Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OCF)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3F)[OH:27])[C:9]2=[O:36])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44]1[S:49](=[O:51])(=[O:50])[O:48]CC[CH2:45]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:36])[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:45][CH2:44][S:49]([OH:51])(=[O:50])=[O:48])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCCO1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2F)C(c2ccc(OCCOCF)cc2)N1c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCS(=O)(=O)O)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg of powdered potassium carbonate and 69 μl of 1,4, -butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was chromatographed on a 10 g SiO2 cartridge (dichloromethane/methanol=5/1) and crystallized from diethyl ether. The product (131 mg) was obtained as a solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33]1([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:33]1([NH:39][CH2:40][CH2:41][CH2:42][NH:43][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCCCNC1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCNC2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.037 (0.23 mmole) of N-1-cyclohexyl-propane-1,3-diamine, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.028 g of N-(3-cyclohexylamino-propyl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-53) as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11](OCC)=O.Cl.[C:20]1(=[N:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>O1CCCC1.CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:11]2[C:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[NH:29][N:30]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cccc(OC)c1
Reactant: NN=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1

Procedure:
In a similar manner to Example 1, indan-1-one hydrazone (3.55 g) was dissolved in tetrahydrofuran (80 ml) at 0° C. under nitrogen with stirring. n-Butyllithium (28.8 ml of a 2.5M solution in hexane) was added to the solution and the mixture was stirred at 0° C. for 0.5 h. Ethyl 3-methoxybenzoate (2.16 g) was added, followed by 3M hydrochloric acid (80 ml) and the mixture was worked up as described in Example 1 to give 3-(3-methoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 172-174° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][C:7]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[OH:24])=[O:11])[CH2:6]1)(=[O:3])[CH3:2].C=O.S(O)([C:36]1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][C:7]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])([C:10]([N:12]2[CH2:13][C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[CH:16][C:15]=3[O:24][CH2:36]2)=[O:11])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OC1CCC(C(=O)NCc2cc(C(F)(F)F)ccc2O)(C(C)OC(C)=O)C1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC1CCC(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)(C(C)OC(C)=O)C1

Procedure:
3-[1-(Acetyloxy)ethyl]-3-({[2-hydroxy-5-(trifluoromethyl)benzyl]amino}carbonyl)cyclopentyl acetate was combined with paraformaldehyde (ca. 6 g) and TsOH H2O (ca. 100 mg) in 130 mL of toluene. The flask was equipped with a Dean Stark trap and condenser and the reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was filtered to remove remaining paraformaldehyde and the filtrate was concentrated. Purification of the resulting residue was accomplished by MPLC (silica, 65% ethyl acetate/hexanes) to afford 3-[1-(acetyloxy)ethyl]-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentyl acetate as a mixture of 8 diasteomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[F:6][CH:7]([F:39])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:16]=[C:15]([O:25][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=O)[CH2:28][CH2:27]3)[CH:14]=2)[C:11]2[CH:35]=[CH:36][CH:37]=[CH:38][C:10]=2[N:9]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[H+].CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C)C=O.C(Cl)(Cl)Cl.O>[F:39][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:16]=[C:15]([O:25][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:34])[CH2:28][CH2:27]3)[CH:14]=2)[C:11]2[CH:35]=[CH:36][CH:37]=[CH:38][C:10]=2[N:9]=1
Reactant: COCCN
Reactant: O=C(O)[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 2-methoxyethanamine (1.9 mg) were added a solution of trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanecarboxylic acid (11.8 mg) and N,N-diisopropylethylamine (10.5 μL) in N,N-dimethylformamide (400 μL), and were added a solution of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylMethanaminium hexafluorophosphoric acid (11.4 mg) in N,N-dimethylformamide (100 μL), followed by stirring at room temperature overnight. To the reaction solution were added water and chloroform, followed by liquid separation, and the organic layer was concentrated under reduced pressure. The residue was subjected to preparative purification with HPLC to obtain trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)-N-(2-methoxyethyl)cyclohexanecarboxamide (5.9 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[N:12]=[CH:11][NH:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([O:29]C)=[O:28])=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH3:6].O.CCOCC>O.CO>[CH2:3]([C:7]1[N:12]=[CH:11][NH:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 86.6 %

Procedure:
0.13 g of NaOH dissolved in 2 ml of H2O were added to a solution containing 0.42 g of 6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) methyl]pyrimidin-4-one in 10 ml of MeOH. After refluxing for 24 hours under stirring the solvent was evaporated. The residue was dissolved in H2O and extracted with Et2O. The aqueous phase was acidified to pH 3. The so obtained waxy solid was treated with a H2O/Et2O mixture. After filtering, 0.35 g of a white solid was obtained (yield 88%; m.p.=197°-200° C.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CCN(CC)CC.CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:21]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a DMF (780 mL) suspension of tert-butyl 4-aminopiperidine-1-carboxylate (78.0 g) and 3-methoxybenzoic acid (65.2 g), Et3N (130 mL), HOBt.H2O (71.7 g) and EDC.HCl (82.8 g) were added and the mixture was stirred at room temperature for 12 hours. H2O (1.56 L) was added and the mixture was stirred in a water bath for 1.5 hours. The precipitation was filtrated to obtain tert-butyl 4-[(3-methoxybenzoyl)amino]piperidine-1-carboxylate (126 g, a colorless solid substance). To an EtOAc (900 mL) suspension of the compound obtained in the above process, 4 M HCl/EtOAc solution (900 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and thereafter, CHCl3 (2.00 L) and 2 M aqueous NaOH solution (1.00 L) were added to the residue and the mixture was stirred for 15 minutes. A water layer was separated from an organic layer and thereafter extracted twice with CHCl3 (800 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain 3-methoxy-N-piperidin-4-ylbenzamide (87.8 g, a light yellow solid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[CH3:15][O:14][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]([NH:1][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cc1-c1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Reaction time: 4 h

Procedure:
29.5 g of 5-amino-2-methoxybiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bromobutyrate are heated together (while stirring) for 4 hours at 125°. After cooling, the resulting reaction product is stirred with diethyl ether and filtered from the precipitated salt. The residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 22.5 g (48.5% of theory) of ethyl 4-(6-methoxybiphenyl-3-yl)amiobutyrate, MP 71° to 72.
Reaction SMILES: [C:1]([NH:6][CH:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:14](OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:8]([CH:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[CH2:11][CH:12]=[CH2:13])(=[O:10])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC(NC(=O)C(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: C=CCC(NC(=O)C(C)C)C(C)=O

Procedure:
7.77 g of the above synthesized 2-isobutyrylamino-pent-4-enoic acid (41.95 mmol) were dissolved in 36.5 ml of pyridine, treated with 19.83 ml of acetic anhydride (5 eq.), and heated to 100° for 1 h. After cooling, 28.3 ml of water were added and the mixture kept for 20 Min. at 90°. Careful pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=1/1) left finally 6.63 g of the title compound as yellowish oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[Br:16][C:14]1[N:15]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Brc1csc(Br)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Brc1csc(N2CCOCC2)n1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
To a microwave vial was added N,N-diisopropylethylamine (0.86 ml, 4.9 mmol), 2,4-dibromothiazole (1.00 g, 4.1 mmol), and morpholine (0.43 ml, 4.9 mmol) in EtOH (4 mL). The mixture was heated under microwave irradiation at 140° C. for 35 minutes. The reaction mixture was concentrated in vacuo. The crude material was dissolved in minimal DCM/MeOH and purified via MPLC (eluting with 0-30% EtOAc in hexanes) to yield 4-(4-bromothiazol-2-yl)morpholine (0.700 g, 68% yield) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].[CH3:20][N:21]([CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[C:22]1[O:23][C:24]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:25]=2[N:26]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:31][C:28]2[CH:29]=[CH:30][C:24]3[O:23][C:22]([N:21]([CH3:20])[CH:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)=[N:26][C:25]=3[CH:27]=2)=[O:17])=[CH:18][CH:19]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(C(=O)O)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)Nc2ccc3oc(N(C)C4CCN(C)CC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4-butyl-benzoic acid (0.162 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4-butyl-benzoyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aq) (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as an oil (0.098 g, 35%). mass spectrum (m/e): 421.0 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.84-7.78 (m, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.48 (d, J=1.9 Hz, 1H), 7.35 (dd, J 8.8, 1.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 4.21-4.11 (m, 1H), 3.07 (s, 3H), 2.97 (d, J=11.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 2.32 (s, 3H), 2.17 (t, J=11.6 Hz, 2H), 2.01-1.87 (m, 2H), 1.83-1.75 (m, 2H), 1.65-1.56 (m, 2H), 1.40-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:5]2[C:4]=1O)#[N:2].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[C:5]2[N:6]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=2)[N:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Temperature: 75 °C
Yield: 48 %

Procedure:
To a round bottom flask was added POCl3 (200 mL) and ethyl 3-cyano-4-hydroxypyrrolo[1,2-b]pyridazine-6-carboxylate (20 g, 80 mmol). The reaction was heated under nitrogen at 75° C. for 2 hours. The reaction was cooled to room temperature and POCl3 was removed under vacuum. The residue was poured onto ice-water. The aqueous solution was extracted with CH2Cl2. The organic layer was washed with saturated sodium carbonate solution, dried and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 10 g (48%) of the title compound as a yellow solid. H1 NMR (400 MHz, CDCl3) δ ppm: 8.33 (1H, d, J=1.3 Hz), 8.11 (1H, s), 7.41 (1H, d, J=1.6 Hz), 4.41 (2H, q, J=6.8 Hz), 1.41 (3H, t, J=6.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: OCCCc1ccncc1O
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOC1CCCCO1

Procedure:
3-(3-Hydroxypyridin-4-yl)-1-propanol (1.00 g, 6.53 mmol) obtained in Example 62 is dissolved in THF, and thereto are added dihydropyrane (5.0 ml, 55 mmol), D,L-camphore-10-sulfonic acid (1.00 g, 4.30 mmol), and the mixture is heated under reflux for 20 minutes. The reaction solution is poured into an aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 3-hydroxy-4-(3-tetrahydropyranyloxypropyl)pyridine as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13]>[OH-].[Na+].C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:14])[CH:11]([CH3:15])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
4-Bromo-benzaldehyde (available from Aldrich, 10.0 g, 54.3 mmol) was added to a solution of 3-methyl-butan-2-one (available from Aldrich, 4.7 g, 54.7 mmol) in 10 mL of 10% NaOH(aq) and 20 mL of ethanol. After stirring at room temperature for 3 h, the reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (3×20 mL). The organic layer was then washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (95:5 hexane/ethyl acetate) gave the title compound (7.98 g, 58% yield) as a light yellow oil:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:32]I>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[C:13]2[CH2:14][CH:15]([CH2:17][O:18][CH3:32])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(CO)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
NaH (50 mg, 60% in mineral oil, 1.3 mmol) was added to a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200 g) (409 mg, 0.97 mmol) in THF (5 mL). The resulting mixture was stirred at 0° C. for 10 min and then methyl iodide (80 uL, 1.3 mmol) was added. The mixture was stirred at room temperature for 2 hr and then quenched with H2O (20 mL), extracted with EtOAc (2×20 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 1.56 (s, 9 H) 2.89 (dd, J=16.55, 7.20 Hz, 1 H) 3.07 (s, 3 H) 3.08-3.17 (m, 1 H) 3.39-3.44 (m, 3 H) 3.58 (d, J=5.05 Hz, 2 H) 4.99-5.08 (m, 1 H) 7.04-7.10 (m, 2 H) 7.21 (d, J=1.01 Hz, 1 H) 7.30 (d, J=1.26 Hz, 1 H) 7.86-7.93 (m, 2 H); LCMS for C22H26O7S m/z 457.00 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: O=C1COC(c2ccc([N+](=O)[O-])cc2)=NN1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=NNC(=O)CO2)cc1

Procedure:
A solution of 2-p-nitrophenyl-4H,6H-1,3,4-oxadiazin-5-one (Example 17; 2.2 g.) in ethyl acetate (250 ml.) was hydrogenated in the presence of a 5% palladium-on-charcoal catalyst at laboratory temperature and atmospheric pressure until 670 ml. of hydrogen has been absorbed. The mixture was filtered and the filtrate was evaporated to dryness. There was thus obtained as solid residue 2-p-aminophenyl-4H,6H-1,3,4-oxadiazin-5-one, m.p. 253°-255° C. (with decomposition).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
5.23 g of imidazole and 4.85 g of tert-butyldimethylchlorosilane were added, in this order, to a suspension of 4.02 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazole in 60 ml of dimethylformamide at room temperature. The mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added 100 ml of ice water and 200 ml of ethyl acetate. The organic layer was separated, washed with 100 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to obtain 5.14 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tert-butyldimethylsilyloxyphenyl)thiazole.