washed with EtOAc (3×10 mL). The layers of the filtrate were separated, and the aqueous layer was extracted with EtOAc (4×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under a stream of nitrogen at 50° C., giving 281 mg of crude product. The crude product was dissolved in 1:1 MeOH/DCM, and Isolute was added. The mixture was concentrated under reduced pressure, loaded onto a silica cartridge (12 g), and purified on a Combiflash Companion, eluting at 20 mL/min with a gradient running from 20% EtOAc/hexanes to 70% EtOAc/hexanes over 45 min. The desired fractions were concentrated under reduced pressure and dried under high vacuum, giving 53 mg (17%) of the title compound.
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28](=[O:36])[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]2=[O:26])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:26]=[C:17]1[CH:18]=[N:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]1[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][CH2:27][C:28]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:36])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC1CCN(CCn2c(=O)cnc3ccccc32)CC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.26 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 11 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.20 g of N2-(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)-N-(pyridin-2-yl)glycinamide as a light brown oil.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:8][CH:9]=1.N.CO>C(OCC)(=O)C>[NH2:13][CH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][C:2]([CH3:28])([OH:1])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:9]=[CH:8][CH:7]=1
Reactant: CCCCC(C)(O)Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(C)(O)Cc1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-hydroxy-2-methylhexyl)phenyl)propyl)isoindoline-1,3-dione followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate) gradient gave Example 121 a colorless oil. Yield (0.144 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.18-7.24 (m, 1H), 7.00-7.08 (m, 3H), 2.68-2.78 (m, 4H), 2.60-2.68 (m, 2H), 1.71-1.80 (m, 2H), 1.24-1.50 (m, 9H), 1.12 (s, 3H), 0.91 (t, J=7.2 Hz, 3H). ESI MS m/z 250.3 [m+H]+, 232.3 [m+H−H2O]
Reaction SMILES: [OH-].[K+].[F:3][C:4]1([F:34])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=3)=[CH:23][CH:22]=2)([C:16]([O:18]C)=[O:17])[CH2:5]1>CS(C)=O.O>[C:12]([O:11][C:9]([N:7]1[CH2:8][C:4]([F:3])([F:34])[CH2:5][C@@:6]1([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@]1(Cc1ccc(-c2ccc(F)cn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium hydroxide (61 mg, 1.1 mmol) was added to an ambient temperature solution of 1-tert-butyl 2-methyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1,2-dicarboxylate (246 mg, 0.55 mmol) in DMSO/water (1:1) (2 mL). After stirring at ambient temperature for 1 h, the reaction mixture was extracted with chloroform and concentrated in vacuo to afford 1-(tert-butoxycarbonyl)-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]proline.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:16]C(=O)N(C)C)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=O.C[O-].[Na+].Cl>CO>[SH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([SH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(SC(=O)N(C)C)cc(SC(=O)N(C)C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(S)cc(S)c1
Temperature: 0 °C

Procedure:
Methyl 3,5-bis(dimethylcarbamoylthio)benzoate (34.2 g, 0.10 mol) was made to react with a mixture of 43 g of 28% methanol solution of sodium methoxide (0.223 mol) and methanol (150 ml) at 22-25° C. After addition of 500 ml of ice-water, the reaction mixture was neutralized with concentrated hydrochloric acid to give a colorless crystals. The crystals thus obtained were purified by means of recrystallization from methanol giving 12.5 g (62.5%) of methyl 3,5-dimercaptobenzoate as a colorless powder. The melting point is 61-62° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][O:14][C:13](=[O:15])[CH2:12][N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=[N:10]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccccc1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 51.8 %

Procedure:
To a solution of 1 g (4.85 mM) of (5-phenyltetrazol-1-yl) acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=9/1) for separation and purification, to give 630 mg (yield 51.8%) of (5-phenyltetrazol-1-yl) acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:49]([NH:48][C:44]5[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=5)=[O:50])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:39][CH:40]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)Nc4cccc(F)c4)nc3)n2)cc1
Yield: 35.9 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (Example 190, Step 4, 0.156 g, 0.293 mmol) and 3-fluorophenyl isocyanate (0.084 mL, 0.73 mmol) in THF (3 mL) was stirred at rt for 5 h. The resulting precipitate was collected to give 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-(3-fluorophenyl)urea (0.0707 g) as a yellow solid. The filtrate and wash were concentrated and purified by silica gel chromatography (25 g, eluent: EtOAc in hexanes 0%-30%) to give a second batch of the product (0.1218 g). The combined yield was 0.1925 g (98%). 1H NMR (300 MHz, CDCl3) δ 11.77-11.96 (m, 2H); 8.80-8.93 (m, 1H); 8.43 (br. s., 1H); 8.32 (br. s., 1H); 7.93 (br. s., 1H); 7.45-7.63 (m, 2H); 7.27-7.35 (m, 2H); 7.15-7.24 (m, 4H); 6.66-6.95 (m, 7H); 4.85 (br. s., 4H); 3.79 (d, J=10.08 Hz, 6H); 2.62 (s, 3H). m/z (ESI, +ve ion) 672.0 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1.C([O:16][CH:17](O)[C:18]([F:21])([F:20])[F:19])C.O>C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[CH:17]([C:12]1[N:7]=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=1)[OH:16]
Reactant: CCOC(O)C(F)(F)F
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(C(O)C(F)(F)F)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 19.2 %

Procedure:
Potassium carbonate (4.66 g, 36.3 mmol) was added to the mixture of pyridin-3-ol (2.00 g, 21.0 mmol) and 1-ethoxy-2,2,2-trifluoroethanol (3.30 g, 23.1 mmol), and the mixture was stirred for 4 hours at 100° C. under nitrogen atmosphere. This reaction solution was cooled to room temperature, followed by adding water and ethyl acetate to the reaction solution, washing the organic layer with a saturated saline solution, drying the layer with anhydrous sodium sulfate, and thereafter concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (Purif-Pack SI200, hexane:ethyl acetate:=40:60) to obtain the title compound (780 mg, yield: 19%) as a white amorphous.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(O)cc2Cl)c1=O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To 10 ml of DMF, 0.8 g (2.2 mmol) of 3-(2-chloro-4-hydroxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.42 g (3.0 mmol) of potassium carbonate and 0.56 g (3.3 mmol) of ethyl 2-bromopropionate were added, followed by heating and stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.90 g (yield: 94%) of the desired product.