Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[Cl-].O[NH3+:26].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:26])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: [NH3+]O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (3.00 g) is dissolved in ethanol (40 ml) and thereto are added hydroxyl ammonium chloride (1.29 g) and sodium acetate (1.53 g), and the mixture is stirred under nitrogen atmosphere at 60° C. for 1 hour and a half. The reaction solution is concentrated under reduced pressure, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue (3.3 g) is dissolved in methanol (40 ml), and thereto is added Raney nickel (5 g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (1.57 g). MS (m/z): 324 [M+H]+
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:19])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[PH2](O)=O>O>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:6][O:7][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCC(=O)O
Agent: O=[PH2]O
Solvent: O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)(COC(=O)CCCCCCC)COC(=O)CCCCCCC
Temperature: 190 °C

Procedure:
526 g (1.7 moles) of the POE(4) pentaerythritol prepared in (a) above was charged to a flask for esterification having standard apparatus for agitation, heating and distillation. Agitation and a dry nitrogen sparge were started, and 1074 g (7.4 moles) of caprylic acid (alkyl chain 98% minimum C8 acid value 388 mg KOH/g) and 0.8 g of hypophosphorous acid solution (50%) were added. The contents were heated to 180° C. with the removal of the water of esterification by distillation and held at 180°-190° C. until all water was removed. The hydroxyl number of the contents was checked, and the reaction was continued at 180°-190° C. until a maximum hydroxyl number of 5.0 mg KOH/g was reached, indicating greater than 99% conversion to the ester. A vacuum was pulled via the distillation system to 30 inches and the contents were stirred at 190° C. to remove the unreacted caprylic acid by distillation. The Acid value of the contents was checked, and the acid removal was continued at 180°-190° C. until a maximum acid value of 1.0 mg KOH/g was reached. The contents were then cooled to 70° C. and filtered to yield a compound of the formula
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:9]2[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 25.6 %

Procedure:
A mixture of 2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine (30.2 mg, 0.108 mmol), 2-(4-bromo-butyl)-isoindole-1,3-dione (33.5 mg, 0.119 mmol), DMF (3 mL), DIPEA (0.3 mL), and KI (4 mg) were heated to 110° C. for 4 h and overnight at 90° C. The solvent was removed and CH2Cl2 (20 mL) was added to the residue. It was washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted two more times with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 2:1 hexanes:EtOAc) provided 13.3 mg of 2-{4-[2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-azepin-1-yl]-butyl}-isoindole-1,3-dione as a film. 1H NMR(CDCl3) δ 0.53-0.59 (m, 1H), 0.65-1.00 (m, 3H), 2.36 (s, 6H), 2.36-2.41 (m, 1H), 2.47-2.50 (m, 2H), 3.02-3.24 (m, 5H), 4.72 (dd, 2H, J=9.6, 1.8 Hz), 5.80-5.83 (m, 2H), 6.90 (dd, 2H, J=7.5, 4.2 Hz), 7.23 (d, 2H, J=7.5 Hz), 7.67-7.73 (m, 2H), 7.76-7.86 (m, 2H), 8.35 (d, 2H, J=4.2 Hz).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:22]([CH:26]([CH3:28])C)[CH:23]([CH3:25])C.ClC(OCC(C)C)=O.N1CCCC1>C(Cl)Cl>[O:19]=[C:17]([N:22]1[CH2:23][CH2:25][CH2:28][CH2:26]1)[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
N-Boc-(5)-3-(pyridin-4-yl)alanine (0.500 g, 1.88 mmol) was dissolved in CH2Cl2 (15 mL) and DIEA (361 μL, 2.07 mmol) was added. The mixture was cooled to 0° C. and isobutyl chloroformate (270 μL, 2.07 mmol) was added. The mixture was stirred for 10 min and pyrrolidine (267 mg, 3.76 mmol) in CH2Cl2 (5 mL) was added. This mixture was stirred for 15 min at 4° C., 12 h at 25° C., washed successively with NaH2PO4, saturated sodium hydrogen carbonate, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue obtained was purify by column chromatography (SiO2) using a gradient of MeOH 0-10% [v/v] in EtOAc to give tert-butyl (R)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06172 (146 mg, 24% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]([NH:21][C@@H:22]([C:26](O)=[O:27])[CH:23]([CH3:25])[CH3:24])(=[O:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[C:18]([NH:21][C@@H:22]([C:26]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])=[O:27])[CH:23]([CH3:25])[CH3:24])(=[O:20])[CH3:19]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)N[C@@H](C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O)C(C)C

Procedure:
To a solution of the active drug, preferably 2'-deoxy-5-fluorouridine, an N-protected amino acid, preferably N-acetyl-D-valine, and triphenylphosphine in an anhydrous polar aprotic solvent is added diisopropylazodicarboxylate. Upon completion of the reaction, the mixture is concentrated under reduced pressure. The prodrug, preferably a compound of Formula 11, most preferably, 2'-deoxy-5'-O-(N-acetyl-D-valinyl)-5-fluorouridine, may be isolated by conventional means.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][C:7]([Cl:14])=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][C:7]([Cl:14])=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1cnc2cc(Cl)c(Cl)cc2n1
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cnc3cc(Cl)c(Cl)cc3n2)cc1

Procedure:
4-[N-Methyl-N-(6,7-dichloro-2-quinoxalinyl)amino]phenol was reacted with ethyl 2-bromopropionate, following essentially the same procedure as that described in Example 1 Part (b), to give ethyl 2-{4-[N-methyl-N-(6,7-dichloro-2-quinoxalinyl)amino]phenoxy}propionate, mp 79° C. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.25 (1H, s, quinoxaline hetero-ring proton); 7.9 (1H, s, quinoxaline benzo-ring proton); 7.8 (1H, s, quinoxaline benzo-ring proton); 7.2 (4H, m, phenoxy protons); 4.85 (1H, q, CH-CH3); 4.3 (2H, q, CH2 -CH3); 3.55 (3H, s, N-CH3); 1.7 (3H, d, CH-CH3); 1.3 (3H, t, CH2 -CH3).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[C:2]1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.C(Cl)(Cl)Cl.C(OCC)C.CO.[Cu]>[O:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)c1cnc2oc(C(=O)O)cc2c1
Agent: [Cu]
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: O=C(O)c1cnc2occc2c1
Temperature: 200 °C
Yield: 63.4 %

Procedure:
A suspension of furo[2,3-b]pyridine-2,5-dicarboxylic acid (5.35 g, 25.9 mmol) in quinoline (40 mL) containing copper dust (2.5 g) was heated under a nitrogen atmosphere at 200° C. for one hour. The cooled mixture was diluted with chloroform and filtered to remove suspended material. The product was extracted into sodium carbonate solution. This solution was carefully acidified with conc. hydrochloric acid and the precipitated product isolated by filtration. This material was dissolved in a large volume of diethyl ether/methanol, dried over anhydrous sodium sulfate and filtered through a pad of charcoal. The solvents were removed in vacuo and the residue triturated with diethyl ether to give pure product (2.68 g, 63% yield), mp: 274°-275° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:15])[CH:3]=1.Cl>CO.[Fe]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:15])[CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)cc1O
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(N)c(N)cc1O
Yield: 116.8 %

Procedure:
To a solution of methyl 4-amino-2-hydroxy-5-nitrobenzoate (step 5 of intermediate-1) (0.500 g, 2.35 mmol) in methanol (15.0 mL), iron powder (0.646 g, 11.7 mmol) was added with conc. HCl (5 mL). The reaction mass was refluxed for 2 h. Methanol was removed under vacuum and then water was added. The reaction mass was basified with Na2CO3 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.500 g of the desired product. 1HNMR (DMSO-d6): δ 3.76 (s, 3H), 4.29 (s, 2H), 5.64 (s, 2H), 6.01 (s, 1H), 6.89 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:4]=[N:3]1.[CH3:16][CH2:17][Mg+].[Br-].CCOCC>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:16][CH3:17])[CH:4]=[N:3]1
Reactant: CC[Mg+]
Reactant: Cc1c(/C=N/S(=O)C(C)(C)C)cnn1C
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(NS(=O)C(C)(C)C)c1cnn(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (E)-N-((1,5-dimethyl-1H-pyrazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (Step A5A) (600 mg, 2.64 mmol) in CH2Cl2 (15 ml) was added a 3.0 M solution of EtMgBr in ether (1.76 ml, 5.28 mmol) at −48° C. under nitrogen. After being stirred for 120 min, the reaction mixture was allowed to warm to rt slowly over 2 h and further stirred for 15 h at rt. The reaction was quenched by addition of sat. NH4Cl aq., diluted with water, and the aqueous layer was extracted with CH2Cl2 3 times. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2: MeOH=50:1 to 20:1) to give the desired product as a pale yellow oil (650 mg, >96% yield). 1H NMR (270 MHz, CDCl3) δ 0.87 (3H, t, J=5.4 Hz), 1.17 (9H, s), 1.77-1.85 (2H, m), 2.25 (3H, s), 3.78 (3H, s), 3.31 (1H, brs), 4.16-4.22 (1H, m), 7.31 (1H, s).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][C:11]=3[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]1>>[OH:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][C:8](=[O:19])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[C:16]2[O:17][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1oc2c(O)cccc2c(O)c1-c1ccccc1
Product: O=c1oc2c(O)cccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 60.2 %

Procedure:
Prepared as described in Example 30 from 45.9 g. (0.18 mol) of 3-phenyl-4,8-dihydroxy-coumarin and 31.5 g. (0.21 mol) of 2-morpholino-1-chloroethane. After recrystallisation from ethane, 39.8 g. of a white substance are obtained; M.P. 190°-191° C. Yield 60.2% (theoretical yield 66 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C[O:21][C:22](=[O:33])[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([CH3:24])[C:22]([OH:33])=[O:21])=[CH:30][CH:29]=1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Reactant: Cc1cnc2c(Cl)cccc2c1-c1cccc(O)c1
Product: Cc1cnc2c(Cl)cccc2c1-c1cccc(OCc2ccc(C(C)C(=O)O)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 41, substituting 3-(8-chloro-3-methyl-quinolin-4-yl)-phenol and 2-(4-bromomethyl-phenyl)-propionic acid methyl ester. MS (ESI) m/z 432.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH:22]1([N:19]2[CH2:20][CH2:21][CH:16]([C:14]3[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:38])=[O:3])[CH:11]=[C:12]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)[CH:13]=3)[CH2:17][CH2:18]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(C3CCCCC3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(C3CCCCC3)CC2)c1
Temperature: 50 °C

Procedure:
To a solution of a mixture of 2-[5-(1-cyclohexyl-piperidin-4-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester and methyl ester (50 mg, 0.09 mmol) in MeOH (1 mL) was added 3N NaOH (0.100 mL) and heated to 50° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 2-[5-(1-cyclohexyl-piperidin-4-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid. 1H-NMR (DMSO-d6): δ 0.82 (d, 6H), 1.00-1.45 (m, 6H), 1.54 (m, 2H), 1.74-2.06 (m, 9H), 2.83-3.22 (m, 4H), 3.46 (bd, 2H), 3.63 (t, 1H), 7.20 (s, 1H), 7.39 (s, 1H), 7.47 (s, 1H), 7.78 (dd, 4H), 12.35 (bs, 1H); Calcd for C30H38F3NO2 (M+H) 502.62, Found 502.4
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>CN(C)C=O>[NH:11]([CH2:10][CH2:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:3][C:2]=2[N:1]=[C:22]1[OH:23])[C:12]([CH3:13])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2)cc1N
Solvent: CN(C)C=O
Product: CC(=O)NCCn1c(O)nc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
To a solution of 580 mg (2.0 mmol) of 6-(3-amino-4-acetylaminoethylamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone in 50 ml of dimethylformamide, 325 mg (2.0 mmol) of carbonyldiimidazole are added at 50° C. After 45 minutes at 50° C. the mixture is evaporated to dryness and the residue is mixed with 10 ml of water. The product precipitated is suction filtered, washed with 5 ml of water and dried.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[Cl:13][C:14]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][C:18]=1[F:26].Cl>C1COCC1>[C:7]([CH:9]([C:24](=[S:25])[NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:14]=2[Cl:13])=[C:18]([F:26])[CH:19]=1)[C:10]([NH2:12])=[O:11])#[N:8]
Reactant: N#CCC(N)=O
Reactant: Fc1cc(N=C=S)ccc1Oc1cc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(C(N)=O)C(=S)Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 5 °C
Yield: 82.5 %

Procedure:
To a solution of potassium tert-butoxide (0.6 g, 5.36 mmol) in 10 ml of anhydrous THF was added 2-cyanoacetamide (0.45 g, 5.36 mmol) under argon. The mixture was cooled to 5° C. and added dropwise to a solution of 4-(2,5-dichloro-phenoxy)-3-fluoro-phenylisothiocyanate (1.53 g, 4.87 mmol) in 5 ml of dry THF with stirring under argon. After 15 min of stirring at 5° C., this reaction mixture was warmed to room temperature and stirred for another 2 h. The reaction mixture was poured into 200 ml of ice water with stirring and acidified with 10% HCl. The solid was filtered and washed with water. After drying in vacuo, the crude product (1.6 g, 82.5%) was obtained in sufficient purity for the next step.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.[OH-].[K+]>O1CCCC1.C(N(CC)CC)C>[CH:24]1([C:27]([NH:6][C:5]2[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: CN(C)c1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C2CC2)c(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
2-Acetyl-4,5-dimethoxyaniline (2.0 g) was dissolved in tetrahydrofuran (50 ml), and to the mixture were added triethylamine (2.2 g) and dimethylaminopyridine (400 mg), and then a solution of cyclopropylcarbonyl chloride (1.7 g) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 3 hours. After the addition of a 10% aqueous solution of potassium hydroxide, the mixture was stirred and extraction was conducted with chloroform. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 50 g). Elution with a mixed solvent of n-hexane (60 parts) and ethyl acetate (40 parts) gave N-cyclopropylcarbonyl-2-acetyl-4,5-dimethoxyaniline (2.5 g). This amide product (1.0 g) was suspended in t-butanol (50 ml), and potassium t-butoxide (2.1 g) was added to the suspension, and the mixture was heated under reflux for 15 hours. After the mixture was left to cool, extraction was conducted with a mixed solvent of chloroform (90 parts) and methanol (10 parts). The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g). Elution with a mixed solvent of chloroform (97 parts) and methanol (3 parts) gave 2-cyclopropyl-6,7dimethoxy-4(1H)-quinolone (compound 95, 580 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:16]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O>[CH3:35][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:7]=2)=[O:9])=[CH:16][C:15]=1[N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:24]=2)[N:19]=[CH:18]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: C1CCNC1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 100 °C

Procedure:
A mixture of 3-[5-(2-chloropyrid-4-ylcarbonylamino)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (0.18 g) and pyrrolidine (2 ml) was stirred and heated to 100° C. for 16 hours. The mixture was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed with water and dried under vacuum at 40° C. There was thus obtained the title compound (0.11 g); NMR Spectrum: (DMSOd6) 1.94-1.97 (m, 4H), 2.04 (s, 3H), 2.22 (s, 3H), 2.45-2.49 (m, 4H), 3.25-3.28 (m, 4H), 3.4-3.45 (m, 4H), 6.85 (s, 1H), 6.96 (d, 1H), 7.42 (d, 1H), 7.42 (d, 1H), 7.44 (s, 1H), 7.62 (s, 2H), 7.77-7.79 (m, 2H), 8.07 (s, 1H), 8.2 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+ 524.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:8]([S:12][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[S-]
Reactant: O=Cc1ccc(F)cc1Br
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(C=O)c(Br)c1
Temperature: 50 °C

Procedure:
To 2-bromo-4-fluorobenzaldehyde (150 mg, 0.74 mmol) in methanol (2 mL) was added sodium thiomethoxide (80 mg, 1.1 mmol). The reaction mixture was heated to 50° C. for 1 hour. After cooling, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and used as such.
Reaction SMILES: Br[C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:5](=[O:16])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])[N:7]=1.[CH3:26][O-:27].[Na+]>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:4]2[C:3](=[O:25])[C:2]([O:27][CH3:26])=[N:7][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:14][OH:15])[C:5]2=[O:16])=[CH:19][CH:20]=1
Reactant: O=c1c(Br)nn(-c2ccccc2CO)c(=O)n1Cc1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(-c2ccccc2CO)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
According to Scheme 2 Step 4: To a stirred solution of 6-bromo-4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.330 g, 0.79 mmol) in DMF (10 ml) was added, dropwise, at 0° C., 2M solution of sodium methoxide (0.79 mmol, 0.40 ml). The mixture was stirred 1 hour at 0° C. then quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. 270 mg (Yield=92.5%) of 4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione were recovered. The product was pure enough to be used in the next step without any purification.