Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5]2.C([Li])CCC.[CH3:35][N:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1>C1COCC1>[CH3:35][N:36]1[CH2:41][CH2:40][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][N:6]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]3)([OH:42])[CH2:38][CH2:37]1
Reactant: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3c(c2)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C3)CC1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Under nitrogen, a solution of 5-bromo-2-trityl-2,3-dihydro-1H-isoindole (2.03 g, 4.6 mmol) in THF (20 mL) was cooled to −78° C. n-Butyllithium solution (2.5M in hexanes, 2.0 mL, 5 mmol) was added over 5 minutes, then after 10 minutes, 1-methyl-4-piperidone was added dropwise. After a further hour, the cooling bath was removed and the reaction quenched with sodium bicarbonate solution. The mixture was extracted with ethyl acetate then the organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica (gradient elution with 2M methanolic ammonia/dichloromethane, 0% to 5%) to afford 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-ol as a pink foam (1.25 g, 57%). 1H NMR (MeOH-d4) 7.56 (6H, dd), 7.28 (6H, t), 7.25-7.21 (2H, m), 7.15 (3H, t), 7.03 (1H, d), 3.92 (2H, s), 3.91 (2H, s), 2.70 (2H, d), 2.53 (2H, td), 2.33 (3H, s), 2.06 (2H, td), 1.70 (2H, d). MS: [M+H]+ 475.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:22][CH:23]=1
Reactant: Sc1ccncc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccncc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-mercapto-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[F:9])[NH2:5].[Br:13]Br>C(O)(=O)C>[Br:13][C:3]1[C:2]([Cl:1])=[C:8]([F:9])[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5]
Reactant: BrBr
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(Cl)c1Br
Temperature: 0 °C

Procedure:
Into a solution of 3-chloro-4-fluoro-6-nitroaniline (200.3 g) in acetic acid (1.5 litter) was added bromine (339 g) during a period of 80 minutes at 50° C. under stirring and stirred for further 2 hours. The reaction mixture was poured into ice water (3 litter) and the resulting precipitate was collected by filtration, washed with water and added to a mixture of concentrated hydrochloric acid (300 ml) and ethanol (1.2 litter). The mixture was refluxed for 8.5 hrs. After cooling, the precipitate was collected by filtration and washed with water and dried. The title compound thus obtained weighed 235.6 g as yellow needles, mp 146°-147° C.
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[C:19](OC(=O)C)(=O)[CH3:20]>N1C=CC=CC=1>[C:19]([C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])#[CH:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Solvent: c1ccncc1
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A dry 250 mL round-bottomed flask was charged with 5-iodouridine (10 g, 27 mmol Aldrich), anhydrous pyridine (30 mL) and acetic anhydride (30 mL). The reaction was stirred at room temperature for 30 minutes under a nitrogen atmosphere and the solvent removed in vacuo. The compound was diluted with toluene (2×50 mL) and the toluene removed in vacuo. The product was purified on a 75 g flash chromatography column which was eluted with 90:10 (v:v) CHCl3:MeOH. The appropriate fractions were combined and concentrated to give the title compound as a white foam. This was used directly in the next stage.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:3]2[CH:7]=[N:6][N:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: c1nnn[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Brc1ccc(Cn2cnnn2)cc1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Dimethyl sulphoxide (10 mL, dried over 4 A molecular sieve) was added to potassium hydroxide (1.12 g, 0.02 mol, crushed pellets) and the mixture was stirred for 5 minutes. 1H-Tetrazole (0.35 g, 0.005 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (1.87 g, 0.0075 mol) was added and the mixture was cooled briefly and stirred for a further hour before adding water (50 mL). The mixture was extracted with ether (3×80 mL) and each extract was washed with water (3×50 mL). The combined ether layers were dried over MgSO4 and the solvent using removed in vacuo. The residue was chromatographed on silica gel with CHCl3:MeOH (40:1) as eluent yielding the sub-title compound (0.98 g, yield: 82%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13]([NH:15][C@@H:16]1[C:21](=[O:22])[O:20][C:18](=[O:19])[CH2:17]1)=[O:14].Cl>O>[CH:13]([NH:15][C@H:16]([C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22])[CH2:17][C:18](=[O:19])[OH:20])=[O:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: Cl
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To 200 ml of water, 50% caustic solution is added to adjust the pH to 9.5. To the aqueous solution, L-phenylalanine (30 g, 0.181 mole) is dissolved while adding 11.8 ml of 50% caustic solution. After cooling the resultant solution to between -3° C. to +3° C., 14.5 ml of 50% caustic solution and formyl-L-aspartic anhydride (28.6 g, 0.199 mole) is added over a 1 hour period and the resulting reaction mixture is stirred for 1/2 hour at between -3° C. to 3° C. Upon lowering the pH of the mixture using 34.4 ml of hydrogen chloride, a solid precipitate is produced and it is separated by filtration. The precipitate is dried to obtain the desired formyl-α-L-aspartyl-L-phenylalanine (42.6 g, 0.138 mole). The remaining filtrate is collected and acidified to a pH of 6.0 with 9.4 ml of concentrated hydrogen chloride to produce the precipitate. The precipitate is filtered and dried to obtain additional formyl-α-L-aspartyl-L-phenylalanine (2.9 g, 0.009 mole). TLC analysis shows that there is no trace of β-isomer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Br:11])[CH:5]=1.B1([C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)OCCCO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=[C:6]([Br:11])[CH:5]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)cc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 67.6 %

Procedure:
To the solution of Methyl-3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol) in toluene (50 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.24 g, 7.63 mmol), potassium carbonate (8.11 g, 58.7 mmol) and tetrakis(triphenylphoshine)palladium (O) (0.34, 0.29 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 80° C. under argon for 10 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 3% methanol in dichloromethane to isolate Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g, 67%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Li+:33]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[Li+:33]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 40 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of methyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 19) (1.63 g, 3.84 mmol) in methanol (20 mL) was added lithium hydroxide (4.61 mL, 4.61 mmol). The resulting mixture was stirred at 40° C. for 6 h, whereupon it was concentrated under reduced pressure to give lithium 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (1.65 g, 100%) which was not purified but directly used in the subsequent step. LCMS (Formate, 2 min), Rt=0.87, MH+=411.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:26][CH3:27])[CH:11]=[C:12]([O:17][C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:30])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:30])=[CH:13][C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:11][C:10]=2[O:26][CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(OC)cc(OC(=O)c3ccccc3)cc2c1=O
Product: CCCC(=O)c1cnc2c(OC)cc(OCc3ccccc3)cc2c1Cl

Procedure:
3-Butyryl-6-benzoyloxy-8-methoxy-4(1H)-quinolone (18.0 g) was heated under reflux in phosphorus oxychloride (100 ml) for 40 minutes. The solvent was evaporated and the residue dissolved in dichloromethane and poured into a vigorously stirred mixture of ice and sodium hydrogen carbonate solution. The organic phase was washed with sodium hydrogen carbonate solution, dried, filtered and evaporated to give 3-butyryl-6-benzyloxy-4-chloro-8-methoxy quinoline as a brown oil (25 g).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C.C(OCC)C>[C:2]([O:6][C:7](=[O:17])[C@@H:8]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)N1CCCCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of L-phenylalanine tert-butyl ester hydrochloride (3.05 g) in DMF (50 ml) were added potassium carbonate (5.38 g) and 1,5-dibromopentane (2.98 g), and the mixture was stirred at 80° C. for 2 hours, and then at room temperature for 22 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: methylene chloride-methanol) to give 1.24 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[O:10]=[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[O:17][C:18](=O)[O:19]N1C(=O)CCC1=O.C(N(CC)CC)C>C(#N)C>[O:10]=[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[O:17][C:18](=[O:19])[O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OCC(COC(=O)ON2C(=O)CCC2=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 122 %

Procedure:
To a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (0.4 g, 3.0 mmol) in acetonitrile (10 mL) was added carbonic acid bis-(2,5-dioxo-pyrrolidin-1-yl) ester (1.15 g, 4.5 mmol) and triethylamine (0.84 mL, 6.0 mmol). After stirring at ambient temperature for 10 min, the mixture was concentrated at reduced pressure, sat. NaHCO3 (50 mL)was added, and the solution was extracted with ethyl acetate and organic phase was separated and concentrated to obtain 1.0 g of crude product that was used without further purification in the next step. MS (APCI) m/z: 273 [M+H]+ 1H NMR (DMSO-d6) δ: 4.50 (m, 1H), 4.40-4.29 (m, 2H), 4.04 (m, 1H), 3.73 (dd, J=6.0 and 9.0 Hz, 1H), 2.80 (s, 4H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.O.[Pt]=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:11]3[N:10]=[C:9]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]=3[CH:15]=[N:16]2)=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: O=c1c2cnn(-c3ccc([N+](=O)[O-])cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Agent: O=[Pt]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (100 mg, 0.195 mmol) is dissolved in 20 mL of dioxane. Platinumoxide (11.0 mg, 0.0484 mmol) was added as a slurry in 2 mL of water to the reaction mixture under a nitrogen atmosphere. The mixture was placed under balloon pressure of hydrogen and the reaction is completed within 1 h. The solids are filtered off and the solution is concentrated. Purification by reverse phase HPLC affords the title compound. 1H NMR (DMSO, 400 MHz) δ 8.78 (s, 1H), 8.15 (d, 2H), 7.97-7.95 (m, 2H), 7.90 (m, 3H), 7.84 (dd, 1H), 7.78 (m, 1H), 7.30 (d, 2H), 6.00 (s, 2H). HPLC-MS calculated for C23H14Cl3N5O (M+H+) 482.0. Found: 482.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH3:32])[N:25]([CH2:26][CH2:27][NH2:28])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH3:32])[N:25]([CH2:26][CH2:27][NH:28][C:9](=[O:11])[CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: O=C(O)Cc1cccc(O)c1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)Cc1cccc(O)c1
Yield: 18.3 %

Procedure:
Using the general method of Example 97 3-hydroxyphenyl acetic acid (0.26 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.13 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(3-hydroxyphenyl)acetamide as a white powder, m.p. 208–210° C. Analysis: Calculated for C23H26N6O2: % C, 66.01; % H, 6.26; % N, 20.08; Found: % C, 65.63; % H, 6.11; % N, 20.30. HRMS (EI) calcd for C23H26N6O2 (M+) 418.2117 found 418.2109.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N+:17]([O-])=O)=[CH:13][N:12]([CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:11]1=[O:29])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:20][C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:11]1=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c([N+](=O)[O-])cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Yield: 67.9 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-5-nitro-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (173 mg, 0.34 mmol) in methanol (5 mL) was added 10% palladium/carbon (36 mg) in a nitrogen atmosphere, followed by stirring at room temperature for 1 hr in a hydrogen atmosphere. After removal of the palladium/carbon by filtration through celite, the filtrate was concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/1/1) and dried in a vacuum to afford 109 mg of the compound as a colorless oil (yield 66%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:42][C:43]1[O:44][C:45](=[O:49])[O:46][C:47]=1[CH3:48].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:48][C:47]1[O:46][C:45](=[O:49])[O:44][C:43]=1[CH2:42][O:37][C:36](=[O:38])[CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(=O)oc1COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Yield: 32.3 %

Procedure:
A solution of 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoic acid (450 mg, 0.82 mmol), 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (146 mg, 0.99 mmol) and potassium carbonate (170 mg, 1.23 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (175 mg, yield 32%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]2[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:14]1[N:19]=[C:18]([OH:20])[C:17]([Cl:21])=[CH:16][N:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:21][C:17]1[C:18]([OH:20])=[N:19][C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:10]3[CH2:11][CH2:12]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:15][CH:16]=1
Reactant: Oc1nc(Cl)ncc1Cl
Reactant: N#Cc1cc(N)ccc1C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: N#Cc1cc(Nc2ncc(Cl)c(O)n2)ccc1C1CC1
Temperature: 110 °C

Procedure:
5-amino-2-cyclopropylbenzonitrile (25.4 mmol; from the previous reaction) was transferred to a large reaction tube with magnetic stir bar in 250 mL isopropyl alcohol. 2,5-dichloropyrimidin-4-ol (4.20 g, 25.5 mmol) and p-toluenesulfonic acid monohydrate (14.50 g, 76.2 mmol) were weighed out and added. This was heated overnight at 110° C. After that time, it was allowed to cool to room temperature and an orange precipitate was filtered off. The filtrate was concentrated to half volume, and a second precipitate crashed out which was filtered off. Again, the filtrate was concentrated to half volume and a third precipitate crashed out which was filtered off. Finally, further concentration crashed out a fourth precipitate which was collected and washed with hexane. This was dried on high vacuum to give 5.63 g of 5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile as a tosylate salt, containing 1.2 equivalents of p-toluenesulfonic acid (45% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19])[CH:6]=1)[CH3:3].[CH3:23][NH2:24]>C(O)C>[N+:18]([CH:17]=[C:16]([NH:24][CH3:23])[NH:15][CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1)([O-:20])=[O:19]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1cc(CN(C)C)ccn1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(CN(C)C)ccn1
Reaction time: 36 h

Procedure:
A solution of 1-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-1-methylthio-2-nitroethylene (0.85 g) in 16% methylamine in ethanol (40 ml) was allowed to stand at ambient temperature for 36 hours. The solvent was removed in vacuo and the product was purified by chromatography on a silica gel column eluted with 15% methanol/chloroform followed by recrystallisation from acetonitrile to give 1-nitro-2-methylamino-2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]ethylene (0.32 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21]
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 99.9 %

Procedure:
N-(2-Fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (VII) (5 g) and platinum dioxide (0.2 g) were suspended in ethyl acetate (50 ml), and the resultant suspension was allowed to catalytic reduction at room temperature under atmospheric pressure until 1.3 liters of hydrogen was taken up. The reaction mixture was filtered and concentrated to give 4.48 g of N-(2-fluoro-5-aminophenyl)-3,4,5,6-tetrahydrophthalimide (VIII). M.P., 117°-119° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:13]([CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:18][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(Cc1ccc(O)cc1)C(=O)OCC
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCC(Cc1ccc(OCCOC2CCCCO2)cc1)C(=O)OCC
Yield: 83.7 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-(4-hydroxybenzyl)caproate (2.40 g), which is the product of Reference example 6(c), 2-(2-bromoethoxy)tetrahydropyran (1.63 g) and potassium carbonate (3.23 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (2.47 g) as a syrup.