Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:33])=[CH:12][C:11]=1[F:34])=O)(C)(C)C.[ClH:35].O1CCOCC1>C(#N)C>[ClH:35].[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:28][CH2:29]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:33])=[CH:12][C:11]=1[F:34]
Reactant: Cc1c(-c2ccc(CNC(=O)OC(C)(C)C)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(CN)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reaction time: 4 h

Procedure:
8-(4-((tert-Butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (24 mg, 0.051 mmol) was dissolved in acetonitrile (4 mL). HCl 4M in dioxane (1 mL, 4 mmol) was added. The mixture was stirred for 4 h and a suspension was formed affording after filtration the title compound EXAMPLE 49 as a yellow solid (17.7 mg, 86%). ESI-MS m/z: 453 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH3:13][N:14]([CH3:15])[C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: CNC
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1cc(N)c([N+](=O)[O-])cn1
Yield: 113.6 %

Procedure:
In a microwave tube, a solution of 4-amino-2-chloro-5-nitropyridine (prepared as described for compound 9) (200 mg; 1.16 mmol) in ethanol (2 ml) was treated sequentially with dimethylamine hydrochloride (471 mg; 5.78 mmol) and triethylamine (781 μl; 6.96 mmol). The tube was quickly sealed and irradiated in the microwave (CEM Discover, 150 W, 85° C., 10 min). The ethanol was evaporated, dichloromethane (15 ml) was added to dissolve the products, and the solution washed with 1M sodium hydroxide solution (2×10 ml). The organic layer was dried (sodium sulphate), the mixture filtered and the filtrate evaporated to dryness to afford N2,N2-dimethyl-5-nitro-pyridine-2,4-diamine (240 mg, 114%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:31])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]OS(C)(=O)=O)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:32])=[CH:10]2)=[C:4]([CH3:33])[CH:3]=1.[Na+].[I-:35].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:31])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][I:35])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:32])=[CH:10]2)=[C:4]([CH3:33])[CH:3]=1
Reactant: [I-]
Reactant: Cc1cc(N2CCC(CCOS(C)(=O)=O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A mixture of methanesulfonic acid 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl ester (0.70 g) and NaI (0.59 g) in acetone (14 mL) was heated at reflux for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=10/1) to obtain 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.65 g) as a white crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@H:3]([OH:20])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[N:6]1.C([Li])CCC.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:29](=[O:30])([O:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[O:20][C@H:3]([CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[C:2]([CH3:22])([CH3:21])[CH3:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](O)Cn1cc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](Cn1cc(-c2ccc(C(F)(F)F)cc2)cn1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To 3.30 g (10.57 mmol) of (2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol in 200 mL of tetrahydrofuran at 0° C. was added 7.26 mL (11.62 mmol) of 1.6 M n-butyllithium in hexanes, and the resulting solution was stirred for 10 min. Then, 3.19 g (15.84 mmol) of 4-nitrophenyl chloroformate in 11 mL of tetrahydrofuran was added, and the solution was stirred at room temperature for 75 min. Saturated aqueous sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (3:7) to give 3.92 g (78%) of (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-nitrophenyl carbonate. Rf=0.19 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.14 (d, J=9 Hz, 2H), 8.08 (s, 1H), 7.79 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 7.27 (d, J=9 Hz, 2H), 4.88 (dd, J=10 Hz, J=2 Hz, 1H), 4.61 (d, J=13 Hz, 1H), 4.32 (dd, J=15 Hz, J=10 Hz, 1H), 1.05 (s, 9H); ES-LCMS m/z 478 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 7.7 %

Procedure:
A mixture of 7-amino-4-(3-bromoanilino)-pyrido[4,3-d]pyrimidine (0.154 g, 0.49 mmol), acetic anhydride (0.14 mL, 1.5 mmol), triethylamine (0.14 mL, 1.0 mmol) and a catalytic amount of 4-(N,N-dimethyl-amino)pyridine are stirred under N2 at room temperature for 18 h. The reaction is then quenched by addition of ice water. The dark precipitate is collected by Buchner filtration and is purified by preparative tlc (Rf=0.25, 7% MeOH/CHCl3). Recrystallization from EtOH gives 7-acetylamino-4-(3-bromoanilino)pyrido[4,3-d]-pyrimidine (13.5 mg, 7.7%). 1H NMR (DMSO) δ 10.92 (1H, s), 10.22 (1H, s), 9.64, (1H, s), 8.70 (1H, s), 8.28 (1H, s), 8.21 (1H, s), 7.88 (1H, d, J=7.7Hz) 7.41-7.34 (3H, m), 2.16 (3H, s).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][NH2:17])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2].C(N(CC)CC)C.O.[O:40]1CCC[CH2:41]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[O:15][C:41](=[O:40])[NH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
72 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carbohydrazide (compound 133) was dissolved in 4 mL of tetrahydrofuran, and 55 mg of N,N′-carbonyldiimidazole and 47 μL of triethylamine were added to the solution. The mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=5:1), and thus 57 mg (cis:trans=4:1, 75%) of the title compound was obtained as a pale green powder.
Reaction SMILES: [CH2:1]([CH:8]([NH:23][C:24]([C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1)=[O:25])[CH:9]([OH:22])[CH2:10][CH:11]([C:18]([NH:20][NH2:21])=[O:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]#[C:37]Br.C(=O)([O-])O.[K+]>O1CCOCC1.O>[NH2:36][C:37]1[O:19][C:18]([CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:22])[CH:8]([NH:23][C:24]([C:26]2[CH:35]=[N:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][N:21]=1
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NN
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1nnc(N)o1
Yield: 55.4 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-7-fluoro-4-hydrazinocarbonyl-2-hydroxy-7-methyl-octyl)-amide (110 mg, 0.228 mmol) in dioxane (0.5 mL) and water (0.5 mL) was added cyanogen bromide (31 mg, 0.296 mmol) and potassium hydrogencarbonate (31 mg, 0.310 mmol). The reaction was heated to reflux for 1 hour then cooled to ambient termperature. The dioxane/water was removed by adding benzene (5 mL) and concentrating (2×). The remaining solid was dissolved in ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. Recrystallization of the crude product using a mixture of ethyl acetate, hexanes and methanol gave the title compound (64 mg, 55%).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]>C(OCC)(=O)C.CCCCCC>[CH3:34][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]
Reactant: CCOC(=O)/C=C(\C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 76 %

Procedure:
Using ethyl (2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)but-2-enoate obtained in Example 179, the title compound was synthesized in the same manner as in Example 180. Yield: 76%. Melting point: 100-101° C. (ethyl acetate-hexane).
Reaction SMILES: [Li]N1C(C)(C)CCC[C:3]1(C)C.CC1CCCN(C)C1(C)C.CN(CCN(C)C)C.[Li]CCCC.[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[CH:48][C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CI>C1COCC1>[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[C:48]([CH3:3])[C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Reactant: [Li]N1C(C)(C)CCCC1(C)C
Agent: CC1CCCN(C)C1(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: -40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol)] in THF (5 mL) was added to a cooled (−40° C.) and stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0° C., for 1 h and then re-cooled to −40° C. MeI (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex afforded 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH+: 380.3. This transformation can also be accomplished by using other amide bases such as LDA.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O.N.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2nc(O)ccc2c1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 115 °C
Yield: 98 %

Procedure:
A solution of 2,6-quinolinediol 10 (5 g) in POCl3 (21 ml) and DMF (3.4 ml) is stirred for 12 h at room temperature, then heated for 1 h at 115° C. The reaction is poured into water (100 ml) at 0° C. and neutralized with a 32% aqueous NH3 solution. The solid obtained by filtration is washed with acetone, and the resulting organic phase is evaporated to give 2-chloro-6-quinolinol 11 as a solid. No further purification is needed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH:27]1([O:35][CH2:36][CH2:37]O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:37][CH2:36][O:35][CH:27]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOC1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOC2CCCCCCC2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.27 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.303 g), stirred for 15 minutes and treated with the tosylate prepared from 2-(cyclooctyloxy)ethanol (2.18 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane-ethyl acetate; 80:20:2) to provide 1.0 g of pure 4-[[2-(cyclooctyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[CH:25]=[CH2:26].[OH-].[K+]>CN1C(=O)CCC1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:26][CH2:25][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[C:18]([F:28])([F:17])[F:27])[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1cnccc1C(F)(F)F
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnccc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 8-ethyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]2[N:23]=[N:24][N:25]=[C:17]2[C:16]=1[NH:26][C:27](=O)[CH2:28][O:29][CH2:30][CH3:31])(=O)C>C(O)C.O>[CH2:30]([O:29][CH2:28][C:27]1[N:14]([CH2:13][CH2:12][CH2:11][OH:10])[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]3[N:23]=[N:24][N:25]=[C:17]3[C:16]=2[N:26]=1)[CH3:31]
Reactant: CCOCC(=O)Nc1c(NCCCOC(C)=O)c(C)c(C)n2nnnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCO
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A solution of 6 M potassium carbonate (0.9 mL, 5.2 mmmol) was added to a solution of crude 3-({8-[(ethoxyacetyl)amino]-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl}amino)propyl acetate from Part C in 3:1 ethanol/water (12 mL) at room temperature. The solution was stirred for 3 days, then was heated to 80° C. More 6 M potassium carbonate (3 mL) was added after 1 day. After another day, 6 M potassium carbonate (5 mL) was added again. The temperature was increased to 85° C. and stirring was continued one more day. The solvent was removed under reduced pressure and the residue was partitioned between chloroform (100 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2>20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 0.35 g of 3-[8-(ethoxyrnethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]propan-1-ol as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:15](=O)O[C:12](=O)[C@@H:4]([NH:5]C(=O)C(F)(F)F)[CH2:3]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18]1.CC(C(O)=O)C[C@@H](C(O)=O)N>>[NH2:5][CH:4]1[CH2:12][C:23]2=[CH:22][C:21]3[O:17][CH2:18][CH2:19][C:20]=3[CH:25]=[C:24]2[CH2:15][CH:2]([CH3:1])[CH2:3]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CC1C[C@H](NC(=O)C(F)(F)F)C(=O)OC1=O
Agent: CC(C[C@H](N)C(=O)O)C(=O)O
Product: CC1Cc2cc3c(cc2CC(N)C1)OCC3

Procedure:
This compound may be prepared by condensing 4-methyl-N-trifluoroacetylglutamic anhydride with 2,3-dihydrobenzofuran according to the process described in Example 2. The synthesis of 4-methylglutamic acid is known (J. Pharm. Scien., (1975), 64, No. 11, p.1855-1858).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.3 min, m/z=487.1; 1H NMR (CD3OD) 1.25-1.37 (m, 1H), 1.55 (d, 3H), 1.61 (m, 1H), 1.95 (m, 2H), 2.17-2.28 (m, 1H), 2.36 (m, 1H), 2.48 (m, 1H), 3.12 (m, 1H), 3.48 (m, 2H), 3.94 (s, 3H), 5.58 (m, 1H), 6.86 (d, 1H), 7.07 (m, 4H), 7.35 (m, 4H), 7.86 (dd, 1H), 8.28 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH:3]([CH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (12 g, 42.2 mmol) in 1,2-dimethoxyethane (80 ml) was added sodium hydride (60% in oil, 1.69 g, 42.2 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (10.1 g, 42.2 mmol) in 1,2-dimethoxyethane (50 ml), and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (200 ml), and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14.0 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[CH2:20]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CN
Reactant: O=C=NCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-aminomethyl-5-[(Z) -6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (13 mg) in pyridine (0.3 ml) was added benzyl isocyanate (0.02 ml) and the mixture was stirred at room temperature for 60 minutes. Water (0.1 ml) was added and the solvent was evaporated in vacuo to give (2R,4R,5S)-4-(3-benzylureidomethyl)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane as a residue. The residue was dissolved in methanol (1.5 ml) and added 0.3 ml of 1N aqueous sodium hydroxide and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and the crude product was purified with preparative TLC (ethyl acetate as an eluent) to give (2R,4R,5S)-4-(3 -benzylureidomethyl)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (20 mg).
Reaction SMILES: ClCC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13]Cl)[C:6]=1Br.[Li]CCCC.C(O)(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C:5]1[C:6]2[CH2:13][CH2:12][O:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: ClCCOc1cccc(OCCCl)c1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Oc1cccc2c1CCO2
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
The product of Step 2 (39.25 g) was dissolved in THF (0.5 L) and cooled to −78° C. nBuLi (2.5M in hexanes, 300 mL) was then added dropwise over 30 minutes and the reaction stirred at −70° C. for an additional 45 minutes. The solution was then warmed to 0° C. over 10 minutes and stirred at this temperature for 1 hour. Glacial acetic acid (16 mL) was added followed by 1N NaOH (160 mL) and the layers allowed to separate. The organics were extracted with 1N NaOH (2×80 mL) and the combined aqueous fractions were then washed with TBME (160 mL). TBME (240 mL) was then added and the aqueous layer acidified with 6N HCl. The aqueous layer was re-extracted with TBME (240 mL), and the combined organics stirred over activated charcoal (5 g) for 15 minutes, filtered through Celite, and concentrated in vacuo. The crude product was crystallized from toluene and heptane to yield the title compound (16.8 g, 99%).