Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[N:12][C:13]([NH:30][C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)=[N:14][C:15]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[N:10]=[CH:9]2)=CC=1>C(O)(C(F)(F)F)=O>[N:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][C:15]3[N:14]=[C:13]([NH:30][C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[N:12]=[C:11]4[C:16]=3[NH:8][CH:9]=[N:10]4)=[CH:19][CH:20]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2cnc3nc(Nc4ccc(C#N)cc4)nc(Oc4ccc(-c5ccncc5)cc4)c32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Nc2nc(Oc3ccc(-c4ccncc4)cc3)c3[nH]cnc3n2)cc1

Procedure:
A solution of 4-(7-(4-methoxybenzyl)-6-(4-(pyridin-4-yl)phenoxy)-7H-purin-2-ylamino)benzonitrile (38 mg, 0.07 mmol) in TFA (0.5 mL) was heated at 60° C. overnight. The desired product was precipitated with EtOAc (2 mL) and collected by filtration. NMR (DMSO-d6): 9.98 (s, 1H), 8.95 (d, 2H), 8.38 (d, 2H), 8.35 (d, 2H), 8.20 (d, 2H), 7.76 (d, 2H), 7.63 (d, 2H), 7.53 (d, 2H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:27])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:8]2[N:7]=1.S(Cl)([Cl:30])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:30][CH2:2][CH2:3][CH2:4][N:5]([CH3:27])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:8]2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2nnc3c4ccccc4c(N(C)CCCO)nn23)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc3c4ccccc4c(N(C)CCCCl)nn23)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To 2.8 g of N-(3-hydroxypropyl)-N-methyl-3-(4-methoxy phenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-amine (the compound of example 32) dissolved in chloroform (30 ml) are added a few drops of N,N-dimethylformamide and then 1.1 ml of thionyl chloride in chloroform (5 ml). The mixture is refluxed for about 5 hours. After cooling to room temperature, the mixture is concentrated to dryness and the residue is taken up with cold aqueous sodium bicarbonate. The product of the title is collected after filtration and crystallized from ethanol. Yield 85%. M.p. 113°-115° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1=[O:18])(=[O:3])[CH3:2].CI.[C:21]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:21])[C:6](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1=[O:18])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccccc2)C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N1CC(=O)N(C)C(=Cc2ccccc2)C1=O
Yield: 45 %

Procedure:
1-Acetyl-3-benzylidene-2,5-piperazinedione (compound 18 prepared in Reference Example 2) was N-methylated by treatment with methyl iodide (2.0 equivalents) in the presence of Na2CO3 (1.0 equivalents) in DMF at room temperature for 24 hours. The solvent was removed and the residue purified by flash chromatography. The product 1-acetyl-3-benzylidene-4-methyl-2,5-piperazinedione, obtained in 45% yield, was treated with 4-methoxybenzaldehyde (1.0-1.1 equivalents) in the presence of Cs2CO3 in DMF at 80° C. for 206 hours to give compound 121, which is (3Z,6Z)-6-benzylidene-3-(4-methoxybenzylidene)-1-methyl-2,5-piperazinedione, in 35% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-bromo-3-nitro-2-hydroxypyridine (24.0 g, 0.11 mol), anhydrous DMF (280 mL) and powdered potassium carbonate (−350 mesh, 33.4 g, 0.24 mol), and the suspension stirred for 15 min at ambient temperature. After this time methyl iodide (17.1 g, 0.124 mol) was added, and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with water (750 mL) and extracted with ethyl acetate (3×1.0 L). The organic extracts were combined, washed with brine (500 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by flash chromatography on silica to afford an 85% yield (21.7 g) of 41 as a yellow solid: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([O:22]C)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[CH:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC2CCOC2)cc(-c2ccc(C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(OC3CCOC3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-(tetrahydrofuran-3-yloxy)biphenyl-3-carboxylate (150 mg, 0.46 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added lithium hydroxide (55 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then acidified with 2N aq. H2SO4 to pH 4-5 and concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2 (10 mL×3). The combined organic layers were dried (MgSO4), and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.85 (t, J=1.6 Hz, 1H), 7.52 (d, 2H, J=8.4 Hz), 7.48 (dd, 1H=2.4, 1.2 Hz), 7.34 (dd, 1H, J=2.4, 1.6 Hz), 7.28 (d, 2H, J=8.4 Hz), 5.15 (m, 1H), 4.05-3.87 (m, 4H), 2.38 (s, 3H), 2.36-2.27 (m, 1H), 2.20-2.11 (m, 1H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:4]2[C:3]1=[O:12].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:7]=[C:6]1[CH:5]2[CH:4]([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3](=[O:12])[N:2]1[O:1][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: O=C1C2CCCCC2C(=O)N1O
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)C(=S)ON1C(=O)C2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 25.38 g (0.15 mol) of N-hydroxy-hexahydrophthalimide (prepared as described in Chem. Pharm. Bull., 16, (1968), 622) and 0.5 g 4-dimethylaminopyridine in 100 ml pyridine were added 18.54 g (0.15 mol) of dimethylthiocarbamoyl chloride. The mixture was stirred at room temperature during 3 h and then poured into 1000 ml of ice water. The precipitate was filtered off and recrystallized from 120 ml of ethanol to give 28.38 g of white crystals, mp. 124-126° C.
Reaction SMILES: [K+].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10](=[O:24])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O-:23])=O)=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C1COCC1.CN(C=O)C>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10](=[O:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[O:23])=[CH:17][CH:18]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NOC1CCCCO1
Reactant: O=C([O-])/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
A mixture of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid potassium salt (1.25 g, 3.6 mmol), EDC (828 mg, 4.32 mmol), HOBT (584 mg, 4.32 mmol), TEA (1.0 ml, 7.2 mmol), NH2OTHP (421 mg, 3.60 mmol) in THF (20 ml) and DMF (20 ml) was stirred at room temperature for 12 h and then partitioned between water and AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 2:8) to give 1.2 g of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow powder.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)=[N:10][C:8]=2[N:9]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[CH2:1]([S:3]([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]([C:20]3[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=3)=[N:10][C:8]=2[N:9]=1)=[O:33])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Solvent: ClCCl
Product: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde (1.0 g, 2.69 mmol) in CH2Cl2 (30 mL) was added m-chloroperoxy benzoic acid (0.660 g, 3.0 mmol). The solution was stirred for 1 hr then quenched with sat. NaHCO3 and 10% Na2S2O3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2, extracted, dried with MgSO4, and filtered to afford the title compound. LRMS m/z (M+H) Calcd: 388.1 found: 388.1
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([O:3][CH3:4])=[O:2].[Br:15]Br>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([Br:15])[CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1NC(C)=O
Reaction time: 17 h

Procedure:
A stirred solution consisting of 14.8 g of N-(2-carbomethoxyphenyl)acetamide and 75 mL of acetic acid was cooled in an ice-acetone bath and 6 mL of bromine were added dropwise. The cooling bath was removed and the solution was stirred for 17 hr. The solution was diluted with 100 mL of methylene chloride and was washed with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The product was purified by elution from a silica gel column with 9:1 methylene chloride: ethyl acetate, which afforded 17.9 g of product as a white solid (m.p. 131°-133° C.). 1H NMR CDCl3) 88.66 (d, 9.0 Hz, 1H), 8.15 (d, 2.0 Hz, 1H), 7.63 (dd, 9.0 Hz, 2.0 Hz, lH), 3.98 (s, 3H, OCH3), 2.27 (s, 3H, COCH3).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CO.[Zn]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[O:21])=[CH:18][CH:19]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: O=C(c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1)N1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a suspension of 125 (1.5 g, 3.24 mmol) in MeOH (60 mL) was added Zinc powder (1.693 g, 25.9 mmol) and NH4Cl (0.346 g, 6.47 mmol) and the reaction mixture was heated to reflux for 5 hours. The mixture was cooled to RT and filtered. The filtrate was concentrated and the residue was dissolved in DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to give title compound 126 (1.3 g, 93% yield) as a brown oil which became a puffy solid after removal of residual solvent in high vacuum. MS (m/z)=434.50 (M+H)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:21]O>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCOc1ccccc1-c1ccc(C(=O)O)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCOc1ccccc1-c1ccc(C(=O)OC)c(=O)[nH]1

Procedure:
A stirred mixture of 6-(2-propoxyphenyl)-1,2-dihydro-2-oxopyridine-3-carboxylic acid, (0.9 g) dry methanol (30 ml) and 3 drops of concentrated sulphuric acid was heated under reflux for ca 24 hours. The cooled mixture was evaporated to yield a pale yellow solid which was dissolved in chloroform, extracted with dilute aqueous potassium carbonate (2×10 ml), washed with water and brine, dried (magnesium sulphate) and evaporated to yield a yellow solid, 0.8 g, m.p. 126°-7° C. This was recrystallised from aqueous methanol (20 ml) to yield the pure title compound, 0.65 g, m.p. 126.5°-127.5° C.
Reaction SMILES: [CH:1]1([CH2:8][C:9]2[NH:13][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[N:11][C:10]=2[C:24](O)=[O:25])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([O:34][C:35](=[O:53])[C:36]1[CH:51]=[C:50]([NH2:52])[CH:49]=[C:38]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:42]([O:41][C:39](=[O:40])[C:38]1[CH:49]=[C:50]([NH:52][C:24]([C:10]2[N:11]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[NH:13][C:9]=2[CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:25])[CH:51]=[C:36]([C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:53])[CH:37]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(NC(=O)c2nc(-c3ccc4ccccc4c3)[nH]c2CC2CCCCCC2)cc(C(=O)OCc2ccccc2)c1
Reaction time: 72 h
Yield: 46 %

Procedure:
To a solution of the product of step c above (500 mg, 1.44 mmol) and 5-amino-isophthalic acid dibenzyl ester (520 mg, 1.44 mmol) in DMF (3 ml) was added 1-hydroxybenzotriazole (HOBt) (195 mg, 1.44 mmol), 4-dimethylaminopyridine (DMAP) (cat.) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC) (280 mg, 1.44 mmol). The solution was kept at room temperature for 72 h, poured over 1M hydrochloric acid (20 ml) and the product was extracted with ethyl acetate (2×20 ml). The product crystallised from the ethyl acetate extracts. The crystals were collected by filtration, dried and triturated with methanol to afford a white solid (453 mg, 46%). 1H NMR (300 MHz, d6-DMSO) 13.00 (1H, br s), 10.50 (1H, s), 8.84 (2H, s), 8.61 (1H, s), 8.28 (2H, m), 8.00 (3H, m), 7.50 (12H, m), 5.41 (4H, s), 2.98 (2H, d), 2.00 (1H, m), 1.69-1.16 (12H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:37][O:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:7]
Reactant: COCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 69 %

Procedure:
The title compound was prepared from reaction of the product of Example 25, Step C, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]amino]benzoic acid with CDI and 2-(aminooxy)ethanol, by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]-amino]-N-(2-hydroxyethoxy)benzamide as a cream solid (69%); m.p. (Et2O/hexanes) 136–137° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.77 (br s, 1 H), 7.43–7.36 (m, 1 H), 7.15–7.00 (m, 2 H), 6.95–6.77 (m, 2 H), 4.71 (br s, 1 H), 3.85 (t, J=4.8, 2 H), 3.56 (t, J=4.8, 2 H), 3.33 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 2.56 (t, J=7.7 Hz, 2 H), 1.80–1.71 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14]([OH:25])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CN(C1C=CC=CN=1)C.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:25][CH:14]1[CH2:13][CH:12]([C:4]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)[C:21]2[C:16](=[CH:17][C:18]([N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=2)[O:15]1)(=[O:43])[CH3:42]
Reactant: COc1cc(C2CC(O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C2CC(OC(C)=O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(3-bromo-4,5-dimethoxyphenyl)-7-dimethylamino-2-hydroxy-chroman (9 mg, 0.022 mmol), dimethylamino-pyridine (catalytic) and pyridine (0.1 ml) in dichloromethane at 0° C. was added acetic anhydride (0.05 ml). The mixture was stirred overnight at room temperature. To the mixture was added ice and the mixture was extracted with dichloromethane. The extract was washed with 1N HCl, saturated NaHCO3 and saturated sodium chloride solution, dried and the solvent was evaporated. The title compound was obtained upon chromatography of the crude material over a bond-elute (hexane:ethyl acetate=9:1 and 4:1 as eluent) (6.0 mg; 61%). 1H NMR (CD3OD): 6.99 (d, J=1.9 Hz), 6.86 (broad signal) and 6.85 (d, J=1.8 Hz) (2H), 6.72 (d, J=8.8 Hz) and 6.54 (d, J=8.5 Hz) (1H), 6.47 (t, J=2.3 Hz) and 6.42 (dd, J=2.2, 9.2 Hz) (1H), 6.35 (overlapping dd, J=2.5, 8.7 Hz) (1H), 6.26 (d, J=2.3 Hz) and 6.22 (d, J=2.5 Hz) (1H), 4.14 (overlapping dd, J=6.0, 11.9 Hz; 1H), 3.76-3.80 (s, 6H), 2.87 and 2.91 (s each, 6H), 2.40-2.45 and 2.11-2.32 (m each; 2H), 2.08 and 1.79 (s each, 3H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[C:3]#[CH:4].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[C:28]([F:52])=[CH:29][C:30]([Cl:51])=[C:31]([CH:50]=1)[O:32][C:33]1[CH:47]=[CH:46][C:36]2[N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[S:39][C:35]=2[C:34]=1[C:48]#[N:49]>O1CCCC1.C(OCC)(=O)C>[Cl:51][C:30]1[C:31]([O:32][C:33]2[CH:47]=[CH:46][C:36]3[N:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[S:39][C:35]=3[C:34]=2[C:48]#[N:49])=[CH:50][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])[CH:7]=2)=[C:28]([F:52])[CH:29]=1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (62 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (72 mg, 56%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=O)[NH:25][N:24]=[N:23]2)=[CH:18][CH:17]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C(=O)N(C2C=CC(F)=CC=2)N=N1)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:26]2[N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[N:23]=[N:24][N:25]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]nnn1-c1ccc(F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1nnn(-c2ccc(F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nnnn1-c1ccc(F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 9.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.43 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.03 g of 1-(4-fluorophenyl)-5(1H,4H)-tetrazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-fluorophenyl)-5(1H,4H)-tetrazolone (1.22 g) and 205 mg of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-fluorophenyl)-1H-tetrazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23](=[O:32])[C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O>CO.CCOC(C)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23](=[O:32])[C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(Cl)cccc2Cl)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NC1CCNCC1)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A solution of 4-{[4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (7.9 g) in MeOH (50 mL) and EtOAc (50 ml) was treated with sat. HCl-EtOAc (40 mL) then stirred at r.t. overnight. The product did not crystallise due to the presence of methanol, and therefore the reaction mixture was evaporated and the residue triturated with EtOAc. The resulting off white solid was collected by filtration, washed with EtOAc and sucked dry on the sinter to give 6.3 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide as the hydrochloride salt. (LC/MS: Rt 5.89, [M+H]+ 382/384).
Reaction SMILES: O[CH:2]([CH3:17])[CH2:3][C:4]([C:6]1[C:7]2([CH2:12][CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[CH3:16][C:15]1[CH:14]=[CH:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:6]=1[C:4](=[O:5])/[CH:3]=[CH:2]/[CH3:17]
Reactant: CC1=C(C(=O)CC(C)O)C2(CC=C1)CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C/C=C/C(=O)C1=C(C)C=CCC12CCCC2
Yield: 69 %

Procedure:
Prepared in 69% yield from 3-hydroxy-1-(7-methylspiro[4.5]deca-6,8-dien-6-yl)butan-1-one (1.88 g, 8.0 mmol), acetic anhydride (1.6 ml) and sodium acetate (0.72 g) as described in Example 10. Boiling point: 120° C. (0.09 mbar).