Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCOCc1c(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)oc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOCc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a mixture of methyl 4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]benzoate (482 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (437 mg, 93%) as a pale-red solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19](Cl)=[O:20]>ClCCl>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([C:19]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:20])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C1CNCCN1
Reactant: Cc1c(C(=O)Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCNC(=O)C2)ccc(F)c1Cl
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.350 g, 3.5 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (15 mL), and to this was added triethylamine (0.585 mL, 4.20 mmol). The solution was then cooled to 0° C. before 3-chloro-4-fluoro-2-methylbenzoyl chloride (I58) (0.797 g, 3.85 mmol) in Dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (50 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, which was then filtered off and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (30 mL) at 55° C. for 30 minutes, before being filtered to yield the product in 0.843 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)c1cccnc1
Reactant: Nc1cccnc1Cl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccnc1

Procedure:
The title compound is prepared by reacting (2-aminophenyl)(3-pyridinyl)methanone as prepared by Abramovitch R. A. & Tertzakian, G., Tetrahedron Letters, 1963, 1511-15 and Abramovitch, R. A. et al., Can. J. Chem. 43(4), 725-31 (1965) with 3-amino-2-chloropyridine.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC>[CH3:1][NH:2][C:3](=[O:17])[C:4]([CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9]
Reactant: CNC(=O)C(CCCN(C)C)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)C(CCCN(C)C)(c1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-methyl-5-dimethylamino-2-phenylpentanamide (5.0 g, 0.023 mol) dissolved in 50 ml THF was added 18.1 ml of a 2.5M solution of n-BuLi in n-hexane with ice-cooling under N2. After stirring at 0° C. for 30 min, benzaldehyde (2.4 g, 0.023 mol) dissolved in 10 ml THF was added dropwise to the foregoing solution. The reaction mixture was stirred for 5 min at 0° C. and then poured into ice-cold HCl. The resulting solution was washed with Et2O, basified by adding dilute NaOH while stirring in the cold, and extracted with CHCl3. The CHCl3 extract were combined, dried (Na2SO4), and evaporated Chromatography of the post-evaporation residue afforded the desired compound as a mixture of diastereoisomers as an oil. Dissolution in EtOH, acidification with HCl, followed by addition of Et2O gave the hydrochloride salt as a colorless solid. [Anal. Calc'd for C21H28N2O2.HCl.1/4EtOH: C, 66.17; H, 7.93; N, 7.18; Cl, 9.08. Found: C, 65.82; H, 8.02; N, 7.04; Cl 10.27.]
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.[F:37][CH:38]([F:47])[O:39][C:40]1[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=1>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:43]4[CH:44]=[CH:45][C:40]([O:39][CH:38]([F:47])[F:37])=[CH:41][CH:42]=4)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(OC(F)F)cc2)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenanthroline with 3,4,7,8-tetramethylphenanthroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.19 mmol) and 1-(difluoromethoxy)-4-iodobenzene (81 mg, 0.3 mmol) gave the title compound as colourless oil after purification by preparative HPLC (47 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[N:7]2.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:23][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
5-Chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline (1.4455 g, 4.479 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.6404 g, 2.240 mmol) were suspended in carbon tetrachloride (44.79 mL, 4.479 mmol). To the mixture was added benzoyl peroxide (0.1447 g, 0.4479 mmol) and the mixture was heated at reflux. After 21.5 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 9% gradient of EtOAc in hexane over 2 min, then 9% isocratic of EtOAc for 13 min, then 9 to 100% gradient of EtOAc in hexane over 23 min, then 100% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-5-chloro-3-(2-(trifluoromethyl)-phenyl)quinoxaline as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (1H, dd, J=8.4, 1.4 Hz), 8.13 (1H, dd, J=7.8, 1.2 Hz), 7.81-8.03 (5H, m), 4.69 (2H, dd, J=88.4, 10.2 Hz); LC-MS (ESI) m/z 400.9 and 403.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1([NH:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)CC1(N)CCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC1(NCc2ccc(F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A solution of (1-amino-cyclopentyl)-acetic acid methyl ester (318 mg, 2.02 mmol) in anhydrous methanol (10 mL) was treated with 4-fluoro-benzaldehyde (0.27 mL, 2.56 mmol) and stirred at 25° C. under a nitrogen environment. After 10 min, glacial acetic acid (0.384 mL, 6.71 mmol) and sodium triacetoxyborohydride (1.1 g, 5.05 mmol) were added sequentially, and the resulting mixture was stirred at 25° C. for 18 h. The reaction was diluted with a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give [1-(4-fluoro-benzylamino)-cyclopentyl]-acetic acid methyl ester (270 mg, 50%) as a colorless oil. LC-MS (ESI) calculated for C15H20FNO2: 265.3, found 266.2 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCCNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.1 %

Procedure:
To a solution of ethyl 4-[(2,6-dinitrophenyl)amino]butanoate (44.0 g, 0.148 mol) in tetrahydrofuran (800 mL) was added 10% palladium on carbon (50% wet; 4.63 g), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen at room temperature for 20 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a brown oil (35.1 g, 0.148 mmol, 100%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:6][C:7]1[CH:8]=[C:9]([O:22][C:23]2[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH:10]=[C:11]([C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:12]=1)[CH2:4][CH3:5].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:33]1([C:29]([C:26]2[N:27]=[CH:28][C:23]([O:22][C:9]3[CH:10]=[C:11]([CH:12]=[C:7]([O:6][C@H:3]([CH2:2][OH:1])[CH2:4][CH3:5])[CH:8]=3)[C:13]([NH:15][C:16]3[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=3)=[O:14])=[N:24][CH:25]=2)=[O:30])[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1

Procedure:
A solution of 5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (12 mg, 0.03 mmol), azetidine hydrochloride (4 mg, 0.06 mmol), HATU (14 mg, 0.04 mmol) and DIPEA (0.02 mL, 0.11 mmol) in DMF (1 mL) was stirred at RT over the weekend. Water (15 mL) was added and the solution extracted with ethyl acetate (25 mL). The ethyl acetate layer was washed with brine (20 mL), dried (MgSO4), and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product along with 15% of a co-eluting impurity (5 mg). 1H NMR δ (CDCl3): 0.92 (t, 3H), 0.97 (t, 0.45H), 1.69 (quin, 2H), 1.76 (m, 0.3H), 2.34 (quin, 2H), 3.76 (m, 2H), 3.86 (s, 3H), 4.23 (t, 2H), 4.49 (sextet, 1H), 4.66 (t, 2H), 4.77 (m, 0.15H), 6.93 (t, 1H), 6.99 (d, 1H), 7.34 (s, 1H), 7.46 (s, 1H), 7.50 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H), 10.68 (s, 1H), 10.78 (s, 0.15H); m/z 468 (M+H)+
Reaction SMILES: [F:1][C:2]1([F:38])[CH2:5][C:4]([NH:30]C(=O)OC(C)(C)C)([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:12]=3)[N:7]=2)[CH2:3]1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:30][C:4]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:12]=3)[N:7]=2)[CH2:5][C:2]([F:38])([F:1])[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3(NC(=O)OC(C)(C)C)CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(C3(N)CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.5 h

Procedure:
To a flask was added tert-butyl (3,3-difluoro-1-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)carbamate (165) (169 mg, 0.3 mmol) and 4N HCl in 1,4-dioxane (1 mL). The reaction was stirred for 30 minutes. The solvent was concentrated and placed under high vacuum to afford N-(5-(5-(1-amino-3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (166). MS m/z 425.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][N:19](C(OCC(Cl)(Cl)Cl)=O)[C@@H:9]([C@:10]3(C(OCC(Cl)(Cl)Cl)=O)[CH2:11][CH2:12][C:13](=[O:28])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH4+].[Cl-].C([OH:41])C>[Zn]>[OH:41][C@:10]12[C@@H:9]3[NH:19][CH2:18][CH2:17][C@:15]1([C:16]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8]3)[CH2:14][C:13](=[O:28])[CH2:12][CH2:11]2
Reactant: COc1cccc2c1[C@]13CCN(C(=O)OCC(Cl)(Cl)Cl)[C@H](C2)[C@]1(C(=O)OCC(Cl)(Cl)Cl)CCC(=O)C3
Reactant: CCO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: COc1cccc2c1[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a mixture of 2.9 g (4.54 mmol) 4-methoxy-N,14-bis(2,2,2-trichloroethoxycarbonyl)-morphinan-6-one in 130 ml ethanol were added 15 g (280.4 mmol) NH4Cl and this mixture was stirred and refluxed. During 0.5 h 12 g (177 mg) activated zinc powder were added portionwise and the resulting mixture was refluxed for 1 h. After cooling and filtration, the filtrate was evaporated. The residue was dissolved in water, basified with saturated NaHCO3 solution and extracted with CHCl3. The organic layer was washed with brine, dried and evaporated to give an oil which was crystallized with isopropyl ether to yield 690 mg (53%) 14-hydroxy-4-methoxymorphinan-6-one, m.p. 137°-139°, [α]D26 --66.5°. (C 1.08, CHCl3).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[C:20]([OH:34])[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[C:20]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Benzyl bromide (0.80 mL) was added to a mixture of benzyl 4-benzoyloxy-2-hydoxybenzoate (2.23 g) and cesium carbonate (2.29 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at 50° C. for 3 hrs, and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to afford benzyl 4-benzoyloxy-2-benzyloxybenzoate (2.87 g).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH2:5]/[CH:6]=[CH:7]/[C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3].Br[CH2:15][C:16]([O:18]C)=[O:17].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O.CO.O>[ClH:1].[CH2:2]([N:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]#[C:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:15][C:16]([OH:18])=[O:17])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CCNC/C=C/C#CC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C/C=C/C#CC(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
1.0 g of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride was dissolved in 20 ml of dimethylformamide, and 0.7 g of methyl bromoacetate and 1.0 g of potassium carbonate were added. The mixture was stirred overnight at room temperature, and worked up in a customary manner. The resulting glycine ester compound was dissolved in a methanol solution (50 ml) of 0.5 g of sodium hydroxide, and 25 ml of water was added. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The residue was dissolved in water, and the solution was made weakly acidic with hydrochloric acid, then butanol and a saturated aqueous solution of sodium chloride were added. The organic layer was separated and the solvent was evaporated, then the residue was dissolved in a 10% hydrogenchloridemethanol solution. The solvent was re-evaporated, and the residue was treated with hexane to give 1.36 g of the captioned compound as a pale yellow powder.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([F:19])=[C:15](Cl)[N:14]=1>CO.O>[Cl:12][C:13]1[N:18]=[C:17]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([CH2:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=2)[C:16]([F:19])=[CH:15][N:14]=1
Reactant: Nc1ccc(CCCF)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: FCCCc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(3-Fluoropropyl)aniline and 2,6-dichloro-5-fluoropyrimidine (1.5 g) were dissolved in methanol (5 mL) and water (1 mL). The reaction solution was stirred at rt for 3 d. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were evaporated and purified by flash column chromatography (EtOAc/hexanes=1/4, 1/2) to give 2-chloro-5-fluoro-N4-[4-(3-fluoropropyl)phenyl]-4-pyrimidineamine.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>ClCCCl.ClC(Cl)C>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: Oc1ccccc1Oc1ccccc1
Yield: 82.3 %

Procedure:
A solution of 23.4 g (74.9 mmol) of boron tribromide-dimethyl sulfide complex in 150 mL of 1,2-dichloroethane was added dropwise to 3.00 g (15.0 mmol) of 2-methoxyphenyl phenyl ether in 50 mL dichloroethane at room temperature. The mixture was stirred at reflux overnight. 50 mL 3M NaOH was added to quench the reaction. After separation of layers, the organic layer was extracted with 3×100 mL 3M NaOH. The combined aqueous layer was acidified with conc. HCl, and the precipitated product was extracted with 3×150 mL ethyl ether. After washing with brine solution, drying over MgSO4, and filtering, solvents were evaporated under reduced pressure to give 2.30 g (82.4%) of an off-white solid, which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 5.57 (s, 1H); 6.81-6.90 (m, 2H); 7.01-7.07 (m, 4H); 7.12 (t, 1H, J=7.3 Hz); 7.31-7.38 (m, 2H). ##STR105##
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]([C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=2)=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[O:53]([C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:67]=2)=[CH:62][CH:61]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.023 g of product in 78% yield: LCMS (ESI) m/z 518 (MH+).
Reaction SMILES: [CH:1]1[CH:14]=[C:13]2[C:4]([CH:5]3[C:16]([C:17](O)=[O:18])=[C:15]([C:20]([OH:22])=[O:21])[CH:12]2[C:11]2[C:6]3=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[CH:9]1[CH:10]=[C:11]2[C:6]([CH:5]3[C:16]4[C:17]([O:22][C:20](=[O:21])[C:15]=4[CH:12]2[C:13]2[C:4]3=[CH:3][CH:2]=[CH:1][CH:14]=2)=[O:18])=[CH:7][CH:8]=1
Reactant: O=C(O)C1=C(C(=O)O)C2c3ccccc3C1c1ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1OC(=O)C2=C1C1c3ccccc3C2c2ccccc21
Temperature: 0 °C
Yield: 92.5 %

Procedure:
As shown in FIG. 2A, diacid 2 (8.76 g, 29.2 mmol) was suspended in dry dichloromethane (ca. 300 mL) in a dry, septum-capped round-bottom flask, to which was added a few drops of dry dimethylformamide. The mixture was cooled to 0° C. in an ice-water bath and the flask was connected to a oil-bubbler with flexible plastic tubing. Oxalyl chloride (3.9 g, 30.7 mmol) was added dropwise with a syringe as the suspension was stirred. Within few minutes, gas was released through the oil bubbler as the reaction began. The reaction mixture was adequately cooled prior to the addition of oxalyl chloride to avoid a violent release of gas. The reaction mixture was allowed to warm to room temperature as it was stirred overnight (ca. 16 h), during which the reaction mixture became homogeneous. The solvent was evaporated under vacuum and the resulting crude product was recrystallized from toluene to give the title compound as pale beige crystals (7.41 g, 90%). 1H NMR (500 MHz, CDCl3): 7.45 (4H, dd, J=5.2 and 3.2 Hz), 7.09 (4H, dd, J=5.0 and 3.5 Hz), 5.55 (2H, s).
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([I:1])=[CH:3][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(Nc2ccc(I)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(I)cc2)n1Cc1ccccc1
Yield: 61 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (2.36 mmol) of 2-(4-iodoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 23 mg of lithium hydride and 458 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 678 mg of 3-benzyl-2,3-dihydro-2-[(4-iodophenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (61%, recrystallized from a mixture of ether and hexane).