Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=[O:31])C>OO>[OH:28][CH2:27][CH2:26][N:24]1[CH:25]=[C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N+:1]([O-:31])=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)[CH:22]=[N:23]1
Reactant: OCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reactant: CC(=O)O
Agent: OO
Product: [O-][n+]1cccc2cc(Cn3nnc4ccc(-c5cnn(CCO)c5)nc43)ccc21
Reaction time: 12 h
Yield: 14 %

Procedure:
To a solution of example 146 (0.100 g, 0.269 mmol) in acetic acid (1 ml), hydrogen peroxide solution (50%, 1 ml) and heated to 100° C. After 12 h, the mixture was concentrated, extracted with chloroform, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using dichloromethane: methanol to afford the title compound as an off-white solid (0.015 g, 14%), M.P.: 222-224° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.58-8.48 (m, 4H), 8.19 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.85 (dd, J=9.0, 1.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 6.0 Hz, 1H), 6.12 (s, 2H), 4.95 (t, J=5.2 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([CH2:21][CH:22]([CH3:24])[CH3:23])([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C>[CH2:1]([S:8][CH2:9][C:10]([CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:16][OH:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CSCc1ccccc1)(CC(C)C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CC(CO)(CO)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethyl 2-benzylthiomethyl-2-isobutylmalonate (32.0 g.) in dry diethyl ether (60 ml.) was added to a stirred suspension of lithium aluminium hydride (7.0 g.) in dry diethyl ether (400 ml.), at 0°, under nitrogen. The mixture was stirred at room temperature for three hours and then refluxed with stirring for a further three hours. The mixture was cooled and 10% aqueous sodium hydroxide solution (25 ml.) was added very carefully. The mixture was filtered and the solid was washed with ether. The filtrates were dried over anhydrous magnesium sulphate and evaporated in vacuo. 2-Benzylthiomethyl-2-isobutyl-propan-1,3-diol was obtained as a colourless solid (20 g.) and was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][CH2:10][C:11](=[O:14])[N:12]([CH3:26])[N:13]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NN(C)C(=O)CS3)c(F)c2)C(=O)O1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of N-{3-[3-fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide (0.100 g, 0.273 mmol), potassium carbonate (0.075 g, 0.546 mmol), and iodomethane (0.0187 ml, 0.300 mmol) in DMF (3 ml) is heated at 80° C. overnight. The reaction mixture is filtered and evaporated to dryness. The residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.104 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 1.82 (s, 3H), 3.39 (s, 3H), 3.42 (t, J=5.5, 2H), 3.66 (s, 2H), 3.76 (dd, J=6.6, 9.3 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.71-4.80 (m, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=1.9, 14 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 8.25 (t, J=5.8 Hz, 1H); mp 179-80; MS (m/z): [M+H]+=381.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6](C(C)(C)C)[C:5]([OH:17])=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:18]([CH3:21])([CH3:19])[CH3:20])[C:5]([OH:17])=[CH:6][C:7]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)cc(C(C)(C)C)c(O)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Yield: 97.9 %

Procedure:
Into a 1-liter four-necked flask, were charged 58.4 g of methyl 6-methyl-2,4-di-t-butyl-3-hydroxyphenylacetate, 400 ml of toluene, and 6 ml of concentrated sulfuric acid. The mixture was heated under reflux for about 5 hours under a nitrogen stream. After completion of the reaction, the reaction mixture was neutralized with an aqueous sodium carbonate solution, washed with water, dehydrated, and freed from the solvent under reduced pressure to obtain 46.2 g (98% yield) of pale yellow methyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate which was distilled under reduced pressure (1 mmHg, 130°-140° C.) or recrystallized from n-hexane to yield white crystals having a melting point of 100.0°-101.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c(OC)c(Cl)ccc2c1Cl
Product: CCCCNc1c(C(=O)OCC)cnc2c(OC)c(Cl)ccc12

Procedure:
4,7-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.84 mmol) was treated with butylamine following general procedure B to afford 7-chloro-4-butylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (210 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (125 mg) following general procedure E. The above ethylamide (0.37 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 8-chloro-3-ethyl-1-butyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (75 mg). LCMS: m/z 380 [M+1]+.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: COC(=O)c1cc(I)ccc1OCCN1CCCC1
Product: COC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from methyl 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (3.0 g, 8.0 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.76 g, 8.24 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:34][C:8]2[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:11][C:7]=2[CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH2:12]([C:10]1[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:21][CH:22]=2)[C:8]2[S:34][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2cc(C(=O)OC)sc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc2cc(C(=O)O)sc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
2-butyl-3-[(2'-{1H-tetrazol-5-yl}{1,1'-biphenyl}-4-yl)methyl]-3H-thieno[2,3-d]-imidazole-5-carboxylic acid methyl ester (1, A-B-C are --CH=C(CO2CH3)--S--; R6 -E=butyl; R1 =tetrazol-5-yl) prepared as described in Example 5 can be saponified with lithium hydroxide hydrate in THF/H2O (5:1) at room temperature for 24 hours to give the title compound.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C:14]([F:16])([F:15])[CH:13](OS(C)(=O)=O)[O:12][C@@H:11]1[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:44]>CC(C)=O>[C:1]([O:9][C@H:10]1[C:14]([F:16])([F:15])[CH:13]([I:44])[O:12][C@@H:11]1[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C1(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(I)C1(F)F)c1ccccc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
(2R,3R)-4,4-difluoro-5-(methylsulfonyloxy)-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 9 (2 g, 3.37 mmol), acetone (20 mL), and NaI (5 g, 33.56 mmol) were charged into a round bottom flask. The resulting mixture was refluxed for >6 hours. HPLC indicated that all starting material 9 was consumed. The reaction mixture was cooled to ambient temperature and filtered. The solvent was removed in vacuo. The residue was partitioned between dichloromethane (105 mL) and water (65 mL). The aqueous layer was extracted with dichloromethane (30 mL). The combined dichloromethane layers were washed sequentially with a 5% aqueous solution of NaHSO3 (2×30 mL), a 1:1 mixture of water and brine (20 mL), and brine (2×20 mL). The solution was dried over MgSO4, filtered, and concentrated to give 1.68 g of (2R,3R)-4,4-difluoro-5-iodo-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 10. H1 NMR (CDCl3): δ3.44-3.57 (dd, 2H), 4.41 (m, 1H), 5.60-5.65 (dd, 1H), 6.95 (d, 1H), 7.21-8.15 (m, 20H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][CH3:15])[C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[N:16]1([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][CH3:15])[C:6]=3[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCCSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-piperidino-8-n-propylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [CH2:1]([N:18]=[C:19]=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O.C(Cl)(Cl)Cl.[CH2:26]([OH:30])[CH2:27][CH2:28][OH:29]>C(Cl)Cl>[CH2:1]([NH:18][C:19]([O:29][CH2:28][CH2:27][CH2:26][OH:30])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCNC(=O)OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
In a mixture of 5.7 g of 1,3-propanediol and 30 ml of methylene chloride is dissolved 5.0 g of n-heptadecyl isocyanate and the mixture is stirred at room temperature overnight. To the reaction mixture are added 20 ml each of water and chloroform, and the organic layer is taken and concentrated to dryness. Then, silica gel column chromatography is carried out [eluent: chloroform-water (97:3)] and the eluate is concentrated to dryness. The procedure provides 3.0 g of the above-indicated compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:12]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][C:11](=[O:12])[CH:16]=[CH:5]2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1O
Solvent: CN1CCCC1=O
Product: O=c1ccc2cccc(Br)c2o1
Temperature: 210 °C
Yield: 25.8 %

Procedure:
To a solution of 3-bromo-2-hydroxybenzaldehyde (402 mg, 2.0 mmol) in NMP (5 mL) was added carbethoxymethylene triphenylphosphorane (765 mg, 2.2 mmol). The reaction was heated at 210° C. for 3 h, then was cooled to RT and partitioned between water and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4. Purification by flash chromatography on silica gel (2:1 hexanes/ethyl acetate) yielded the title compound (116 mg, 26%) as a light beige solid: MS (ES) m/e 227.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CC1(C)C(C)(C)OB([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:26][CH:25]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(OCCN2CCOCC2)cc1
Yield: 33.5 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1, using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.36 g, 1.35 mmol), 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-morpholine (0.45 g, 1.35 mmol), Pd(PPh3)4 (0.078 g, 0.068 mmol) and Cs2CO3 (0.53 g, 1.6 mmol). The crude was filtered, diluted with 1M HClaqueous (3 ml) and purified via reverse phase chromatography with a Biotage C18 SNAP 120 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to afford the title compound (0.179 g, 33%).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]([CH2:24][CH:25](OC)[O:26]C)[C:7](=[O:23])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:30]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:24][CH:25]=[O:26])[C:7](=[O:23])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:31]
Reactant: CCN(CC)CCN(CC(OC)OC)C(=O)CCOCCc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCN(CC=O)C(=O)CCOCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-[2-(diethylamino)ethyl]-N-(2,2-dimethoxyethyl)-3-[2-(1-naphthyl)ethoxy]propanamide (93 g) in DCM (270 mL) was treated dropwise at 0° C. with trifluoroacetic acid (270 mL) over 1.5 hours. After the addition the reaction mixture was allowed to warm to room temperature and stirred for a further 1 hour. The reaction mixture was concentrated and the residue poured into aqueous saturated sodium bicarbonate solution (1800 mL, caution). The aqueous mixture was extracted with DCM (4×400 mL) and the combined extracts were dried over magnesium sulphate and concentrated. The residue was used directly in the following reaction.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:8]=[CH:7][C:6]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I.[Cl-].[NH4+]>CN(C=O)C.C1COCC1>[F:16][C:12]1[CH:11]=[C:10]([N:9]2[C:5]([N:4]([CH3:24])[C:1](=[O:3])[CH3:2])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[N:8]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1NC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(F)c2)c1N(C)C(C)=O
Reaction time: 0.17 h

Procedure:
A solution of ethyl 5-acetamido-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (3.56 g, 12.2 mmol) in 8 mL of DMF and 8 mL of THF at 0° C. was treated with NaH (60% wt. in mineral oil, 850 mg, 21.2 mmol). After 10 min of stirring, MeI (1.4 mL, 21.9 mmol) was added, and the reaction mixture was stirred at 0° C. for 15 min followed by RT for 1 h. the mixture was treated with saturated ammonium chloride and extracted with EtOAc twice. The combined EtOAc layers were washed with brine, dried and concentrated. Purification of the resulting crude material on an ISCO (80 g column, 30-50% EtOAc in Hexanes) provided ethyl 1-(3-fluorophenyl)-5-(N-methylacetamido)-1H-pyrazole-4-carboxylate as a colorless amorphous solid. MS (ESI, pos.ion) m/z: 306.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](O)=[O:21]>CO>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH3:11])[C:20](=[O:21])[NH:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1CO
Reactant: COc1ccccc1CC(=O)O
Solvent: CO
Product: COc1ccccc1-c1cc2ccc(Cl)cc2[nH]c1=O

Procedure:
2-Amino-4-chlorobenzyl alcohol (2 g, 12.86 mmol) and 2-methoxyphenylacetic acid (4.70 g, 28.3mol) were reacted in a similar manner as described in Example 19 to give 7-chloro-3-(2-methoxyphenyl)-2(1H)-quinolone as fine white needles mp 235°-236° C. (MeOH). (Found: C, 67.49; H, 4.22; N, 4.93. C16H12ClNO2 requires C, 67.26; H, 4.23; N, 4.90%); δH (360 MHz, d6 -DMSO) 3.73 (1H, s, CH3) 6.97 (1H, dt, J=0.8 and 7.4 Hz, 5'-H) 7.08 (1H, d, J=8.3 Hz, 3'-H) 7.22 (1H, dd, J=8.4 and 2.1 Hz, 6-H) 2.27 (1H, dd, J=7.5 and 1.7 Hz, 6'-H) 7.34 (1H, d, J=1.8 Hz, 8-H) 7.37 (1H, dt, J=1.7 and 8.2 Hz, 4'-H) 7.70 (1H, d, J=8.4 Hz, 5-H) 7.87 (1H, s, 4-H) 11.87 (1H, br s, NH); m/z (EI+) 285 (M+). The quinolone (300 mg) and boron tribromide (3.15 ml, 1N solution in CH2Cl2) were reacted as described in Example 20 to give 286 mg of 7-chloro-3-(2-hydroxyphenyl)-2(1H)-quinolone as a yellow crystalline solid; mp 246°-248° C. (dec) (methanol). (Found: C, 66.43; H, 3.70; N, 5.17. C15H10ClNO2 requires C, 66.31; H, 3.71; N, 5.15%); δH (360 MHz, DMSO-d6) 6.87 (1H, t, J=8.2 Hz, 5'-H), 6.90 (1H, d, J=7.8 Hz, 3'-H), 7.22 (1H, dt, J=1.7 and 7.8 Hz, 4'-H), 7.26 (1H, dd, J=8.4 and 2.1 Hz, 6-H), 7.31 (1H, dd, J=8.2 and 1.7 Hz, 6'-H), 7.39 (1H, d, J=2.1 Hz, 8-H), 7.77 (1H, d, J=8.4 Hz, 5-H), 8.03 (1H, s, 4-H), 9.56 (1H, br s, OH), 12.14 (1H, br s, NH); m/z (EI+) 271 (M+).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[Cl:7][CH2:8][C:9](=[N:11]O)[NH2:10].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:7][CH2:8][C:9]1[N:11]=[C:4]([CH2:3][C:1]#[N:2])[O:6][N:10]=1
Reactant: N#CCC(=O)O
Reactant: NC(CCl)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: N#CCc1nc(CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 8.50 g of cyanoacetic acid and 10.1 g of chloroacetamidoxime was added 20.6 g of N,N'-dicyclohexylcarbodiimide with ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with 20 ml of ethyl acetate and the insoluble material was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and the residue was dissolved in 50 ml of toluene. The resultant solution was heated under reflux for 20 minutes with a water separator. After cooling and adding 50 ml of ethyl acetate, the solution was decanted and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as eluent to give 8.18 g of 3-chloromethyl-5-cyanomethyl-1,2,4-oxadiazole as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14]C)=O)=[CH:4][NH:3]1.[OH-].[Na+].Cl.O=C1C2C(=CC=CC=2)C(C(O)=O)=CN1.S(Cl)(Cl)=O.[Cl-].[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH3+:42].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CO.ClCCl.CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:42][CH2:41][C:40]([O:39][CH3:38])=[O:43])=[O:14])=[CH:4][NH:3]1
Reactant: COC(=O)C[NH3+]
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Agent: Cl
Agent: O=C(O)c1c[nH]c(=O)c2ccccc12
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)c1c[nH]c(=O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
6.00 g (29.53 mmol) of methyl 1-oxo-1,2-dihydroisoquinoline-4-carboxylate were dissolved in 20 ml of methanol, and 20 ml of 6 N aqueous sodium hydroxide solution were added. The solution was heated at 80° C. for 3 h, cooled to room temperature and, with ice bath cooling, adjusted to pH=3 using concentrated hydrochloric acid. The resulting precipitate was filtered off through a Büchner funnel and washed with cold methanol. The filter cake was air-dried. This gave 5.65 g (99% of theory) of the desired 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 12.69 (br. s, 1H), 11.78 (br. s, 1H), 8.83 (d, 1H), 8.02 (d, 1H), 7.79 (t, 1H), 7.56 (t, 1H). Under an atmosphere of inert nitrogen gas, 0.200 g (1.057 mmol) of 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were dissolved in 5 ml of dichloromethane and, with 0.093 ml (1.269 mmol) of thionyl chloride and a drop of N,N-dimethylformamide, heated at the boil for 1 h. The solvent was then removed under reduced pressure and the residue was, under an atmosphere of inert nitrogen gas, dissolved in 5 ml of dichloromethane. To this solution, a solution of 0.245 mg (2.750 mmol) of 2-methoxy-2-oxoethanaminium chloride and 0.383 ml (2.750 mmol) of triethylamine in 5 ml of dichloromethane was added dropwise over a period of 10 min. The suspension was stirred overnight, and 5% strength sodium bicarbonate solution was then added. The solution was extracted with ethyl acetate, the phases were separated, the organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by chromatography (ethyl acetate:n-heptane 2:1). This gave 120 mg (40% of theory) of the desired methyl N-[(1-oxo-1,2-dihydroisoquinolin-4-yl)carbonyl]glycinate. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.62 (br. s, 1H), 8.81 (t, 1H), 8.24-8.21 (m, 2H), 7.73 (t, 1H), 7.55-7.52 (m, 2H), 3.99 (d, 2H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][OH:11])[CH:5]=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: COc1c(CO)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Manganese dioxide (2.29 g) was added at room temperature to a toluene (30 mL) solution of (2-chloro-6-cyclopropyl-2′,4′-difluoro-3-methoxybiphenyl-4-yl)methanol (1.07 g), and the mixture was stirred at 80° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered through celite, and then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (978 mg).