Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([CH3:10])[CH3:9])(=O)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH2:26])[CH3:25])=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1.CCOC(C)=O>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH:26][CH2:7][C:8]([F:11])([CH3:10])[CH3:9])[CH3:25])=[CH:15]1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Temperature: 90 °C
Yield: 91.1 %

Procedure:
2-Fluoro-2-methylpropyl trifluoromethanesulfonate (8.04 g, 35.87 mmol) was added to a solution of (R)-1-(1H-indol-3-yl)propan-2-amine (5.00 g, 28.70 mmol) and N-ethyl-N-isopropylpropan-2-amine (7.44 ml, 43.04 mmol) in dioxane (50 ml). The reaction was heated to 90° C. for 3 h. After cooling to room temperature, the reaction was diluted with EtOAc (200 ml) and washed with saturated. NaHCO3 solution (2×100 ml). The aqueous phase was extracted with EtOAc (150 ml), then the combined organics were dried over MgSO4 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 100% EtOAc. Pure fractions were evaporated to dryness to afford (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (6.49 g, 91%) as a brown oil. 1H NMR (400 MHz, CDCl3, 27° C.) δ 1.14 (3H, d), 1.31 (3H, d) 1.37 (3H, d), 1.94 (1H, s), 2.63-2.87 (3H, m), 2.92 (1H, dd), 3.07 (1H, h), 7.07 (1H, d), 7.08-7.15 (1H, m), 7.16-7.24 (1H, m), 7.37 (1H, d), 7.62 (1H, d), 8.04 (1H, s). m/z: ES+ [M+H]+ 249
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH2:13]3)=[CH:9][CH:10]=2)[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:4]=1.[ClH:35]>ClCCl>[ClH:35].[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[CH2:15][CH:14]([N:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)[CH2:13]3)=[CH:9][CH:10]=2)[N:5]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CC(N4CCN(C(=O)OC(C)(C)C)CC4)C3)ccc12
Agent: Cl
Solvent: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(N3CC(N4CCNCC4)C3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 4-(1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)azetidin-3-yl)piperazine-1-carboxylate (100 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (20 mL). To the resulting mixture, HCl (g) was introduced at 0-5° C. The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration to yield 3-(methylthio)-1-phenyl-6-(3-(piperazin-1-yl)azetidin-1-yl)-1H-indazole hydrochloride as a white solid.
Reaction SMILES: C(CC([O:6][C@@H:7]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C@@H:10]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:9][C@H:8]1[N:33]1[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]1=[O:35])=O)C.[BH4-].[Na+].[NH4+].[Cl-].C([O-])(O)=O.[Na+].[CH3:51][CH2:52][OH:53]>C(Cl)Cl>[OH:53][CH2:52][CH2:51][O:6][C@@H:7]1[C@H:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[O:9][C@H:8]1[N:33]1[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]1=[O:35]
Reactant: CCO
Reactant: CCCC(=O)O[C@@H]1[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@H]2OCCO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-[2′-O-(2-Ethylacetyl)-3′,5′-bis-O-(2,4-dichlorobenzyl)-β-D-ribofuranosyl]thymine (9.92 g, 15.0 mmol) was dissolved in hot EtOH (150 mL) and the solution was cooled to ambient temperature in a water bath. To the solution was cautiously added NaBH4 (1.13 g, 30.0 mmol) over 10 minutes. After 3 hours additional NaBH4 (282 mg, 7.45 mmol) was added the mixture was stirred for 1 hour and left to stand for 8 hours. The pH was adjusted to 4 by addition of Saturated NH4Cl (25 mL) to give a gum. The solvent was decanted and evaporated in vacuo to afford a white solid which was dissolved in CH2Cl2 (250 mL). The gum was dissolved with saturated aqueous NaHCO3 and this solution was gently extracted with the CH2Cl2 containing the product. The organic layer was separated and the aqueous layer was extracted again with CH2Cl2 (2×50 mL). After combining the organic layers, the solvent was dried over MgSO4 and evaporated in vacuo to afford a white foam. The foam was dissolved in CH2Cl2 and purified by flash chromatography using hexanes-EtOAc, 20:80, to give the title compound as a white foam (8.39 g, 90%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1cccc(CCn2ncc(-c3ccccc3)c2-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(CCn2ncc(-c3ccccc3)c2-c2ccccc2)c1
Yield: 70.3 %

Procedure:
A mixture of methyl [3-[2-(4,5-diphenyl-1H-pyrazol-1-yl)-ethyl)phenoxy]acetate (0.42 g, 1 mmol), 3N NaOH solution (1.0 mL, 3 mmol) and methanol (30 mL) was heated on a steam bath for 15 minutes before being concentrated in vacuo. The residue was diluted with water, 1N HCl solution added until pH=1 and the mixture extracted with CH2Cl2. The combined organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in CH2Cl° and diluted with hexanes to furnish [3-[2-(4,5-diphenyl-1H-pyrazole-1-yl)ethyl]phenoxy]acetic acid (0.28 g, 68%) m.p. 133°-138° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20]C)(=O)[CH:17]=[CH2:18]>>[N:6]1[CH:7]=[CH:12][CH:13]=[C:14]([CH2:1][C:17]2[C:16](=[O:20])[C:4]3[CH:3]=[CH:2][CH:1]=[C:14]4[C:5]=3[N:6]([CH:18]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]4=[O:15])[CH:5]=1
Reactant: C=CC(=O)OC
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Product: O=c1c(Cc2cccnc2)cn2c3ccccc3c(=O)c3cccc1c32
Yield: 13 %

Procedure:
According to Example 5<steps 1 and 2>,9(10H)-acridone (10 g) was reacted with methyl acrylate (11.5 mL) to obtain the title compound (1.8 g; 13%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@@H:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]4[F:30])[C:12]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:11]=4[C:10]=3[C:9](=[O:36])[NH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CC(O)C>[CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@@H:17]4[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]4[F:30])[C:12]4[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:11]=4[C:10]=3[C:9](=[O:36])[NH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nc3c(C#CC4CC4)c[nH]c(=O)c3c3cc(F)ccc23)[C@H](F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=c1[nH]cc(C#CC2CC2)c2nc(N[C@@H]3CCNC[C@H]3F)c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl trans-4-{[4-(cyclopropylethynyl)-9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl]amino}-3-fluoropiperidine-1-carboxylate (160 mg, 0.324 mmol) in THF (5 mL) under a nitrogen atmosphere was added HCl (4.0 M in 1,4-dioxane) (2 mL, 8.0 mmol), and the reaction was left stirring for two days at room temperature. The reaction mixture was then added to a separatory funnel containing 3:1 CHCl3:2-propanol and saturated aqueous NaHCO3. The phases were separated, and the organic layer was washed with water, then brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product mixture was purified by silica gel chromatography (0-10% CH3OH in CH2Cl2), followed by trituration with methanol afforded the title compound 4-(cyclopropylethynyl)-9-fluoro-6-[(trans-3-fluoropiperidin-4-yl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (APCI) calc'd (C22H20F2N4O3) [M+H]+, 395.2; found 395.1. 1H NMR (500 MHz, DMSO-d6) δ 11.51 (d, 1H), 9.57 (dd, 1H), 8.51 (dd, 1H), 8.19 (d, 1H), 7.57 (d, 1H), 7.53 (dt, 1H), 4.80-4.64 (m, 2H), 3.35 (m [under H2O], 1H), 2.97 (d, 1H), 2.55 (t, 2H), 2.12 (m, 1H), 1.56 (m, 1H), 1.50 (m, 1H), 1.15 (m, 1H), 0.89 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=[O:10])=[CH:3][CH:2]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=C=O)=[CH:18][CH:17]=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)(Cl)Cl>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1C=O
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 170 °C

Procedure:
A mixture of o-phthalicdicarboxaldehyde (17.54 g, 0.131 mol) and p-carbethoxyphenylisocyanate (25.0 g, 0.131 mol) is heated in an oil bath at 170° C. for 4.0 hours under nitrogen atmosphere. The hot melt is then slowly poured into CHCl3 (300 ml). The solution is then evaporated to dryness when a solid residue is obtained. The crude 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester is triturated with isopropyl ether and then recrystallized from CH2Cl2 - isopropyl ether (1:1, 300 ml) to give white solid. Yield 5.07 g (13.8%); mp 182°-184° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])(=[O:11])=[O:10])=[CH:5][N:4]=1)=[CH2:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1I.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:2]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])(=[O:10])=[O:11])=[CH:5][N:4]=1
Reactant: Fc1ccccc1I
Reactant: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(/C=C/c2ccccc2F)nc1)c1ccccc1F
Temperature: 170 °C
Yield: 57.4 %

Procedure:
2-Vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine (Step 1, 50 mg, 0.19 mmol), 2-fluoroiodobenzene (46 mg, 0.207 mmol), palladium(II) acetate (2 mg, 0.01 mmol) and tri-o-tolylphosphine (12 mg, 0.039 mmol) were taken up in acetonitrile/triethylamine (0.5 mL/0.5 mL) and the reaction heated to 170° C. for 20 minutes in a Smith synthesiser microwave reactor. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (39 mg, 57%). δH (500 MHz, d6 DMSO): 9.03 (1H, d, J=2.2 Hz), 8.28 (1H, dd, J=1.6, 8.3 Hz), 8.05 (1H, td, J=7.6, 1.6 Hz), 7.92 (1H, d, J=16.1 Hz), 7.84 (1H, td, J=8.0, 1.4 Hz), 7.80–7.74 (2H, m), 7.47 (1H, d, J=16.1 Hz), 7.47 (1H, d, =0.7 Hz), 7.42–7.36 (2H, m), 7.27–7.21 (2H, m); m/z (ES+) 358 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[CH:29]1[CH2:31][CH2:30]1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13]([CH:29]3[CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C3CC3)cc2C1

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and tributylcyclopropylstannane. Yellow oil. MS (m/e): 286.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:24]=2)=[O:22])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(OCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC(OCCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-[5-[1-(4-isobutylphenyl)pentyloxy]valeryl]-1-indolyl]butyrate obtained in Ex. 36 was used in place of ethyl 4-[3-[8-(4isobutylphenyl) undecanoyl]-1-indolyl]butyrate to give 4-[3-[5-[1-(4-isobutylphenyl)pentyloxy]valeryl]-1-indolyl]butyric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25]([O:29][C:30]([NH:32][C@H:33]([C:39](O)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])([CH3:28])([CH3:27])[CH3:26].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.N1C=CC=NC=1>C(#N)C>[C:25]([O:29][C:30]([NH:32][C@H:33]([C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1cncnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A suspension of 5.78 g (25 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid and 100 ml of acetonitrile is stirred at room temperature and 5.25 g (52 mmol) of triethylamine is added. The mixture is stirred for 1 hr and the resulting solution is added to a solution of mixed anhydride prepared as follows. A suspension of 9.24 g (37.5 mmol) of N-t-butoxycarbonyl-L-glutamine and 200 ml of acetonitrile is stirred at 0° C. and 7.58 g (75 mmol) of N-methylmorpholine is added. The resulting solution is cooled to -30° C. and 4.52 g (37.5 mmol) of pivaloyl chloride is added and stirring is continued at -10°±5° C. for 1 hr. The pyrimidine acid solution is added, keeping the temperature below -10° C., and stirring is continued for 2 hrs and the reaction is placed in an ice bath and allowed to warm to room temperature overnight. The solvent is evaporated and the residue dissolved in ice water. The pH is adjusted to 3.2 with solid citric acid and the resulting precipitate is filtered, washed with water, and redissolved in ethanol. The solution is clarified by filtration and the filtrate evaporated. The residue is triturated with ether, filtered, and the precipitate washed with ether, and dried to give 7.5 g of 2-[4-(N-t-butoxycarbonyl-L-glutaminylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; [α]D23 -16° (cl, pH 7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][NH:15][CH3:16])[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.O1CCCC1.C(N(CC)CC)C.[CH2:29]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH2:38][CH3:39])[C:32]=1[C:40](=[O:44])[C:41](Cl)=[O:42])[CH3:30]>O>[CH2:29]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH2:38][CH3:39])[C:32]=1[C:40](=[O:44])[C:41]([N:15]([CH3:16])[N:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:42])[CH3:30]
Reactant: CNN=C(CS(C)(=O)=O)c1ccc(F)cc1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(CS(C)(=O)=O)c1ccc(F)cc1
Yield: 60.8 %

Procedure:
To a 30 ml volume two-necked flask, 1-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-2-methylhydrazine (5-2-4) (0.90 g) and anhydrous tetrahydrofuran (5 ml) were added under a nitrogen atmosphere, and added triethylamine (0.37 g) under cooling. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (0.88 g) was added dropwise below 0° C., and stirred under ice-cooling for 2 hours. The reaction mixture was added to water, and extracted with tert-butyl methyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (tert-butyl methyl ether) to give 1.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-1-methylhydrazine ((4-64)-(1)-39).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C1(N2CCC3C=[CH:37][C:38]([O:40]C4SC(NC(=O)C)=CN=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([NH:22][C:38](=[O:40])[CH3:37])=[CH:20][CH:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Reactant: CC(=O)Nc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1

Procedure:
Example 212 (E212) was prepared from 3-cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E211) using an analogous method to that described for Example 210 (E210); MS (ES+) m/e 357 [M+H]+.
Reaction SMILES: [OH-].[CH3:2][O:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)=[O:5].[F:14][C:15]1[C:16](=[O:49])[NH:17][C:18](=[O:48])[N:19]([CH:47]=1)[C@@H:20]1[O:46][C@H:24]([CH2:25][O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:22]([OH:23])[CH2:21]1>O1CCOCC1>[F:14][C:15]1[C:16](=[O:49])[NH:17][C:18](=[O:48])[N:19]([CH:47]=1)[C@@H:20]1[O:46][C@H:24]([CH2:25][OH:26])[C@@H:22]([O:23][CH2:10][C:9]2[CH:12]=[CH:13][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH2:21]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)cc1
Temperature: 25 °C

Procedure:
Pottasium hydroxide (4.30 g) and 1.70 g of 4-methoxycarbonylbenzyl bromide were added to a solution of 3.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 200 ml of dioxane. The mixture was stirred at room temperature for a day. The reaction mixture was concentrated under a reduced pressure. To the concentrate was added 200 ml of ethyl acetate for extraction. The extract was washed with water, dried over magnesium sulfate and concentrated. The concentrate was dissolved in 20 ml of a 80% aqueous solution of acetic acid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([SH:14])[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([S:14][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]
Reactant: COc1ccc(CCl)cc1
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1CO
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of allyl (2S)-2-(hydroxymethyl)-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (218 mg, 0.7 mmol) in THF (3 ml) were added at 0–5° C. 4-methoxybenzyl chloride (95 ml, 0.70 mmol) and triethylamine (98 ml, 0.7 mmol). The mixture was stirred for 3 hours and then at room temperature for 45 minutes. To the solution were added an aqueous sodium hydrogen carbonate solution and ethy acetate. The mixture was separated with a separating funnel. The organic layer was washed with a saturated aqueous sodium solution, dried over magnesium sulfate and the organic layer was removed in vacuo. The residue was purified with preparative TLC to give allyl (2S)-2-(hydroxymethyl)-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (150 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 87.1 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.15 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give 2-[[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.42 g, 87.2%) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([OH:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([O:13][CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)ccc(O)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)c(C(=O)OC)c1C
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of methyl 6-bromo-3-hydroxy-2-methylbenzoate (114b, 0.701 g, 2.86 mmol) in DMF (6 mL) was added cesium carbonate (0.997 g, 3.0 mmol) and then iodoethane (0.400 mL, 5.00 mmol). The reaction was stirred at 65° C. for 30 minutes. The reaction mixture was poured into ethyl acetate and washed with water (×2). The ethyl acetate layer was concentrated under vacuum to give methyl 6-bromo-3-ethoxy-2-methylbenzoate (114c, 0.75 g, 96% yield) as a clear oil.