Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH3:32][N:33]([CH3:37])[C:34]([N:2]([CH3:1])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:35]
Reactant: CN(C)C(=O)Cl
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (67 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH:NH3 (90:5:5) to give the title compound (84 mg, 39%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.90-6.88 (d, 2H), 4.03 (t, 2H), 3.81-3.78 (m, 2H), 3.56-3.52 (m, 4H), 2.70 (s, 6H), 2.66 (t, 2H), 2.29 (s, 3H), 2.05-2.01 (m, 4H), 1.86-1.81 (m, 6H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([NH:17]C(OC(C)(C)C)=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:7][CH2:8][C@H:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(=O)C(C)(C)C)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)OC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A cooled solution of compound 94 (1.006 g, 3 mmol) in CH2Cl2 (10 ml) at 0° C. was treated with trifluoroacetic acid (2.5 ml) and stirred for 1 hr at room temperature. The mixture was concentrated in vacuo to give compound 96 as a yellow oil which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:21][CH2:22][N:23]([C:33]([NH:32][C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:24][CH2:25]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)ccc2Cl)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCC(=Cc2ccc(Cl)c(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
To a solution of 2-(2-chloro-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (250 mg, 0.677 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (137.9 mg, 0.643 mmol) followed by triethylamine (0.24 mL, 1.69 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% acetone-70% hexane) to give the pure title compound (180 mg, 54% yield). 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.95 (d, J=7 Hz, 1H), 7.33 (s, 1H), 7.18 (d, J=3.5 Hz, 2H), 7.12 (d, J=8 Hz, 1H), 6.72 (s, 1H), 6.37 (s, 1H), 3.64 (m, 2H), 3.56 (m, 2H), 2.62 (m, 2H), 2.49 (m, 2H); 13C NMR (125 MHz, CDCl3): δ164.98, 154.54, 147.45, 145.35, 145.32, 143.84, 141.01, 138.68, 136.94, 136.22, 136.10, 130.79, 128.50, 127.62, 127.07, 126.69, 123.61, 123.45, 122.05, 121.78, 111.19, 45.68, 44.61, 40.91, 35.69, 29.14, 28.47; m/z (489.3, 491.1 M+ H+); HPLC: 96.8%.
Reaction SMILES: [N:1]#[C:2]Br.CO.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([NH2:14])=[C:9]([NH2:15])[CH:8]=1.C>CC#N.O>[NH2:1][C:2]1[NH:15][C:9]2[CH:8]=[C:7]([Cl:6])[C:12]([Cl:13])=[CH:11][C:10]=2[N:14]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: N#CBr
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 24 h

Procedure:
A modified procedure of the procedure described by Leonard, N. J., et al., J. Am. Chem. Soc. 69:2459 (1947), was followed. Cyanogen bromide (136.6 g, 1.3M, 260 mL of a 5M solution in CH3CN from) was added to a solution of MeOH (250 mL) in H2O (1500 mL). 4,5- Dichloro-1,2-phenylenediamine (available commercially from Aldrich Chemical Company) (222.4 g, 1.26M) was then added in five portions, as the initial reaction is exothermic. The reaction mixture was stirred without heating for 80 hr. then treated with activated charcoal (5 g). The 80 hr time period was for convenience alone, since the reaction is probably complete within 24 hr. After stirring for two hrs, the reaction mixture was filtered through Celite. The filter cake was washed with MeOH (250 mL) and H2O (750 mL) and the filter cake was discarded. The filtrate was diluted with H2O (1.5 L), adjusted to pH 10 with conc. NH4OH (1750 mL) and then allowed to stand overnight at 5° C. The precipitate (yellow leaflets) was collected by filtration, washed with H2O and then dried under reduced pressure at 50° C. for 60 hr. Crude yield: 265 g. This product was purified by recrystallization from CH3CN to yield: 205.6 g (80.7%) of 4. MP: 264°-266° C. TLC: Rf =0.22 (CHCl3 -MeOH), 10:1; SiO2). See Homer, J. K. et al., J. Med. Chem. 11:946-949 (1968), lit. MP: 260°-262° C. As an alternative, the crude material is dissolved in absolute ethanol, treated with activated charcoal, and the solution diluted with an equal volume of H2O and stored at 5° C. for 18-24 hr.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].OOS([O-])=O.[K+].[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[OH2:24]>CO>[CH3:15][S:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:2])=[O:24]
Reactant: O
Reactant: CSc1ccc(O)cc1
Reactant: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
A suspension of potassium peroxymonosulphate (120 g) in the form of OXONE (Trademark) in water (100 ml) was slowly added to a solution of 4-methylmercaptophenol (15 g) in methanol (50 ml). The reaction mixture was stirred for 2 hours. Water (500 ml) was added and the resulting mixture extracted with ethyl acetate (200 ml and 100 ml). The ethyl acetate extracts were combined, washed with water (800 ml), dried (MgSO4) and evaporated to give 4-methylsulphonylphenol (11.54 g) as a colourless oil which slowly crystallised on standing, NMR(CDCl3): 3.06(3H,s), 6.80(1H,s), 6.98(2H,d) and 7.79(2H,d); m/z 190 (M+NH4).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>O.[OH-].[Na+]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:2])=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(S(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4.49 g of sodium metaperiodate in 80 ml of water is added a solution of 5.57 g of [p-(p-chlorophenylthio)phenyl]acetic acid in 75 ml of 1.75% NaOH. A white solid precipitates immediately. After stirring overnight the mixture is filtered and the filtrate is acidified with concentrated HCl to give a white solid. This product, which contains some starting material, is reworked, as above, to yield the pure product. Recrystallization from chloroform-hexane affords white crystals, mp 139°-141° C and 144°-148.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=CC2C3C(=CC=CC=3)C[C:4]=2[C:3]=1Br.[OH-].[K+].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([C:27]([NH3+])([C:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=O)[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=O)=O.[Cl-].C([Br:56])CCCCCCC>ClCCl>[Br:56][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[C:25](=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3)[C:27]([CH2:37][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([CH2:28][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:18]=2[CH:19]=1
Reactant: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Reactant: Brc1ccc2c(c1Br)Cc1ccccc1-2
Reactant: CCCCCCCCBr
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dibromofluorene (320 g) prepared previously (as described above) is added to a KOH solution (1-l, 50% w/w) and Aliquat-336 (3 ml) at 85° C. in a 3 l three-necked round bottomed flask equipped with a magnetic stirrer, reflux condenser and dropping funnel. The suspension was heated to 85° C. at which temperature n-octylbromide (500 ml) is added dropwise, to form eventually a two-phase system. Once the addition is complete the reaction is stirred at 85° C. overnight, and then allowed to cool to room temperature. Dichloromethane is then added to the reaction mixture (500 ml).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:5]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][C:17]#N)[CH:8]=[CH:7]2.Cl.C[OH:31]>>[Cl:3][C:4]1[C:5]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:31])=[O:1])[CH:8]=[CH:7]2
Reactant: N#CCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [K+]
Product: O=C(O)CCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Temperature: 50 °C

Procedure:
Potassium hydroxide (2 mL, 50% solution in water) was added to a stirred solution of N-[6-chloro-2-(3-cyanopropyl)-5-quinolinyl]-cyclohexaneacetamide (Example 67(a)) (190 mg) in methanol (2 mL). The reaction mixture was heated to 50° C. for 6 hours then allowed to cool. The mixture was acidified with aqueous 2M hydrochloric acid until a precipitate formed which was collected by filtration. Purification by HPLC (Symmetry—0.1% aqueous ammonium acetate/acetonitrile) afforded the title compound as a solid (45 mg).
Reaction SMILES: N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.[OH-].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:30]Cl>C(O)C>[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:30][O:26][C:22]1[CH:21]=[C:20]([Br:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)CCCC(C)CCCl
Reactant: Oc1cccc(Br)c1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCCC(C)CCOc1cccc(Br)c1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
450 ml of ethanol were initially introduced, and Nal (10.5 g; 70 mmol) and KOH (67.3 g; 1.2 mol) were added. A temperature increase from 25 to 40° C. after addition of the KOH was observed. After the mixture had been cooled to room temperate, 3-bromophenol (176.5 g; 1 mol) was added, during which the white suspension became beige. 3,7-Dimethyloctyl chloride (186.32 g; 212.94 ml; 1.05 mol) was added over the course of 3 minutes via a dropping funnel. The mixture was stirred at RT for a further 2 hours and subsequently stirred at an internal temperature of 80° C. for 96 hours. Ethanol was distilled off. The residue was taken up in ethyl acetate, and the precipitate was separated off by filtration. The organic phase was extracted three times with 10% strength by weight aqueous NaOH solution and washed once with H2O, three times with H2O which had been acidified using CO2 and again with H2O. After the mixture had been dried using MgSO4, the solvent was stripped off again in a rotary evaporator, and the crude product was purified by fractional distillation under reduced pressure.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:11][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[NH:9][CH:8]=1
Reactant: O=c1[nH]cnc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2c(Br)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (200 mg, 1.5 mmol, 1 equiv.) and N-bromosuccinimide (320 mg, 1.8 mmol, 1.2 equiv.) in 10 mL of DMF was stirred for 18 hours at room temperature. The reaction was diluted with water and resulting solid was collected by filtration, dried, suspended in MeOH, and filtered. The filtrate was concentrated in vacuo to provide 7-bromo-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a beige solid which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N+:11]([O-:13])[CH2:12][C:6]2=[N:5][N:4]=1.[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:8]2[N:7]3[C:3]([CH2:2][N:26]([CH3:27])[CH3:25])=[N:4][N:5]=[C:6]3[CH2:12][N+:11]([O-:13])=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[CH:20]=1
Reactant: CNC
Reactant: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2-n2c(CBr)nnc2C1
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2

Procedure:
To a suspension of 2.0 parts of 1-bromomethyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-oxide in 20 volume parts of dimethylformamide is added 5 volume parts of 40 weight % aqueous solution of dimethylamine under stirring, and the resulting solution is stirred for 30 minutes at room temperature. After removing the solvent, the crystalline residue is recrystallized from ethyl alcohol to give 8-chloro-1-dimethylaminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-oxide as colorless prisms melting at 217° to 219° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH:11]1([N+:17]#[C-:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>Cl(O)(=O)(=O)=O>[CH:11]1([NH:17][C:18]2[N:3]3[C:4]([CH3:10])=[C:5]([Br:9])[CH:6]=[C:7]([Br:8])[C:2]3=[N:1][C:23]=2[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[O:20][CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1nc(N)c(Br)cc1Br
Reactant: [C-]#[N+]C1CCCCC1
Reactant: COc1ccccc1C=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1nc2c(Br)cc(Br)c(C)n2c1NC1CCCCC1

Procedure:
Compound (11) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3,5-dibromo-6-methylpyridine solution (0.1 M, DCM), 0.575 ml of cyclohexyl isocyanide solution (0.2 M, DCM), 0.500 ml of 2-methoxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH3:17])[C:3](=[O:6])[CH:4]=[CH2:5].[NH2:18][C:19]1[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:18][C:19]1[N:24]=[CH:23][C:22](/[CH:5]=[CH:4]/[C:3]([N:2]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH3:17])[CH3:1])=[O:6])=[CH:21][N:20]=1
Reactant: Nc1ncc(Br)cn1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc(N)nc1
Yield: 128.8 %

Procedure:
A solution of N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide (1.18 g, 6.5 mmole), 2-amino-5-bromopyrimidine (0.5 g, 2.9 mmole), Pd(OAc)2 (0.11 g, 0.49 mmole), tri-ortho-tolylphosphine (0.17 g, 0.55 mmole), and diisopropylethylamine (1.5 mL, 8.6 mmole) in propionitrile (100 mL) and DMF (10 mL) was heated at reflux overnight. The dark mixture was filtered through Celite®, and the filtrate was concentrated. Flash chromatography on silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (1.2 g, 65%): MS (ES) m/e 372 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH3:18])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[Na+].[Na+].O.[CH2:26]([OH:28])[CH3:27]>C1(C)C=CC=CC=1.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>[C:26]([C:19]1[O:22][C:2]2[C:1]([C:4]3[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:6]([CH3:7])[CH3:5])[C:5]=3[O:16][CH2:17][CH3:18])=[CH:3][CH:9]=[CH:4][C:1]=2[CH:2]=1)(=[O:28])[CH3:27]
Reactant: CCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: CCO
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-diisopropyl-2-ethoxy phenylboronic acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example 4, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-7-(3,5-diisopropyl-2-ethoxyphenyl)-benzo[b]furan as a clear yellow pasty solid.
Reaction SMILES: [OH-].[K+].O.[C@@H:4]1([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]([O:28]CC)=[O:27])[C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>CO>[C@@H:4]1([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]([OH:28])=[O:27])[C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCOC(=O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Temperature: 50 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 24 g of potassium hydroxide, 80 ml of water, 240 ml of methanol, and 20 g (0.035 mol) of ethyl 7-β-galactosylcoumarin-3-carboxylate [Burd et al, Clin. Chem. 23:1402 (1977)] was stirred at 50° C. for 15 hours. When cool, the methanol was removed under reduced pressure. The concentrated aqueous solution was acidified to pH 2 with concentrated hydrochloric acid. The precipitate was collected, washed with cold water, and recrystallized from hot water. The crystals were collected, washed with acetone, and dried at 80° C. for 1 hour. This gave 12 g (54% yield) of 7-β-galactosylcoumarin-3-carboxylic acid as white crystals, mp 250°-255° C.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[CH3:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:74])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[C:48]([C:70]([F:73])([F:72])[F:71])[CH:47]=2)[CH:39]=[CH:40][C:41]=1[CH3:42]>>[CH3:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:74])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[C:48]([C:70]([F:73])([F:71])[F:72])[CH:47]=2)[CH:39]=[CH:40][C:41]=1[CH3:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C)c(C)c4)cc3C(F)(F)F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(C(F)(F)F)c2)cc1C
Yield: 92 %

Procedure:
The compound of example 422 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 421.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(O)C>[OH:32][CH2:31][CH2:33][NH3+:34].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([O-:30])=[O:29])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Reactant: NCCO
Solvent: CCO
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)[O-])cn(C5CC5)c4c3F)C2)nn1
Product: [NH3+]CCO
Reaction time: 8 h

Procedure:
A suspension of 2 0 mg (0.05 mmol) of 1-cyclopropyl-6,8-difluoro-7-[3-(4-methyl-1,2,3-triazol-1-yl) pyrrolidine-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 2 ml of ethanol was reacted with 3.054 mg (0.05 mmol) of ethanolamine at room temperature for 2 hr. Additional equivalent of ethanolamine was added and the reaction mixture was stirred overnight. The solid was then collected, m.p. 215.5°-216.8° C. 1H NMR (D20) δ: 8.46 (s, 1H), 7.86 (bs, 1H), 7.68 (bd, 14Hz, 1H), 5.46-5.25 (m, 1H), 4.4-3.7 (m, 7H), 3.17-3.07 (m, 2H), 2.76-2.2 (m, 5H), 2.31 (s, 3H), 1.3-1.0 (m, 4H). Anal. calcd. for C22H26F2N6O4H2O: C, 53.44; H, 5.71; N, 16.99. Found: C, 53.68; H, 5.93; N, 16.48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14](=O)[NH:15][N:16]=[CH:17][C:18]=2[N:19]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:14]1[C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:19][C:18]=2[CH:17]=[N:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc2nc(Nc3ccc(F)cc3F)ccc12
Product: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Temperature: 100 °C

Procedure:
A heterogeneous mixture of 2-(2,4-difluorophenylamino)pyrido[3,2-d]pyridazin-5(6H)-one (1.08 g, 3.9 mmol) and phosphorus oxychloride (10.00 mL, 39 mmol) was heated at 100° C. for 1.5 h. The excess POCl3 was removed on the rotovap and the crude residue was treated with ice cold 1N NaOH. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether, and dried in a vacuum oven at 45° C. for 18 h to provide 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine as a tan solid. MS (ESI, pos.ion) m/z: M+1=293.0
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24](Cl)=[O:25])[S:22][CH:23]=1)[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].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:25])[S:22][CH:23]=1)[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: CS(N)(=O)=O
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)NS(C)(=O)=O)c1

Procedure:
A solution of 25 g. of 4-hexadecylamino-2-thiophenecarbonyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N hydrochloric acid and the organic layer seperated, dried over magnesium sulfate, and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords the product as a white solid.