Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29](OC)=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
To a solution of methyl 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (10 g) and NaBH. (2.2 g) in tetrahydrofuran (100 ml) was added dropwise methanol (19 ml) during 80 minutes. The mixture was heated for 27 further hours under reflux, and the reaction mixture was concentrated to dryness. To the concentrate was added water, which was neutralized with conc. HCl. Crystals thus separated were collected by filtration. Recrystallization from methanol afforded colorless needles (8.8 g, 93%), m.p. 203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1C=C[N:17]=[C:16]1[CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O.NN.[CH2:35](O)[CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:35]=[CH:36][N:17]=[C:16]2[CH2:20][N:21]=1
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Reactant: CCO
Agent: NN
Product: Clc1ccccc1C1=NCc2nccn2-c2ccccc21

Procedure:
In the manner given in Example 33, 2'-chloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].N1([CH:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:27][C:28](=[O:30])[O-:29])C=CC=N1>>[C:34]([O:33][C:32](=[O:38])[N:31]=[C:26]([NH:27][C:28]([O:29][C:5]([CH3:6])([CH3:20])[CH3:4])=[O:30])[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][CH:18]=[C:7]([CH2:8][CH2:9][C:10]([OH:17])([CH2:11][CH2:12][CH3:13])[CH2:14][CH2:15][CH3:16])[CH:6]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Reactant: CCCC(O)(CCC)CCc1cccc(CCCN)c1
Product: CCCC(O)(CCC)CCc1cccc(CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate following the method described in Example 168 gives tert-butyl(tert-butoxycarbonylamino)(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylamino)methylenecarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:34].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:34])=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(F)c(C(F)(F)F)c1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(F)c(C(F)(F)F)c1

Procedure:
According to the general procedure (GP12), chlorination of 3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (844 mg; 1.482 mmol), and purification by FC (DCM/MeOH=60/1) gave the expected product 1-chloro-3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange solid (186 mg; 26%). LC-MS: tR=1.04 min.; [M+H]+=478.39 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([NH:18]CC3C=CC(OC)=CC=3)=[C:12]2[N:11]=[C:10]1[CH3:29].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([NH2:18])=[C:12]2[N:11]=[C:10]1[CH3:29]
Reactant: COc1ccc(CNc2cc(C)nc3c2nc(C)n3-c2ccc(Cl)cc2Cl)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 0 °C

Procedure:
Stir a solution of [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](4-methoxybenzyl)amine (4.23 g, 10 mmol), anisole (3.2 mL, 29.6 mmol), trifluoroacetic acid (80 mL), and concentrated sulfuric acid (2 mL) at ambient temperature for 14 h. Add the resulting mixture dropwise to ice-water and dilute with NaHCO3. Filter the resulting precipitate and wash thoroughly with water to obtain the title compound as a brown solid.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15]>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.02 His: 0.99 Phe: 0.96 Ala: 0.98
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([C:22](OCC)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:22][OH:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
To a stirred solution of ethyl 4-[3-(benzyloxy)-5-fluorophenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (1.54 g, 4.3 mmol) in ether (150 ml) was added lithium aluminium hydride (0.16 g, 4.3 mmol) in three portions. The resulting suspension was stirred at room temperature under a nitrogen atmosphere for 20 min. Excess of hydride was destroyed by adding saturated aqueous sodium sulfate. The mixture was diluted with 10% aqueous sulfuric acid (100 ml) and the organic layer was separated. The ethereal layer was washed with water (100 ml), saturated aqueous sodium bicarbonate (100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness to afford the titled compound as white solids (1.28 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([NH2:15])[CH:5]=1.[CH:17](O)=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][C:13]#[N:14])[CH:17]=[N:15][C:6]=2[CH:5]=1)=[O:16]
Reactant: COC(=O)c1ccc(NCCC#N)c(N)c1
Reactant: O=CO
Product: COC(=O)c1ccc2c(c1)ncn2CCC#N
Temperature: 50 °C
Yield: 95 %

Procedure:
To 3-amino-4-(2-cyano-ethylamino)-benzoic acid methyl ester (4.0 g) was added formic acid (25 ml) and the mixture heated to 50° C. for 3 h. It was then concentrated and the residue recrystallised from EtOAc to afford 4.0 g (95%) of 1-(2-cyanoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 230 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.95 (t, 2H), 4.0 (s, 3H), 4.55 (t, 2H), 7.4 (d, 1H), 8.1 (m, 1H), 8.15 (s, 1H), 8.55 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([NH:45][C:14]([NH:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:11]=2)=[O:22])[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 89 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.203 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.55 (d, 1H), 7.68 (m, 2H), 7.55 (m, 2H), 7.41 (m, 4H), 7.20 (d, 1H), 6.96 (d, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>C(Cl)Cl>[C:6]([NH:1][CH2:2][CH2:3][OH:4])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To 0° C. cold of CH2Cl2 solution (300 mL) of 2-aminoethanol (10.8 g, 0.177 mole) and TEA (26.8 g; 0.265 mole) was added slowly a CH2Cl2 solution (50 mL) of benzyl chloroformate (33.2 g, 0.194 mole). After complete addition, the resulting solution was gradually warmed to room temperature and stirring was continued at room temperature overnight. The reaction was worked up and purified by flash column chromatography on silica gel, affording 22.8 g in 66% yield of title compound. 1H NMR (CDCl3): δ 7.34-7.40 (m, 5H), 5.20-5.32 (m, 1H), 5.14 (s, 2H), 3.74 (q, 2H), 3.37 (q, 2H), 2.38 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[C:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>ClC(Cl)C>[C:25]1([CH2:31][CH2:32][NH:33][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: NCCC1=CCCCC1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@H](CNCCC1=CCCCC1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-(1-cyclohexenyl)ethylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS-80%, [M+H]+=411.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO>[C:40]([O:39][C:37]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (3.0 g) was dissolved in THF-methanol (4:1, 10 mL), 2 N lithium hydroxide solution (4.8 mL) was added, and the resulting reaction mixture was stirred at 0° C. for 5 h. The reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (2.9 g). LC-MS (m/z) 614. The Boc group of (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester may be removed to provide the compound Intermediate C (“Intermediate C”).
Reaction SMILES: Cl[C:2]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCOC(C)=O>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)(Cl)c1ccc(I)cc1
Solvent: CCOC(C)=O
Product: CC(C)(c1ccc(I)cc1)N1CCOCC1

Procedure:
To a solution of 1-(1-Chloro-1-methylethyl)-4-iodobenzene (2 g, 7 mmol) in morpholine (10 mL) is added KI (0.5 g). The mixture is irradiated under microwave irradiation for 20 min at 160° C. (×10). The combined reaction mixtures are dissolved in EtOAc, washed with water, brine and dried over sodium sulphate. The solvent is concentrated under vacuum and purified by column chromatography (50% EtOAc in pet ether) to afford title compound as a light brown liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.65-7.63 (dd, J=2, 6.8 Hz, 2H), 7.30-7.28 (dd, J=2, 6.8 Hz, 2H), 3.53-3.65 (t, 4H), 2.33-2.31 (t, 4H), 1.22 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+]>C(OCC)(=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 6 h

Procedure:
4-Hydroxy-1,1'-biphenyl (61.3 g, 0.36 mol) and decyl bromide (218 g, 0.72 mol) were heated at 80° C. To this solution, a 50% potassium hydroxide aqueous solution (57 g) was added dropwise at 80° C. and then stirring was continued for 6 h at the same temperature. After cooling, the mixture was diluted with ethyl acetate, the organic layer was separated, washed with H2O and dried over MgSO4. The solvent was removed under reduced pressure and the resultant residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to give the title compound as a white crystals; yield: 70 g (62.6%); mp 70.0°-73.0° C.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1ccccn1
Product: CCCc1c(OCCCCCC(=O)NCCCCc2ccccn2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 2-pyridine butanamine according to procedure A and the product was purified by crystallization from ether-hexane to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(2-pyridinyl)butyl]hexanamide, the title compound, mp 63°-66° in 76% yield,
Reaction SMILES: [Mg].BrCCBr.CC([Si](C)(C)[O:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)(C)C>C1COCC1>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][OH:11])=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1

Procedure:
To 2.67 g of magnesium (shavings) in 5 ml of THF under inert atmosphere and at ambient temperature, is added in 50 minutes at the reflux after priming to 1.2-dibromoethane, a solution of 32.9 g of (1.1-dimethylethyl) dimethyl [[3-(4-bromophenyl)propyl]oxy]silane (stage C) in 100 ml of THF and maintained 5 hours at reflux. (Heading by iodometry: 0.86M)
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([OH:17])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:5]2=[O:27])[CH2:3][CH2:2]1.C(#N)C.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([O:17][S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:5]2=[O:27])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)cc(O)c2c(=O)n(C3CC3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 110 °C
Yield: 82.4 %

Procedure:
To 3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 10 (18 g) obtained in Step 5 were added acetonitrile (180 ml), tosyl chloride 11 (11 g) and triethylamine (8 ml), and the mixture was stirred with heating under reflux at 110° C. for 1 hr. The reaction mixture was concentrated under reduced pressure. Water (100 ml) was added to the residue and the mixture was extracted with chloroform (800 ml). The organic layer was washed with brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform:diethyl ether=1:5 to give toluene-4-sulfonic acid 3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 12 (21 g, 82%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].I[CH3:20].O>CN(C)C=O>[CH3:20][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: CI
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
4.0 g (18.3 mmol) of ethyl 2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in N,N-dimethylformamide (100 mL), and under a nitrogen stream, 0.81 g (20.3 mmol) of 60% sodium hydride (oily) was added thereto, while maintaining the liquid temperature in the range of 5° C. to 10° C. After stirring the mixture for one hour at room temperature, 3.9 g (27.5 mmol) of iodomethane was added dropwise to the reaction solution. The mixture was stirred for a day at room temperature, and then the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=3:2), to obtain 3.0 g (yield: 71%) of ethyl 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](C)([CH3:28])[O:25][C@@H:24](CC(N(OC)C)=O)[CH2:23]2)=[C:9]([CH:37]([CH3:39])[CH3:38])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].S(=O)(=O)(O)[OH:41]>C(#N)C>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](=[O:41])[CH2:28][C@H:24]([OH:25])[CH2:23]2)=[C:9]([CH:37]([CH3:39])[CH3:38])[N:8]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(-c3ccc(F)cc3)nc(N(C)S(C)(=O)=O)nc2C(C)C)OC(C)(C)O1
Reactant: O=S(=O)(O)O
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 3 h
Yield: 82 %

Procedure:
E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (5.0 g), acetonitrile (30.0 mL), and sulfuric acid (0.47 mL) were added to a reactor and then the reaction mixture was stirred at 50˜60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and then ethyl acetate (30.0 mL) and water (30.0 mL) were added thereto. The separated organic layer was dried under reduced pressure to obtain E-6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (3.4 g, yield 82%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=CC(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:20][CH2:21][CH:22]([OH:41])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])=CC=1.O>CN(C)C=O>[C:4]1([CH2:3][O:41][CH:22]([CH2:21][OH:20])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COCCOCCOCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCCCCCCCOCC(CO)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred suspension of 3.26 g of unwashed 50% sodium hydride and 10.9 g of benzyl bromide in 40 ml of dimethylformamide, under argon, was added a solution of 27.14 g of 20-[(4-methoxyphenyl)diphenylmethoxy]-2,5,8,17-tetraoxaeicosan-19-ol in 50 ml of dimethylformamide over 1/2hour. This mixture was stirred overnight, water was then added and the mixture extracted with ether. The ether extract was washed with water, dried and the solvent removed. The residue was dissolved in hot methanol and stirred with 10 g of a strongly acidic ion exchange resin. This mixture was filtered and the solvent removed. The residue was purified by HPLC, eluting with hexane:ethyl acetate (65:35) giving the desired compound as 12.9 g of a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: BrCCCc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
To a solution of intermediate 50 (Example 100) (3.5 g, 13 mmol) in dioxane (40 mL) was added pyrrolidine (2.1 mL, 25 mmol), followed by cesium carbonate (8.2 g, 25 mmol). The mixture was stirred at room temperature for 15 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10% MeOH/DCM to 25% MeOH and 2% TEA/DCM) to afford the title compound (1.8 g, 53%) as a pale orange oil.