Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26](C4C=CC=CC=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:11](CCCC)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:40])=[CH:10][C:11]=3[CH2:16][CH2:17][CH2:18][CH3:22])[N:19]=2)=[CH:25][CH:26]=1
Reactant: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1 N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ8.2 (d, J=1.5 Hz, 1H), 7.95 (d, J 7.8 Hz, 1H), 7.66-7.63 (m, 3H), 7.52-7.35 (m, 4H), 6.73 (d, J 2.9 Hz, 3H), 4.20 (t, J=6.1 Hz, 2H), 3.02 (t, J=6.1 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.51-1.42 (m, 8H), 1.29 (quintet, J=7.2 Hz, 2H), 0.86 (t, J=7.1 Hz, 3H); MS (ES) m/e 514 (M+1).
Reaction SMILES: [N:1]1[C:9]([S:10]CC2OC(=O)C3C(C=2C2C=CC=CC=2)=CC=CC=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.Br[CH:30]([C:32]1[O:33][C:34](=[O:49])[C:35]2[C:40]([C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:31].O.N1C(S)=C2C(NC=N2)=NC=1.C([O-])([O-])=O.[K+].[K+]>>[N:1]1[C:9]([S:10][CH:30]([C:32]2[O:33][C:34](=[O:49])[C:35]3[C:40]([C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:31])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Reactant: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: Sc1ncnc2[nH]cnc12
Agent: [K+]
Solvent: O
Product: CC(Sc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Yield: 63 %

Procedure:
The title compound was made in a similar way as that of the compound of example 10, 3-(1-bromoethyl)-4-(3-fluorophenyl)-1H-isochromen-1-one (intermediate C6, 70 mg, 0.202 mmol), 9H-purine-6-thiol hydrate (34.3 mg, 0.202 mmol) and K2CO3 (27.9 mg, 0.202 mmol). The resulting mixture was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (53 mg, 63%).
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[NH3:17]>CC#N>[ClH:9].[Cl:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]([NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N
Reactant: Clc1ccccc1C(Br)c1ccccc1Cl
Solvent: CC#N
Product: Cl
Product: NC(c1ccccc1Cl)c1ccccc1Cl
Temperature: 94.5 °C
Reaction time: 0.5 h

Procedure:
Under N2, 1,1′-(bromomethylene)bis(2-chlorobenzene) (110 g, 0.35 mol) was dissolved in CH3CN (550 ml) at 20 to 25° C. Over 30 min, gaseous ammonia (28.5 g, 1.7 mol) was passed into the solution at 20 to 25° C. (slight cooling is necessary). The mixture was heated in an autoclave to 93 to 96° C. for 3 h at a pressure of 6 bar. The mixture was stirred at 93 to 96° C. and the reaction was followed by HPLC. After complete reaction (10 to 14 h), the mixture was cooled to 20-25° C. and degassed. The suspension was concentrated under vacuum at 45 to 50° C. to a volume of 140 ml. Water (330 ml) was added and the mixture was concentrated again to a volume of 330 ml. To the residue, TBME (550 ml) was added and the phases were separated. The aqueous layer was extracted with TBME (110 ml). The combined organic phases were washed with water (110 ml, then 55 ml). The organic layer was evaporated to dryness at 45 to 50° C. and co-evaporated with ethanol (165 ml). Ethanol (330 ml) was added to the residue and the suspension was filtered after 30 min at 0 to 5° C. The solid was washed with ethanol (55 ml) and the combined filtrates were concentrated at 45 to 50° C. to a volume of 160 ml. The residue was added over 60 min to a mixture of water (960 ml) and conc. HCl (56 ml) at 0 to 5° C. The suspension was stirred for 2 h at 0 to 5° C. and filtered. The product was washed with 55 ml cold water (0 to 5° C.) and dried in vacuum at 50° C. to constant weight. Yield: 81.1 g (81%). Assay (HPLC): 100% pure vs. standard
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH2:57][CH:58]([NH:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=1)[CH2:59][CH:60]([CH3:62])[CH3:61])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:71][C:68]1[CH:67]=[CH:66][C:65]([CH2:64][N:63]2[CH:58]([CH2:59][CH:60]([CH3:61])[CH3:62])[CH2:57][C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:70][CH:69]=1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)CC(CC(C)C)NCc1ccc(F)cc1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC(C)CC1CC(O)=C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.5 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.088 g, 0.249 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.104 g, 0.274 mmol) and 4-methylmorpholine (0.055 mL, 0.500 mmol) were added sequentially to a solution of rac-3-(4-fluoro-benzylamino)-5-methyl-hexanoic acid ethyl ester (0.070 g, 0.249 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 20 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.322 mL, 0.994 mmol) was added and the reaction mixture was heated to 60° C. for 4 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-6-isobutyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.032 g, 0.056 mmol, 23%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.81 (3H, d, J=6.3 Hz), 0.87 (3H, d, J=6.2 Hz), 1.30-1.37 (1H, m), 1.50-1.60 (1H, m), 2.47 (1H, d, J=18.0 Hz), 2.96 (3H, s), 3.10 (1H, dd, J1=6.4 Hz, J2=16.3 Hz), 3.35-3.40 (1H, m), 3.51-3.55 (1H, m), 4.14 (1H, d, J=14.9 Hz), 4.24 (2H, d, J=5.5 Hz), 5.04 (1H, d, J=15.1 Hz), 7.13-7.18 (2H, m), 7.24 (1H, s), 7.36-7.39 (2H, m), 7.64 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C23H27FN4O6S3 570.11. found 571.3 [M+H+].
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8]1([C:14]2[CH:18]=[C:17](NC3C=CC=CC=3)[NH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>C(#N)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:3][C:6]2[CH:7]=[CH:10][C:9]([C:17]3[CH:18]=[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:15][N:16]=3)=[CH:8][CH:13]=2)=[O:35])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ccc(Nc2cc(-c3ccccc3)n[nH]2)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 23.4 %

Procedure:
Triethylamine (64 mL, 0.45 mmol) was added to a suspension of N-[4-(3-phenyl-1H-pyrazol-5-yl)aminobenzene (0.102 g, 0.43 mmol) and 4-chloro-3-trifluoromethyl-phenylisocyanate (0.096 g, 0.43 mmol) in anhydrous acetonitrile (2.0 mL) at room temperature. After twelve hours the reaction was concentrated in vacuo and purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title compound (23 mg, 16% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 9.01 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.81 (m, 2H), 7.74 (m, 2H), 7.62 (m, 2H), 7.53 (m, 2H), 7.42 (t, J=8.0 Hz, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.10 (s, 1H); MS (EI) for C23H16ClF3N4O: 457.1 (MH+).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][NH:4][C:3]1=[O:7].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1>Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:1][N:2]2[CH:6]=[N:5][NH:4][C:3]2=[O:7])[CH:9]=1
Reactant: Nn1cn[nH]c1=O
Reactant: O=Cc1cccnc1
Agent: Cl
Product: O=c1[nH]ncn1N=Cc1cccnc1

Procedure:
A mixture of 4 g of 4-amino-1,2,4-triazol-3-one and 100 ml of alcohol is heated to the reflux temperature and 4.3 g of pyridine-3-carbaldehyde and 2 drops of 6N hydrochloric acid are added thereto. After 30 minutes under reflux the reaction mixture is cooled to 20°. The product that has precipitated is then filtered off with suction and dried under a high vacuum. 4.6 g of the title compound having a melting point of 264°-265° are obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[S:5](=[O:18])(=[O:17])[N:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:3]1.[Li+].[OH-]>C1COCC1.CO.O>[CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[S:5](=[O:17])(=[O:18])[N:4]([CH2:19][C:20]([OH:22])=[O:21])[CH2:3]1
Reactant: COC(=O)CN1CC(C)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1CN(CC(=O)O)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To methyl 2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetate (2.3 g, 5.4 mmol) in THF (12 mL) and MeOH (12 mL), was dropwisely added LiOH (1.1 g, 27.0 mmol) in H2O. The reaction mixture was agitated for 3 hr at room temperature. After the completion of the reaction, the resultant was concentrated and its pH was adjusted down to 3 with 2 N HCl after the addition of water. The resultant was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure, giving the title compound (2.0 g, y=83%, solid). 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=2.4 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 4.53 (d, J=17 Hz, 1H), 4.16-3.88 (m, 4H), 3.40-3.38 (m, 1H), 3.20-3.15 (m, 1H), 2.57-2.11 (m, 1H), 0.93 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]1([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([C:21]3[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>O.O1CCOCC1>[C:6]1([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)=[N:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(-c2nn(-c3ccccc3)c3ncccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(-c2nn(-c3ccccc3)c3ncccc23)cc1
Yield: 59.7 %

Procedure:
In 300 ml of water was dissolved 5.1 g of sodium hydroxide, and 800 ml of ethanol was added to the solution. While stirring, thereto was added a solution of 40 g of ethyl 4-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenoxyacetate dissolved in 200 ml of dioxane. After the mixture was stirred at room temperature for 4 hours, it was poured into about 3 l of cold water. The mixture was neutralized by the addition of dilute hydrochloric acid. The resulting crystals were collected by filtration and recrystallized from hydrous dioxane to give 22.1 g of 4-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenoxyacetic acid, m.p. 220°-222° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.[CH3:24][N:25](C)C=O.O.[C-]#N.[Na+]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:24]#[N:25])[CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CN1CCC(=C2c3ccccc3CCc3ccc(Br)cc32)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CN1CCC(=C2c3ccccc3CCc3ccc(C#N)cc32)CC1

Procedure:
A mixture of 9.17 gm. (0.0249 mol) of 1-methyl-4-(3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4.58 gm. (0.0498 mol) of cuprous cyanide, and 30 ml. of dry dimethylformamide is stirred and heated under reflux for 6.5 hr. To the cooled solution (25° C.) is added 54 ml. of water, 27 ml. of a saturated aqueous solution of sodium cyanide, and 75 ml. of benzene. The mixture is stirred until a two phase system is obtained. The benzene phase is removed and the aqueous phase is extracted with two 75 ml. portions of benzene. The combined benzene phases are washed with 100 ml. of aqueous 0.1M sodium cyanide, three 100 ml. portions of water, and dried over magnesium sulfate. After filtering, evaporation of the benzene gives 7.40 gm. of a crystalline residue. This material is dissolved in the minimum volume of chloroform and passed over an alumina column (15" × 1-) packed in chloroform. The column is eluted with chloroform. Evaporation of the chloroform gives a crystalline product that is recrystallized from isopropyl alcohol to give pure 1-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 152°-154° C.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][C:15]3=[C:18]([C:21]([NH2:23])=[O:22])[NH:19][N:20]=[C:14]3[CH2:13]2)=[N:10][CH:11]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[NH:35][C:36](=[O:37])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][C:15]3=[C:18]([C:21]([NH2:23])=[O:22])[NH:19][N:20]=[C:14]3[CH2:13]2)=[N:10][CH:11]=1
Reactant: NC(=O)c1[nH]nc2c1CCN(c1ccc(N)cn1)C2
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: NC(N)=O
Product: NC(=O)c1[nH]nc2c1CCN(c1ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cn1)C2

Procedure:
The urea function is introduced onto the 6-(5-aminopyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxamide according to the method described in Example 1, using 2-fluoro-5-(trifluoromethyl)phenyl isocyanate, and results in the obtaining of 6-{5-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]pyridin-2-yl}4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carb-oxamide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[OH:35]>CN1C(=O)CCC1.CCOC(C)=O.O>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[O:35][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1ccn2nc(Oc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
To a solution of 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (250 mg, 0.85 mmol) and Cs2CO3 (834 mg, 2.56 mmol) in NMP was added 2,4 difluoro phenol (211 mg, 1.7 mmol). The mixture was heated to 90° C. for 2 hrs until the reaction was complete via LCMS analysis. The reaction was cooled to ambient temperature and diluted with EtOAc and H2O. The aqueous layer was washed with EtOAc and the combined organic layers were washed with 1N NaOH, H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.
Reaction SMILES: [Na].[C:2]([O:11]C)(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[SH:5].[C:13]1([NH:19][C:20](=[N:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:24]1([NH:23][C:20]([C:21]2[S:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[C:2]=2[OH:11])=[N:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCC(=Nc1ccccc1)Nc1ccccc1
Reactant: COC(=O)c1ccccc1S
Agent: [Na]
Solvent: CO
Product: Oc1c(C(=Nc2ccccc2)Nc2ccccc2)sc2ccccc12
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A solution of 2.3 g (0.1 mol) of sodium in 150 ml of methanol is mixed with 16.8 g (0.1 mol) of methyl thiosalicylate and then a solution of 24.4 g (0.1 mol) of N,N'-diphenyl-2-chloroacetamidine in 250 ml of methanol is added. After heating under reflux for 1 hour, the mixture is poured into ice water and the precipitate filtered and recrystallized from an ethanol/water solution to yield 26.5 g of yellow needles having an m.p. of 152-153° C.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCC1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of formic acid (15.3 mL, 0.4 mol) in dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.75 mL, 60 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cyclohexanecarboxylic acid from Preparation 19 (4.41 mmol theoretical) in dichloromethane (50 mL) was added. The mixture was stirred at room temperature for 18 h and was concentrated in vacuo. Brine (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale, orange oil (1.77 g, 100%). MH+292.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=C[C:9](F)=[C:8](C#N)[CH:7]=1)[CH3:2].[C:16]([NH:19][OH:20])(=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+].C[N:28](C=O)C>O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:20][N:19]=[C:16]([NH2:28])[C:17]=2[CH:11]=1)[CH3:2]
Reactant: CC(=O)NO
Reactant: CCOC(=O)Cc1ccc(F)c(C#N)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1ccc2onc(N)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a solution of (3-cyano-4-fluoro-phenyl)-acetic acid ethyl ester (Preparation 127, 400 mg, 1.93 mmol) and acetohydroxamic acid (362 mg, 4.83 mmol) in DMF (40 mL) and water (15 mL) was added potassium carbonate (1.6 g, 11.58 mmol) and the reaction mixture stirred at room temperature for 12 hours. The reaction mixture was diluted with water (100 mL) and the resulting white precipitate and collected by filtration. The crude material was purified by silica gel column chromatography eluting with a gradient of dichloromethane:methanol 100:0 to 97:3 to afford the title compound as an off-white solid in 59% yield, 250 mg.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([C@@H:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([C@@H:42]4[CH2:46][CH2:45][O:44][CH2:43]4)[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1cnn([C@@H]2CCOC2)c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnn([C@@H]3CCOC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 31 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(R)-tetrahydro-furan-3-yl]-1H-pyrazole following a procedure analogous to that described in Example 1. Yield: 31% of theory; LC (method 3): tR=3.16 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:18][C:19]([NH:21][C:22]1([C:25]2[C:26]([F:44])=[C:27](F)[C:28]3[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]4[CH:31]([CH3:35])[CH2:32][O:33][C:34]=2[C:29]=34)[CH2:24][CH2:23]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:8][C:27]1[C:28]2[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]3[CH:31]([CH3:35])[CH2:32][O:33][C:34]([C:29]=23)=[C:25]([C:22]2([NH:21][C:19]([O:18][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:20])[CH2:23][CH2:24]2)[C:26]=1[F:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(OCc3ccccc3)c3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
In 2 ml of N,N-dimethylformamide was dissolved 230 mg of benzyl alcohol. To the resulting solution was added 85 mg of 60% sodium hydride with ice-cooling. The resulting mixture was stirred at room temperature for 30 minutes. Thereto was added, with ice-cooling, 250 mg of 10-(1-benzyloxycarbonylaminocyclopropyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was added to a mixture of 15 ml of ethyl acetate and 15 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/ethanol=10/1) to obtain 73.0 mg (yield: 24.6%) of 8-benzyloxy-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.