Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O1CCCC1>O1CCCC1.O.CCCCCCC>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(NCc1ccc(O)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To a stirred solution of 4-aminomethylphenol (1 g, 8.13 mmol) in tetrahydrofuran/water (1:1 ratio, 20 ml) at 0° C. was added solid NaHCO3 (0.888 g, 10.16 mmol) followed by dropwise addition of benzyl chloroformate (1.16 ml, 8.13 mmol). The mixture was stirred at 0° C. for 10 minutes then allowed to warm slowly to r.t. After stirring the mixture for 90 minutes the tetrahydrofuran was removed in vacuo. The aqueous layer was extracted with EtOAc (2×10 ml). The organic layer was washed with water (2×10 ml), dried (MgSO4), and the solvent removed in vacuo to a residue. Trituration with heptane gave the product as a white solid (2.10 g, 100% yield). LCMS purity 100%, m/z 258 [M++H]−.
Reaction SMILES: [Mg].[O-]CC.[Mg+2].[O-]CC.[C:9]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])(=[O:11])[CH3:10].[F:18][C:19]1[CH:27]=[CH:26]C(C(Cl)=O)=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1.FC1C=CC(C(O)=O)=C([N+]([O-])=O)C=1.S(Cl)(Cl)=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(O)C>[F:18][C:19]1[CH:27]=[CH:26][C:10]([C:9]([CH:12]2[CH2:17][CH2:16][O:15][C:13]2=[O:14])=[O:11])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(=O)C1CCOC1=O
Agent: CC[O-]
Agent: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCCC1C(=O)c1ccc(F)cc1[N+](=O)[O-]
Yield: 83.6 %

Procedure:
A mixture of 8.0 g of magnesium turnings, 33 g of anhydrous ethanol and 3 ml of carbon tetrachloride was allowed to react on standing for several minutes. After the exothermic reaction had subsided, 250 ml of anhydrous toluene was slowly added under stirring, and the reaction mixture was stirred at 30°-35° C for an additional 3 hours. To the resulting suspension of magnesium ethoxide, a solution of 84.6 g of α-acetyl-γ-butyrolactone in 100 ml of anhydrous toluene was added dropwise under cooling at 0°-5° C. After the resulting mixture was stirred at room temperature for one hour, crude 4-fluoro-2-nitrobenzoyl chloride, prepared from 55.5 g of 4-fluoro-2-nitrobenzoic acid and 170 ml of thionyl chloride, in 100 ml of anhydrous toluene was added dropwise at 20°-25° C and stirred for an additional 3 hours. After 700 ml of 5% sulfuric acid was added to the resulting mixture under cooling with an ice-salt bath, the organic layer was separated, and the aqueous layer was extracted with portions of toluene. The resulting organic layer contained α-acetyl-α-(4-fluoro-2-nitrobenzoyl)-γ-butyrolactone as the main product. The combined organic layer was washed with water and aqueous saturated sodium chloride solution and extracted with three portions of cold 5% aqueous ammonium hydroxide solution. The combined aqueous ammonium hydroxide layer was washed with toluene and acidified by slow addition of 25% sulfuric acid under cooling. The precipitated solid was collected by filtration, washed with water and dried to give 63.5 g (83.6%) of α-(4-fluoro-2-nitrobenzoyl)-γ-butyrolactone. M.P. 87°-89° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][C:27]([Cl:32])=[CH:28][C:29]=3[Cl:31])[NH:24][C@@H:23]([C:33]([O:35][CH3:36])=[O:34])[CH2:22]2)=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:31].[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][C:27]([Cl:32])=[CH:28][C:29]=3[Cl:31])[NH:24][C@@H:23]([C:33]([O:35][CH3:36])=[O:34])[CH2:22]2)=[O:19])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Cc2ccc(CCNC(=O)OC(C)(C)C)cc2)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)Cc2ccc(CCN)cc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 182.8 %

Procedure:
To a solution of trans-4(4-tertiary-butyloxycarbonylaminoethylphenyl)methylcarbonylamino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (Example 106c) (0.150 g, 0.28 mmol) in ethyl acetate (5 ml) was added a saturated solution of hydrogen chloride in ethyl acetate (5 ml) and the resulting mixture was stirred at room temperature for 40 minutes. The solvent was then removed under vacuum and the residue was triturated with hot ethyl acetate. A gummy solid was collected by filtration and this was dissolved in water and freeze dried to give the title compound as a colourless solid (0.121 g), m.p. decomposes above 200° C. δ (360 MHz, DMSO 1.65 (1H, ddd, J=13.0, 12.5 and 3.8 Hz, CHACHBHCCHD), 2.14 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.86 (2H, m, ArCH2CH2NH3), 3.00 (2H, m, ArCH2CH2NH3), 3.36 (2H, s, NHCOCH2Ar), 3.72 (3H, s, CO2CH3), 3.97 (1H, dd, J=12.5 and 2.5 Hz, CHACHBHCCHD), 5.00 (1H, m, CHACHBHCCHDNHCO), 6.69 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.88 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.93 (1H, s, ArNH), 7.17 (2H, d, J=8.2 Hz, ArH), 7.21 (2H, d, J=8.2 Hz, ArH), 8.04 (3H, brs, NH3), 8.49 (1H, d, J=7.0 Hz, CHDNHCO); m/e 435 (M+), 198 (100%, M-NHCOCH2C6H4CH2CH2NH2, CO2CH3 and H); Found C, 51.47; H, 5.37; N, 8.60; C21H23Cl2N3O3.HCl.H2O requires C, 51.39; H, 5.34; N, 8.56%.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([CH:6](C(OCC)=O)[C:7]([O:9]CC)=[O:8])([CH3:5])[CH3:4].[OH-].[K+].CCO>>[F:1][C:2]([F:17])([F:18])[C:3]([CH3:5])([CH3:4])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(CC(=O)O)C(F)(F)F
Yield: 77.2 %

Procedure:
A solution of diethyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)malonate (iv, 20.93 g, 77.45 mmol) and KOH (17.23 g, 307.1 mmol) in EtOH (200 mL, 3000 mmol) was heated at 80° C. for 16 h. The reaction was concentrated and partitioned between water and Et2O. The aqueous layer was acidified with 6 N HCl and then extracted with Et2O (2×). The organic layers were combined, dried over MgSO4, filtered and concentrated to provide and orange oil. A low pressure distillation gave the product as a light pink liquid (10.17 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5](=[O:23])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([O:21]C)=[O:20].[OH-].[Li+].CO.C(OCC)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5](=[O:23])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1cccc(F)c1
Yield: 84.7 %

Procedure:
Dissolve 3-[(m-fluorophenacyl)methylamino]-2-carbmethoxy-6-chloroindole (650 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithium hydroxide (227 mg, 5.4 mmol). Add methanol dropwise until an homogeneous solution forms. Stir the reaction at room temperature overnight. Dilute the reaction with water(10 mL) and ethyl acetate (25 mL). Acidify with 1N HCl and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate 50% with heat. Reconstitutewit h hot hexane. Repeat the concentration and reconstitution steps and cool to yield the title compound (550 mg, 89%); mp 258°-260°C.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20].C(Cl)Cl>C(OCC)C>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][C:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: CCOC(CBr)OCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(Cc1cccc2c1Cc1ccccc1-2)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of n-butyllithium (100.0 mL, 1.6 M, 0.161 mol) in hexanes was added dropwise to a cooled (0° C.) solution of fluorene (26.75 g, 0.161 mol) in 200 mL of diethyl ether. The reaction solution turned orange and was warmed to 25° C. for 30 minutes. The orange solution was added dropwise to a cooled (0° C.) solution of bromoacetaldehyde diethylacetal (25.0 mL, 0.161 mol) in 50 mL of diethyl ether. The reaction solution was stirred for 12 hours and the solvent then removed in vacuo leaving purple oil. Methylene chloride (300 mL) was added to the residue to give a cloudy white mixture, which was extracted with deionized water (5×100 mL). The yellow organic layer was dried over Na2SO4 and the solids were then separated by filtration. Solvent was removed from the filtrate in vacuo to leave a pale yellow oil which solidified to a yellow waxy solid upon standing. Yield: 42.2 g, 0.149 mol (93%). 1H NMR (CDCl3, 600 MHz): δ 7.73 (d, 3JHH=7.8 Hz, 2H, flu-H4), 7.54 (d, 3JHH=7.8 Hz, 2H, flu-H1), 7.34 (t, 3JHH=7.2 Hz, 2H, flu-H3), 7.28 (t, 3JHH=7.2 Hz, 2H, flu-H2), 4.69 (t, 3JHH=6.0 Hz, 1H, CH), 4.08 (t, 3JHH=7.2 Hz, 1H, flu-CH), 3.52 (dm, 4H, OCH2CH3), 2.21 (dd, 2H, CH2), 1.13 (t, 3JHH=7.2 Hz, 6H, OCH2CH3). 13C{1H} NMR (CDCl3, 150.8 MHz): 147.25 (s, C1-a), 140.81 (s, C4a), 126.96 (s, C2), 126.82 (s, C3), 124.73 (s, C1), 119.78 (s, C4), 101.41 (s, CH), 61.45 (s, OCH2CH3), 43.93 (s, C9), 37.49 (s, CH2), 15.27 (s, OCH2CH3). MS (ES) m/z (assignment, relative intensity): 305.2 (C19H22O2Na, [M+Na]+, 100%). Anal. Calcd. for C19H22O2: C, 80.82; H, 7.85. Found: C, 80.89; H, 8.09.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH2:23][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH3:25])[N:19]3[N:32]=[CH:33][C:34]([CH:35]=O)=[C:18]3[N:17]=2)[CH:14]=1.N1CCCCC1>C(O)C.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH2:23][CH:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH3:25])[N:19]3[N:32]=[CH:33][C:34]([CH:35]=[C:7]4[NH:1][C:2](=[O:3])[NH:4][C:5]4=[O:6])=[C:18]3[N:17]=2)[CH:14]=1
Reactant: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2c(C=O)cnn12)N1CCOCC1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2c(C=C3NC(=O)NC3=O)cnn12)N1CCOCC1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
Hydantoin (7 mg, 0.07 mmol) and 5-(5-chloro-2-fluorophenylamino)-7-(2-morpholinopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (15 mg, 0.035 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (7 uL, 0.07 mmol). The reaction was heated at 80° C. for 1 hour in the microwave. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 5-((5-(5-chloro-2-fluorophenylamino)-7-(2-morpholinopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (5 mg, 28% yield). LCMS (M+1=515)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O>>[CH3:1][N:2]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(CC(F)(F)F)c1ccccc1
Temperature: 105 °C

Procedure:
Fluorinated light-absorbing electron donors were prepared. N-Methyl-N-2,2,2-trifluoroethylaniline was prepared as follows. Into a flask were placed N-methylaniline (6.0 g) and potassium carbonate (10.0 g) the flask was assembled with a refluxing condenser. To the flask was slowly added 2,2,2-trifluoroethyl trifluoromethanesulfonate (13 g). After addition, the reaction mixture was stirred and heated to 100-110° C. overnight. The reaction mixture was then quenched by addition of 100 mL of water. The water solution was extracted with diethyl ether (2×50 mL). The organic layer was separated and dried over MgSO4. Ether was removed under vacuum. The organic liquid was distilled to receive a fraction (a clear yellow liquid, 9.2 g) at 44-45° C. (at 0.05 mm Hg). The clear liquid was sampled and analyzed by 1H and 19F NMR. 1H NMR: δ7.28 (t, 2H, J=8 Hz), 6.81 (m, 3H), 3.83 (q, 2H, J=9H), 3.04 (s, 3H); 19F NMR: δ−73.37 (t, 3F. J=9 Hz).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1)=[O:3].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.[Cl:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][C:57]=1[C:63]([F:66])([F:65])[F:64]>CN(C=O)C.CCOC(C)=O>[Cl:55][C:56]1[CH:62]=[CH:61][C:59]([NH:60][C:19](=[O:21])[CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:2]([NH2:1])=[O:3])[CH:9]=3)=[CH:16][CH:15]=2)=[CH:58][C:57]=1[C:63]([F:64])([F:65])[F:66]
Reactant: NC(=O)c1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
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
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1

Procedure:
A solution of 3-(4-{[2-(aminocarbonyl)pyridin-4-yl]oxy}phenyl)-propanoic acid (200 mg, 0.70 mmol), HATU (319 mg, 0.84 mmol), DIPEA (0.24 mL, 1.4 mmol), and 4-chloro-3-(trifluoromethyl)aniline (136 mg, 0.70 mmol) in DMF (5 mL) was stirred overnight at rt. EtOAc was added to the reaction and the mixture was washed with 1N HCl, 1N NaOH, and brine, dried over Na2SO4 and concentrated. Purification by column chromatography (SiO2, 20-100% EtOAc in hexane) followed by recrystallization in EtOAc/hexane provided A-3 (37 mg, 11%). 1H NMR (300 MHz, d6-DMSO) δ: 10.36 (s, 1H), 8.48 (d, J=5.7 Hz, 1H), 8.18 (d, J=2.5 Hz, 1H), 8.09 (bs, 1H), 7.81 (dd, J1=2.5 Hz, J2=8.8, 1H), 7.7 (bs, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35-7.40 (m, 3H), 7.12-7.16 (m, 3H), 2.97 (t, J=7.3 Hz, 2H), and 2.70 (t, J=7.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](=O)[CH3:10])=[C:4](Cl)[N:3]=1.[NH2:13][NH2:14]>C(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]2[NH:13][N:14]=[C:9]([CH3:10])[C:5]=12
Reactant: NN
Reactant: CC(=O)c1c(Cl)nc(N)nc1Cl
Solvent: ClCCl
Product: Cc1n[nH]c2nc(N)nc(Cl)c12
Yield: 53.6 %

Procedure:
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone (200 mg, 0.97 mmol) was dissolved in CH2Cl2 and treated with anhydrous hydrazine (31 mg, 0.97 mmol, 1 equiv.) at r.t. overnight. The precipitate was collected by filtration, washed with CH2Cl2, dissolved in DMSO (0.5 mL), and partitioned between EtOAc (100 mL) and water (25 mL). The organic layer was dried (brine, Na2SO4) and concentrated to afford the title compound as a white solid (95 mg, 0.52 mmol, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C@H:27]([NH2:30])[CH2:28][OH:29]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:30][C@@H:27]([CH3:26])[CH2:28][OH:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: CN(C)C=O
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and S-(+)-2-amino-1-propanol employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ tautomers are observed 11.71 (1H, br s), 10.71 (1H, br s), 10.05 (1H, br s), 8.18 (0.59H, s), 8.14 (0.41H, s), 7.36-7.23 (3H, m), 7.14-7.08 (2H, m), 4.78 (1H, t, J=5 Hz), 3.98 (2H, s), 3.97-3.95 (1H, m), 3.49-3.41 (1H, m), 3.26-3.21 (1H, m), 1.13 (1.62H, d, J=6.6 Hz), 1.08 (1.388H, d, J=6.6 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1356.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1OC.[C:11](O)(=O)[CH2:12][C:13](O)=[O:14].P(Cl)(Cl)(Cl)=O>>[NH:8]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:12][C:13]1=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cccc(N)c1Br
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1ccc2ccccc2[nH]1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To 2-bromo-3-aminoanisole 2B4 (378 mg, 1.87 mmol, 1 eq) and malonic acid (194 mg, 1.87 mmol) was added phosphorous oxychloride (175 μL, 1.87 mmol). The reaction was placed in a pre-heated bath (95° C.) and stirred for 30 minutes. The mixture was cooled, and diluted with ice water and stirred ca. 2 h to afford a grey solid. This was filtered and washed with water until free of acid and then taken up into 1N NaOH. Insoluble material was removed by filtration and the resulting aqueous solution was treated with EtOH (8 mL) before adjusting the pH to 5-6 with 1N HCl (aq). The desired product was filtered and dried to afford quinolone 3J1 (0.12 g, 24%) as a yellow solid. MS: 270.0 (M+H)+ and 291.9 (M+Na)+.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:30]([C:29]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:28]=3[Cl:27])=[O:31])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
35 mL of nitrobenzene were cooled in an ice bath and then treated in succession with 5.2 g of aluminium chloride and 5.0 g of 4-methylbiphenyl. The mixture was brought to room temperature and then treated slowly with 7.7 g of 2,4-dichlorobenzoyl chloride. The mixture was stirred at room temperature overnight, poured into water and extracted with methylene chloride. The extracts were washed with 2N hydrochloric acid and water, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel with toluene/ethyl acetate 9:1. There were obtained 6.7 g (63%) of 2,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone as a colorless solid with a m.p. of 184°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:21][CH:23]2[O:25][CH2:24]2)[CH:9]=1
Reactant: Cc1ccc(-c2cccc(O)c2)n1C
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cccc(OCC3CO3)c2)n1C

Procedure:
While stirring, a mixture of 10 g of the resulting crude 1,5-dimethyl-2-(3-hydroxyphenyl)-pyrrole, 50 ml of epichlorohydrin and 15.2 g of potassium carbonate is heated at boiling point for 3 hours. The reaction mixture is cooled, filtered and concentrated by evaporation. The residue is divided between 200 ml of ether and 20 ml of 2N sodium hydroxide solution; the ether phase is separated off, dried over magnesium sulphate and concentrated by evaporation. The crude 1,5-dimethyl-2-[3-(2,3-epoxypropoxy)-phenyl]-pyrrole is obtained in the form of an oil and is further used in that form.
Reaction SMILES: C([O:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([NH:22][CH3:23])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25])(=O)C.[OH-].[K+]>O.CO>[CH3:24][N:12]1[C:13]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([NH:22][CH3:23])[C:14]=2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:26])[C:11]1=[O:25]
Reactant: CNc1cc(C)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1cc(C)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To the crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N-methylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was added a solution of potassium hydroxide (100 mg) in 20% water-methanol (2 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to remove methanol. The aqueous mixture was extracted with ethyl acetate (10 ml). The extract was dried over sodium sulfate and the residue was purified by short column chromatography eluting with ethyl acetate to provide (R)-1,7-dimethyl-3-(5-hydroxyhexyl)-5-(N-methylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 15 mg, 76% yield for 2 steps) as an oil. 1H NMR (300 MHz, benzene d6) δ 0.98 (d, 3H), 1.25-1.50 (m, 4H), 1.70-1.82 (m, 2H), 2.18 (d, 3H), 2.27 (s, 3H), 3.49-3.58 (m, 1H), 3.60 (s, 3H), 4.11 (t, 2H), 5.70 (s, 1H), 9.09 (broad s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]#N)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[Ba+2].[OH-:18].S(=O)(=O)(O)O>O>[CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]([OH:18])=[O:16])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC12CC1CN(Cc1ccccc1)C2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Solvent: O
Product: O=C(O)C12CC1CN(Cc1ccccc1)C2
Yield: 95.7 %

Procedure:
A mixture of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (2.77 g, 14.0 mmol) and barium hydroxide (4.47 g, 14.2 mmol) in water (100 ml) was heated to reflux for 18 hours. The reaction was then cooled and brought to neutral pH with sulfuric acid. The thick white mixture was filtered and washed twice with ethanol and twice with water. The filtrate was concentrated in vacuo, and the residue mixed with hot ethanol and filtered again. The filtrate was concentrated to provide the title product (2.91 g, 13.4 mmol, 96% yield). 1H NMR (D2O): 7.50 (bs, 5H), 4.36 (s, 2H), 3.9 (bs, 1H), 3.6 (m, 1H), 3.5 (bm, 2H), 2.14 (bs, 1H), 1.53 (bs, 1H), 1.09 (bs, 1H).