Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC.[CH2:17]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CO>[CH2:17]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:9])[OH:6])=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCOC(OCC)P(=O)(CCCN)OCC
Reactant: CCCCCCCCc1ccc(C=O)cc1
Solvent: CO
Product: CCCCCCCCc1ccc(CNCCC[PH](=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
A mixture of 98.5 mg (0.389 mmol) of ethyl 3-aminopropyl (diethoxymethyl)phosphinate (from Step B) and 84.9 mg (0.389 mmol) of 4-octylbenzaldehyde in 1 mL of MeOH at rt was treated with 12.2 mg (0.194 mmol) Na(CN)BH3. The resulting reaction mixture was stirred at rt for 16 hr. The reaction was quenched with 0.5 mL of 12 N HCl, then heated up to 80° C. for 1 hr. The mixture was cooled and concentrated. HPLC purification (LC-2) afforded 60 mg (47%) of the title compound: 1H NMR (500 MHz, CD3OD) δ 0.88 (t, J=7.1, 3H), 1.25-1.33 (m, 10H), 1.59-1.66 (m, 4H), 1.90-1.96 (m, 2H), 2.63 (t, J=7.7, 2H), 3.09 (t, J=6.9, 2H), 4.12 (s, 2H), 7.03 (d, J=505.6, 1H), 7.27 (d, J=8.0, 2H), 7.38 (d, J=8.0, 2H); LC-1: 3.02 min; ESI-MS 326 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])[CH:11]=[CH:10][C:9]1=2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCCC2=O)c1ccc(-c2ccccc2)cc1
Yield: 86 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (143 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (150 mg, 0.43 mmol, 86% yield) as a white powder after purification by flash chromatography on silica gel (EtOAc/DCM 1/9 to 2/8).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 118° C.; 1H NMR (300 MHz, CDCl3): δ 7.31 (s, 1 H), 7.24 (s, 1 H), 7.13 (s, 1 H), 4.98–4.90 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.66 (dd, J=10.7, 5.9 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.13 (t, J=7.9 Hz, 2 H), 1.85–1.74 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Br2Cl (M+H)+: 489.0543; Found m/z 489.9534.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)[C:13]([OH:15])=O.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[CH2:35][NH2:36].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.O.C(Cl)CCl.CN(C=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[CH2:35][NH:36][C:13](=[O:15])/[C:12](=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)/[CH2:11][CH2:10][CH2:9][Cl:8]
Reactant: NCc1ccc(N2CCOCC2)c(F)c1
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)NCc2ccc(N3CCOCC3)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a DMF (4.0 mL) solution of 5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-valeric acid trifluoroacetic acid salt (200 mg) obtained in Example 418 and 3-fluoro-4-(morpholin-4-yl)benzylamine (112 mg), IPEA (231 mg), EDC (171 mg) and HOBT (120 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 135 mg of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=90:10). The physical properties of the compound are as follows.
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9]([CH:11]=[C:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[N:16]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][C:26]=2[CH3:41])[CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH2:6]([O:8][C:9]([CH2:11][CH:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[N:16]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][C:26]=2[CH3:41])[CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Yield: 43.2 %

Procedure:
In 30 ml of a 1:1 mixture of tetrahydrofuran and methanol were dissolved 0.30 g of 5-ethoxycarbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and 0.55 g of nickel chloride hexahydrate. Thereto was slowly added 0.26 g of sodium borohydride with ice-cooling and stirring. The mixture was stirred for 10 minutes with ice-cooling. The resulting insolubles were removed by filtration with Celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/n-hexane=1/1) to obtain 0.13 g of 5-ethoxycarbonylmethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:46]1[CH:50]=[CH:49][C:48]([CH2:51]O)=[CH:47]1.C(P(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:51][C:48]1[CH:49]=[CH:50][O:46][CH:47]=1)[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: OCc1ccoc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(Cc2ccoc2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide (0.015 g) in THF (0.5 ml) was treated with diisopropyl azodicarboxylate (0.01 ml), 3-furanmethanol (0.004 ml) and tri-n-butylphosphine (0.008 ml) and shaken at room temperature for 60 h. The mixture was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.015 g) as a colourless gum.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:20][CH3:21])=[C:6]([CH:12]([OH:19])[CH2:13][NH:14][C:15](=[O:18])[CH2:16]Cl)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[H-].[Na+]>O1CCCC1>[C:1]([C:4]1[C:5]([O:20][CH3:21])=[C:6]([CH:12]2[CH2:13][NH:14][C:15](=[O:18])[CH2:16][O:19]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CNC(=O)CO1
Reaction time: 1 h

Procedure:
To a solution of N-[2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]-2-chloroacetamide (170 mg, 0.50 mmol) (single enantiomer from step 3) in tetrahydrofuran (4 mL) cooled at 0° C., a mixture of sodium hydride (60% dispersion in mineral oil; 39 mg, 1.0 mmol) was added and stirred for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the crude residue as a single enantiomer, 61 mg, 41%. LCMS calculated for C14H17ClNO4 (M+H)+: m/z=298.1; found: 298.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[OH:6].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>C1COCC1>[Cl:20][C:21]1[CH:26]=[C:25]([O:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:4]([F:3])([F:18])[F:19])[N:24]=[CH:23][N:22]=1
Reactant: OC(c1ccccc1-c1ccoc1)C(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccoc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
Sixty percent NaH (12 mg, 0.3 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethanol (54 mg, 0.2 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, after which 4,6-dichloro-pyrimidine (30 mg, 0.2 mmol) was added. The mixture was then heated at 70° C. until the reaction was complete. After cooling, 5 ml of water was added to quench the reaction, and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give of 67 mg 4-chloro-6-[2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethoxy]-pyrimidine (yield: 94%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[O:5][CH2:4]1.[CH:26]1([CH2:32][CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:38]([O:37][C:35]([C@H:34]([NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[O:5][CH2:4]1)[CH2:33][CH2:32][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)C(=O)CCC1CCCCC1
Reactant: N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Yield: 18.5 %

Procedure:
Benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride (1.5 g) and ethyl 4-cyclohexyl-2-oxobutyrate (2.63 g) are subjected to reductive alkylation reaction in a manner similar to that described in Example 16, and the product is purified by silica gel column chromatography (hexane:ethal acetate=5:1-4:1). From the first fraction, 0.4 g of benzyl 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate is obtained as a colorless oil.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[I-:15].[Na+]>C(#N)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:5]([O:4][CH2:2][CH2:3][I:15])=[O:6])=[CH:9][CH:10]=1
Reactant: Cc1ccc(SC(=O)OC(C)Cl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(SC(=O)OCCI)cc1
Temperature: 50 °C

Procedure:
A 50 mL, three-neck, round-bottomed flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and a nitrogen inlet was charged with chloro-ester D1 (2 g, 8 mmol) and sodium iodide (1.8 g, 12 mmol) in acetonitrile (10 mL). The resulting slurry was warmed to 50° C. for 36 hours. The reaction mixture was cooled to room temperature and inorganic solids were removed by filtration. The clear organic phase was concentrated to give a viscous-oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E3b as a viscous-oil (1 g, ˜30% yield). 1H NMR (CDCl3, 400 MHz): δ 2.31 (d, J=5.6 Hz, 3H), 2.47 (s, 3H), 6.80 (q, J=6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=2)[N:10]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][CH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][C:9]1[N:10]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][C:8]=1[CH3:21]
Reactant: Cc1oc(-c2ccco2)nc1COc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccco2)nc1COc1cccc(CCl)c1
Yield: 98.6 %

Procedure:
To a mixture of (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol (8.0 g) and toluene (100 mL) was added thionyl chloride (4.00 g), and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:4, v/v) to give {4-[(3-chloromethylphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole as a colorless oil (8.40 g, yield 99%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[N:7]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6]=1[CH3:37])=[O:4].[OH-].[K+]>CS(C)=O.O>[CH3:24][O:23][C:21]([C:9]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:37])[N:7]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]=1[CH3:25])=[O:22]
Reactant: COC(=O)C1=C(C)N(CCCOCc2ccccc2)C(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1=C(C)N(CCCOCc2ccccc2)C(C)=C(C(=O)O)C1c1ccc(OC)c(OC)c1
Temperature: 100 °C
Yield: 42 %

Procedure:
After 2.15 g (4.2 mmols) of 1,4-dihydro-4-(3,4-dimethoxy-phenyl)-2,6-dimethyl-1-(3-benzyloxypropyl)-3,5-pyridine-dicarboxylic acid 3,5-dimethyl ester prepared by the process described in Japanese Patent Application Laid Open No. 1-316357 was dissolved in 8 ml of dimethylsulfoxide, 320 mg (4.9 mmols) of potassium hydroxide dissolved in 0.5 ml of water was added to the solution. The mixture was heated at 100° C. for 5 hours. After the solvent was distilled off under reduced pressure, 10 ml of water was added to the residue followed by extraction twice with ethyl acetate. After the aqueous phase was rendered acidic with diluted hydrochloric acid, extraction was performed 3 times with chloroform. After washing with water, the extract was concentrated and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-n-hexane=1:1) to give 875 mg of 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1-(3-benzyloxypropyl)-3,5-pyridinedicarboxylic acid 3-methyl ester as an oil. Yield, 42%. The obtained monocarboxylic acid was esterified by the method described in Example 1 to give 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1-(3-benzyloxypropyl)-3,5-pyridine-dicarboxylic acid 3-methyl-5-[3 -(4-methylpiperazino)propyl] ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=2)[C:9]1=[O:31].[CH2:32]([N:34]([CH2:45][CH3:46])[CH2:35][CH2:36][O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:33]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:42][C:41]3[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][N:34]([CH2:45][CH3:46])[CH2:32][CH3:33])=[CH:44][CH:43]=3)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=2)[C:9]1=[O:31]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCO)c2)C(=O)N(c2ccccc2Br)C3)cc1
Temperature: 180 °C
Yield: 17.8 %

Procedure:
200 mg (0.40 mmol) of 3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one was treated with 250 mg (1.2 mmol) of 4-[2-(diethylamino)ethoxy]aniline and the mixture heated at 180° C. for 40 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 45 mg (18%) of 3-(2-bromophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 98° C.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:18][C:16]1[N:17]=[C:13]([C:9]2[C:8]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[CH:7][C:6]([CH3:5])=[C:11]([CH3:12])[N:10]=2)[S:14][C:15]=1[CH3:19]
Reactant: Cc1cc(O)c(-c2nc(C)c(C)s2)nc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6-dimethyl-2-(4,5-dimethylthiazol-2-yl)-pyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (143 mg), cesium carbonate (209 mg), and 4-(N,N-dimethylamino)-pyridine (78 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the cooled solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (7.7 mg, yield 9%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[C@@H:9]([N:21]=[N+]=[N-])[C@@H:8]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:7]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[CH3:42][C:43](OC(C)=O)=[O:44]>CO.C1(C)C=CC=CC=1.Cl[Ni]Cl>[C:1]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[C@@H:9]([NH:21][C:43](=[O:44])[CH3:42])[C@@H:8]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:7]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1NC(C)=O)OCC
Yield: 76 %

Procedure:
To a stirred solution of 4 (2.50 g, 4.45 mmol) in MeOH (125 mL) a catalytic amount of NiCl2×6H2O was added followed by portions of NaBH4 (in total 0.34 g, 8.9 mmol) every 10 min until no starting material was observed on TLC (system). Ac2O (3 mL) was added after 50 min and the reaction mixture was diluted with toluene, filtered through a plug of silica and concentrated. The residue was purified by silica gel chromatography to give 5 (1.95 g, 3.4 mmol, 76%). 13C-NMR (CDCl3) 170.4, 169.7, 137.3, 137.0 remaining aromatic C 128.5-127.7, 75.3, 72.6, 72.4, 72.1, 72.0, 67.1, 61.91, 61.8, 61.8, 61.3, 61.2, 48.8, 48.6, 28.5 (d, J=142 Hz), 23.0, 20.6, 16.3, 16.2, 16.1; 31P-NMR (CDCl3) 29.5.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([I:18])=[CH:16][C:15]([CH2:19][CH3:20])=[CH:14][C:13]=1[CH:21]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.I[Si](C)(C)C.C(O)C>ClCCl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([NH:27][CH:21]([C:13]2[CH:14]=[C:15]([CH2:19][CH3:20])[CH:16]=[C:17]([I:18])[C:12]=2[O:11][CH2:10][CH2:9][OH:8])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=1)#[N:35]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(I)c1OCCOCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(I)c1OCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 7.1 g of ethyl (RS)-[2-(2-benzyloxy-ethoxy)-5-ethyl-3-iodo-phenyl]-(4-cyano-phenylamino)-acetate in 50 ml of dichloromethane was treated with 7.29 g of iodotrimethylsilane. After 12 hours at room temperature the same amount of iodotrimethylsilane was added and the mixture was stirred for 18 hours at room temperature. Then, ethanol was added. The reaction mixture was concentrated, poured on to ice/aqueous sodium bisulphite solution and extracted with ethyl acetate. The organic phases were washed with aqueous sodium hydrogen carbonate solution and ice-water, dried over sodium sulphate and concentrated. Crystallization of the residue gave 3.8 g of ethyl (RS)-(4-cyano-phenylamino)-[5-ethyl-2-(2-hydroxy-ethoxy)-3-iodo-phenyl]-acetate. Chromatography of the mother liquor on silica gel gave an additional 1.83 g of product; MS (ISP) m/z 495 (M+H)+, 517 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:5](O)=[N:6][CH:7]=1.O=P(Cl)(Cl)Cl.CCOC(C)=O.O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)[O:21][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nc3cc(Br)cnc3o2)cc1
Reaction time: 5 h
Yield: 64.8 %

Procedure:
Intermediate 56 (2.1 g, 5.4 mmol) was dissolved in Dioxane (30 ml) and added POCl3 (1.5 ml). This mixture was refluxed for 5 h. After 5 h, dioxane was removed on rotavapour to obtain the residue. Work up (EtOAc/H2O) of the residue afforded the crude. Crude was purified by column on 60-120 mesh silica gel using DCM as eluent to afford the titled compound (1.2 g). 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.46 (d, J 2.1, 1H), 8.41 (d, J 8.2, 2H), 8.24 (d, J 2.1, 1H), 7.83 (d, J 8.2, 2H).