Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1)#[N:29]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[C:34]([F:36])[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 290 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 3-Cyano-5-Fluorophenylboronic acid to afford a white solid. HPLC (Condition 10) tR=6.383 min, UPLC-MS (Condition 11) m/z=503.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.81-1.93 (m, 1H) 2.86 (d, J=10.95 Hz, 1H) 3.14-3.29 (m, 2H) 3.35-3.49 (m, 1H) 4.21 (br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.67 (d, J=9.38 Hz, 1H) 7.79 (s, 1H) 7.83-7.91 (m, J=8.99 Hz, 3H) 8.06 (d, J=1.96 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][CH2:7][C:8]([OH:10])=[O:9]>>[C:1]([O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: O=C(O)CO
Product: CCC(=O)OCC(=O)O

Procedure:
a solution consisting of propionyl chloride (64.7 g, 0.7 mol) and hydroxyacetic acid (19.0 g, 0.25 mol) is heated at 40° C., until the hydroxyacetic acid has completely dissolved. The excess propionyl chloride is then distilled off and 35.6 g of crude product containing 82% of (propionyloxy)acetic acid is obtained as a colorless liquid. The crude product can be used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:31])CC.S(=O)(=O)(O)O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][N:21]2[CH:28]=[O:31])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3C(=O)NC(=O)CN3C=O)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1 g of 2-[3,5-dichloro-4-(4-methylsulfonylphenoxy)phenyl]hexahydro-1,2,4-triazine-3,5-dione was suspended in 10 ml of formic acid. 5 ml of propionyl chloride and 1 ml of concentrated sulfuric acid were successively added dropwise, and the mixture was stirred at 80° C. for 5 hours. After it had been cooled, a further 10 ml of propionyl chloride were added to complete the reaction, and the mixture was again heated at 80° C. for 5 hours with stirring. It was then poured onto ice-water, and the precipitate was filtered off with suction and extracted by boiling with a little toluene. The residue was recrystallized from isopropanol/diisopropyl ether, melting point 212° C., decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[O:20]=[C:21]1[CH:25]([C:26](O)=[O:27])[CH2:24][CH2:23][NH:22]1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([CH:25]2[CH2:24][CH2:23][NH:22][C:21]2=[O:20])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: O=C(O)C1CCNC1=O
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCC1C(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 150.0 mg, 0.388 mmol), 2-oxopyrrolidine-3-carboxylic acid (100.3 mg, 0.777 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (223.4 mg, 1.17 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (157.5 mg, 1.17 mmol), N-ethyl-N-isopropylpropan-2-amine (0.347 ml, 1.94 mmol) and THF (100 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (EtOAc/Hexane from 1/4 to 4/1, v/v) to afford product (85.0 mg, 44%). LRMS (APCI pos): >97% purity, 254 nm, m/e 498 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13](=[O:17])[CH:14]([Br:16])[CH3:15])[CH:6]=[C:7](C(F)(F)F)[CH:8]=1.[F:20]C(F)(F)C1C=C(C(=O)CC)C=C(C(F)(F)F)C=1>>[Br:16][CH:14]([CH3:15])[C:13]([C:5]1[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:8]=[C:7]([F:20])[CH:6]=1)=[O:17]
Reactant: CCC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(Br)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(Br)C(=O)c1cc(F)cc(C(F)(F)F)c1
Yield: 86 %

Procedure:
1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one: A stirred suspension of 1 g (3.7 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-propan-1-one (Lancaster, Windham, N.J., USA) treated in a manner similar to that for Example 127, step (a) to give 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one (1.1 g, 86%). 1H-NMR (DMSO-d6; 300 MHz) δ 8.46 (m, 2H), 8.09 (m, 1), 5.26 (q, 1H, J=6.6 Hz), 1.96 (d, 3H, J=6.5 Hz). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C11H7OBrF6, 349.0 (M+H), found 348.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][C:27]([OH:29])=[O:28]>CN(C=O)C>[C:12]([O:29][C:27](=[O:28])[CH2:26][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[C:14]1=[O:18])([CH3:17])([CH3:13])[CH3:11]
Reactant: O=C(O)CBr
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)NCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CC(=O)OC(C)(C)C)CC3)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Part A: 1-(4-Methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (2.0 g, 6.43 mmol) was stirred in dry DMF (8 mL) at 0° C. NaH (60%, 0.35 g, 8.75 mmol, 1.4 eq) was added. Bromoacetic acid and t-butyl ester (1.0 mL, 6.77 mmol, 1.1 eq) were added dropwise. The mixture was stirred at 0° C. for 2 h and at rt overnight. The reaction was quenched with H2O, extracted with EtOAc, washed with brine, concentrated, and purified by silica gel chromatography (1:1 EtOAc:hexanes) to give pure [1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-acetic acid tert-butyl ester (2.73 g, yield: 99%).
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[O:4][C:3]1([F:15])[F:14].S(=O)(=O)(O)[OH:18]>O>[F:16][C:2]1([F:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([NH2:13])=[O:18])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:15]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Solvent: O
Product: NC(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile (200 mg) were added concentrated sulfuric acid (2 mL) and water (0.3 mL) at room temperature. The reaction mixture was stirred at 40° C. for 3 hr, water was added and the mixture was stirred for 40 min at room temperature. The resulting solid was collected by filtration, washed with purified water, and dried under reduced pressure to give the title compound (190.6 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1>>[Cl:27][C:28]1[CH:33]=[C:32]([CH2:34][O:35][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH:31]=[CH:30][N:29]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccnc(Cl)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and (2-chloro-pyridin-4-yl)-methanol (111 mg; 0.736 mmol), example 88 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:8])[CH:6]=O)C.Cl.[OH:10][CH2:11][C:12]([NH2:14])=[NH:13]>>[OH:10][CH2:11][C:12]1[N:14]=[CH:4][C:5]([CH3:8])=[CH:6][N:13]=1
Reactant: N=C(N)CO
Reactant: CCOC=C(C)C=O
Agent: Cl
Product: Cc1cnc(CO)nc1

Procedure:
2-Hydroxymethyl-5-methylpyrimidine was prepared by the reaction of 3-ethoxy-2-methyl acrolein and hydroxyacetamidine hydrochloride following a similar procedure to that described by Kim and McKee (J. Org. Chem., 35, 455 (1970)). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.32 (3H,s); 3.6 (1H,bs); 4.80 (2H,s); 8.54 (2H,s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[S:6][N:5]=1)[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:27][CH3:28])[C:15]([NH:14][C:7]1[S:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:23])[CH3:25]
Reactant: CCOC(=O)c1c(OCC)nsc1NC(=O)Oc1ccccc1
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)nsc1NC(=O)N(CC)CC
Yield: 40.6 %

Procedure:
In the manner of Example II B, 8.4 g of phenyl (3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)carbamate in 20 ml of dimethylformamide were allowed to react with 3.7 g of diethylamine. The solid from the reaction mixture was recrystallized from ethanol:water (70:30) to give 3.2 g of 1,1-diethyl-3-(3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)urea, m.p. 77°-80°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](O)=[O:13])(O)=[O:2].B.[H][H]>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Reactant: [H][H]
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccccc1CCO
Temperature: 0 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
(2-Carboxymethyl-phenyl)-acetic acid (5.0 g/25 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Borane (1 M in THF, 100 mL/100 mmol) was then added dropwise while stirring (hydrogen evolution). The reaction was left to stir a 0° C. for four hours then carefully quenched by the addition of water (ca. 20 mL). The reaction was partitioned between diethyl ether (200 mL) and water (200 mL). The organic layer was extracted with an additional portion of ether (100 mL) and the combined organics washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated. To give 2-[2-(2-Hydroxy-ethyl)-phenyl]-ethanol (3.3 g/80%). 1H NMR (400 MHz, CDCl3) δ 7.2 (m, 4H), 3.9 (t, J=6.8 Hz, 4H), 2.95 (t, J=6.8 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([O:17][C:18]([C:20]#[C:21][C:22](OCCCC)=[O:23])=[O:19])[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:13]([O:17][C:18]([C:20]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CCCCOC(=O)C#CC(=O)OCCCC
Solvent: CCO
Product: CCCCOC(=O)c1cc(=O)nc2scc(-c3ccccc3)n12
Reaction time: 48 h

Procedure:
A mixture of 8.8 g of 2-amino-4-phenylthiazole, 50 ml of absolute ethanol and 11.3 g of acetylene dicarboxylic acid di-n-butyl ester is heated to 50° to 60° C. for about 10 minutes. After standing for 2 days at room temperature the solution is evaporated to dryness. The residue is dissolved in ethyl acetate, filtered and the filtrate is mixed with an equal volume of ether. The precipitate is filtered off. 3-phenyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid n-butyl ester is thus obtained. Yield: 5 g=30.5% of the theoretical. Melting point 152°-154° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:17][CH2:18][CH2:19][OH:20]>CN(C)C=O>[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:17][CH2:18][CH2:19][OH:20])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OCCCBr
Reactant: CCCCCOc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(OCCCO)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 0.80 g of 60% NaH in 28 ml of anhydrous dimethylformamide is cooled in an ice bath. To this is added 3.01 g of the above 3-pentyloxyphenol oil dissolved in 7 ml of anhydrous dimethylformamide. This mixture is then stirred at room temperature for 45 minutes; 1.81 ml of 3-Bromopropanol are added; and the resultant mixture is stirred at 60° C. for 17 hours. The solvent is removed under vacuum, and the residue worked up in same manner as above. The residue obtained is flash chromatographed on normal phase silica gel eluting with a 3:2 ratio of hexane:ether to yield 3-[3-(pentyloxy)phenoxy]propanol as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:6])=[CH:3][C:2]=1[O:1][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(N)c(OCCCCC)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 142.3 %

Procedure:
3-Hydroxy-4-nitrobenzoic acid (5 g, 27.4 mmol), DMF (40 ml), potassium carbonate (13.8 g, 100 mmol) and pentyl bromide (8.7 ml, 70 mmol) were mixed, and this solution was stirred at 100° C. for 1.5 hours. The reaction mixture was filtered to remove the inorganic salt, and DMF was evaporated under reduced pressure. Ethyl acetate (100 ml) was added to the obtained residue, and the mixture was washed 3 times with saturated brine (30 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (150 ml) and 10% palladium carbon catalyst (0.5 g) were added to the obtained residue, and the mixture was stirred at room temperature for 5.5 hours in a stream of hydrogen. The palladium-carbon catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=5/1) to give pentyl 4-amino-3-pentyloxybenzoate (5.72 g, 70% in 2 steps) as a pale-yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([CH:23]([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[C:29]([O:1][C@@H:2]([CH:23]([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)OC(=O)c1ccccc1

Procedure:
In analogy to Example 1(a), 1.7 g of (1S,5R,6R,7R)-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one, 8 ml of pyridine, and 1 ml of benzoyl chloride yield 2.06 g of the dibenzoate as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:29])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:20][CH:19]=2)[N:14]=1.S(Cl)(Cl)=O.[NH2:34][C:35]([NH2:37])=[O:36]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:29])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([NH:34][C:35]([NH2:37])=[O:36])=[O:28])=[CH:20][CH:19]=2)[N:14]=1
Reactant: Cc1oc(-c2cc3ccccc3s2)nc1CCOc1ccc(CCC(=O)O)cc1
Reactant: NC(N)=O
Solvent: O=S(Cl)Cl
Product: Cc1oc(-c2cc3ccccc3s2)nc1CCOc1ccc(CCC(=O)NC(N)=O)cc1
Temperature: 60 °C
Yield: 11.7 %

Procedure:
To 3-[4-[2-(2-(benzothiophen-2-yl)-5-methyl-4-oxazolyl)ethoxy]phenyl]propionic acid (850 mg, 2.09 mmol) obtained in Example 14 was added thionyl chloride (2 ml, 27.4 mmol) and the mixture was stirred under heating for 40 min at 60° C. The reaction mixture was concentrated and N,N-dimethylaniline (10 ml) was added to the residue. Urea (250 mg, 4.17 mmol) was added and the mixture was stirred under heating for 5 hr at 150° C. Urea (250 mg, 4.17 mmol) was again added and the mixture was heated for 10 hr at 150° C. The reaction mixture was cooled to room temperature and the precipitated solid (468 mg) was collected by filtration. A part (260 mg) thereof was washed successively with water, ethyl acetate/tetrahydrofuran (9:1), 10% aqueous sodium hydroxide solution, 1N hydrochloric acid, water and tetrahydrofuran, and dried to give the title compound (110 mg, yield 21%) as a gray-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.[F:14][C:15]([F:34])([F:33])[C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([CH2:31]Cl)[N:27]=2)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>>[F:34][C:15]([F:14])([F:33])[C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([CH2:31][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH3:13])[N:27]=2)[CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.49 (s, 1H), 7.94 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 5.87 (s, 2H), 2.51 (s, 3H); MS (ES) m/z 485 (M+1).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3](=O)[C:4](=[CH:9][N:10]1CCCCC1)[C:5]([O:7][CH3:8])=[O:6].O.[NH2:19]N>C1(C)C=CC=CC=1>[F:1][CH:2]([F:17])[C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][NH:10][N:19]=1
Reactant: NN
Reactant: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]nc1C(F)F
Temperature: -50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
At −50° C., a solution of methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (97.9%, 20.0 g, 79 mmol) in toluene (150 ml) was added dropwise to a solution of hydrazine hydrate (100%, 4.36 g, 87 mmol) in toluene (150 ml). The reaction mixture was stirred at −50° C. for 2 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. According to GC analysis, the residue obtained (9.2 g) consisted to 65.3% of methyl 3-difluoromethyl-1H-pyrazol-4-yl-carboxylate (Yield: 66%). 1H-NMR (CDCl3): δ=3.9 (s, 3H), 7.25 (t, 1H), 8.2 ppm (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25]N(C)C=O.CI>>[C:1]([O:5][C:6](=[O:24])[N:7]([CH3:25])[C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CSc1ncc(NC(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Solvent: CI
Product: CSc1ncc(N(C)C(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 1.60 g (4.61 mmol) (2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 20 ml N,N-dimethylformamide 0.25 g (6.4 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 h. After the addition of 0.48 ml (7.83 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was poured into 100 ml ice-water and three times extracted with 80 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 1.60 g (98%) methyl-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert-butyl ester as a colorless oil, MS (EI): 361 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:7]([NH:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)Nc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCCC(=O)Nc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4′-hydroxybutyranilide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (60%, white solid). HPLC-MS: m/z=313.2 (M+1); Rt: 3.58 min.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.O.[NH2:28][NH2:29]>CN(C=O)C>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:29][N:28]=1
Reactant: O=C(Cc1cccs1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccs3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 76.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2-thienyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (30 mg, 0.08 mmol, prepared in Synthetic Example 17) in DMF (1.5 ml) was added hydrazine monohydrate (80%, 30 μl, 0.75 mmol, 9.4 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(2-thienylmethyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (22 mg, 72%).