Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]2.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C(OCC)(=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:17][C:16]([C:15]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:18]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Solvent: CCOC(C)=O
Product: CN(C)C=CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Temperature: 25 °C
Yield: 52 %

Procedure:
A 50 ml round bottom flask is charged with the 1-[6-(2-chlorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone (952 mg, 3.65 mmol) and dimethylformamide dimethylacetal (22 ml). The mixture is refluxed for 5 hours and then cooled to room temperature. The mixture is diluted with ethyl acetate (150 ml) and washed three times with 100 ml each of a saturated sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product is purified by flash chromatography on silica gel (ethyl acetate), yielding 604 mg of a pale brown solid (52%). M.p.=187-189° C.; 300 MHz 1H NMR (CDCl3) δ: 8.07 (d, J=1.6 Hz, 1H), 7.62-7.35 (m, 6H), 4.78 (d, J=12.5 Hz), 1H), 3.04-3.01 (m, 3H), 2.4-2.32 (m, 3H). LCMS: 316[M+H]; calc. for C16H14ClN3O2: C, 60.76; H, 4.49; N, 13.28; found. C, 60.81; H, 4.39; N, 13.35.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH3:6])[CH3:2].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:27][O:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[CH:27][O:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])[CH3:6])[CH3:2]
Reactant: CCON=C(C)c1cccc(O)c1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCON=C(C)c1cccc(OCc2ccccc2C(=COC)C(=O)OC)c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 54.4 %

Procedure:
7.5 g (0.042 mol) of 3-(1-ethoxyiminoethyl)phenol and 10.0 g (0.035 mol) methyl α-(2-bromomethylphenyl)-β-methoxyacrylate are dissolved in 100 ml of dimethylformamide, and 7.3 g (0.053 mol) of potassium carbonate are added. The mixture is stirred at room temperature (20° C.) for 48 hours, hydrolyzed with water and extracted with diethyl ether. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The resulting oil is purified by chromatography on alumina (cyclohexane). 7.3 g (54%) of the title compound are obtained as a colorless oil (compound no. 447).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:11])=[N:31][CH:30]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 448 [M+1]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:36][C:33]([F:34])([F:35])[C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([NH:25][CH2:24][C:22]([NH:21][C@@H:18]1[CH2:19][CH2:20][N:16]([CH:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]2)[CH2:17]1)=[O:23])=[O:37]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of the ketone of step A (0.4 g, 1.9 mmol) and the pyrrolidine intermediate obtained in step C, Example 114 (0.4 g, 1.3 mmol) in THF (15 mL) was added sodium triacetoxyborohydride (0.4 g, 1.9 mmol). The reaction was stirred at room temperature overnight and quenched by addition of aqueous NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with NaHCO3 and brine, dried over MgSO4 and concentrated. Flash chromatography eluting with a gradient of 0-20% MeOH/CH2Cl2 provided 300 mg of the title compound. MS calculated (M+H)+ 513. found 513.
Reaction SMILES: [C:1](Cl)(=[O:40])[O:2][CH:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:42][N:43]([CH3:66])[CH2:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65].C(N(CC)CC)C>ClCCl>[CH3:66][N:43]([CH3:42])[CH2:44][CH2:45][CH2:46][N:47]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:1](=[O:40])[O:2][CH:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCNCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(CCCCCCCC/C=C\C/C=C\CCCCC)CCCN(C)C
Yield: 55.2 %

Procedure:
To a solution of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl carbonochloridate (590 mg, 1.0 mmol), N,N-dimethyl-N′-((9Z,12Z)-octadeca-9,12-dienyl)propane-1,3-diamine (350 mg, 1 mmol) and triethylamine (500 μL, 3.6 mmol) in dichloromethane (8 mL) was stirred overnight at room temperature. Upon completion, the solution was concentrated in vacuo to dryness and purified by column chromatography on silica gel to afford (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 3-(dimethylamino)propyl((9Z,12Z)-octadeca-9,12-dienyl)carbamate as a colorless oil (500 mg, 55%). 1H NMR (CDCl3, 400 MHz) δ 5.42-5.28 (m, 12H), 4.79-4.70 (m, 1H), 3.32-3.12 (m, 4H), 2.78 (t, 6H, J=6.3 Hz), 2.38-2.20 (m, 8H), 2.09-2.02 (m, 12H), 1.82-1.63 (m, 2H), 1.57-1.43 (m, 6H), 1.41-1.23 (m, 52H), 0.89 (t, 9H, J=7.0 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].N[C:32]1C(C)=CC(C)=C[C:33]=1C(C1CC1)=O>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:1]([CH:2]1[CH2:33][CH2:32]1)=[O:3])=[O:14])(=[O:21])=[O:22]
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reactant: Cc1cc(C)c(N)c(C(=O)C2CC2)c1
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)C2CC2)c1

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that cyclopropyl 2-amino-3,5-dimethylphenyl ketone was used instead of 2′-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:31]1([NH:41]N)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:32]4[C:31](=[C:40]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]5=[CH:34][CH:33]=4)[NH:41][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 516.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([O:24][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCCCC(=O)NCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(=O)CCCCCNC(=O)CCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.2 %

Procedure:
1.57 g of 3-hydroxyoctadecanoic acid t-butyl ester and 1.30 g of 6-decanamidohexanoic acid were mixed with 30 ml of methylenechloride and after adding thereto 50 mg of DMAP and 930 mg of DCC while stirring, the mixture was stirred for 2 days at room temperature. Precipitates formed were removed by filtration and the filtrate was washed with 10 ml of 0.1N hydrochloric acid, and then washed twice with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was subjected to column chromatography and eluted with chloroform to provide 610 mg of 3-(6-decanamidohexanoyloxy)octadecanoic acid t-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C@@H:48]([N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[C:49](=[O:52])[NH:50][CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([C@@H:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[F:40])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy) acetic acid (0.19 g; 0.78 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.12 g; 0.86 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.90 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.33 g; 0.78 mmol) and diisopropylethylamine (0.17 mL; 0.86 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 50 mL), water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.47 g of
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C(=O)C(C)(C)OC(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 72 mg (0.34 mmol) 2-hydroxy-4'-(methylthio)isobutyrophenone in 1.7 mL of CH2Cl2 were added 0.2 mL of pyridine and 140 mg (0.81 mmol) of 4-fluorophenylacetyl chloride. The mixture was stirred at room temperature overnight and then quenched with NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with 8:1 hexane/EtOAc to give 95 mg of the title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:13]=1
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) were dissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (52.6 g, 0.38 mol) was added thereto, and the mixture was stirred for 20 h at 100° C. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([F:13])=[C:7](O)[N:6]=1.O=P(Cl)(Cl)[Cl:18]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([F:13])=[C:7]([Cl:18])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1nc(O)c(F)cc1C#N
Product: COC(=O)Cc1nc(Cl)c(F)cc1C#N
Temperature: 95 °C
Reaction time: 7 h
Yield: 95.5 %

Procedure:
A mixture of (3-cyano-5-fluoro-6-hydroxy-pyridin-2-yl)-acetic acid methyl ester (9.10 g, 43.3 mmol), as prepared in the previous step, and POCl3 (40 mL, 433 mmol) was stirred at 95° C. for 7 h. The homogeneous brown solution was then concentrated under reduced pressure, and the residue was put on an ice bath, diluted with ether (200 mL), and then shaken with ice water (100 mL). The aqueous layer was extracted with ether (1×100 mL), and the organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure at 40° C. to afford the title compound as a clear dark amber oil (9.45 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 7.75 (d, 1H), 4.06 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[OH2:20]>CS(C)=O>[O:18]=[C:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:15][CH:14]=1)[CH:17]=[O:20]
Reactant: O
Reactant: CC(=O)c1ccc(OCCc2ccccc2)cc1
Agent: Br
Solvent: CS(C)=O
Product: O=CC(=O)c1ccc(OCCc2ccccc2)cc1
Temperature: 58 °C

Procedure:
A 27.7 g portion of 4'-phenethyloxy-acetophenone was dissolved in 200 ml of dimethylsulfoxide. A 39.2 ml portion of 48% hydrobromic acid was added in small portions (exothermic), then the mixture was heated at 58° C. for 17 hours. The mixture was poured into 500 ml of ice and water and the solid was collected, washed with water and dried, giving the desired product as a yellow solid, mp 44°-59° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(N)CO
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CO)cc1OC
Yield: 20.9 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.5 g of the compound obtained in EXAMPLE 13, 0.5 g of 2-amino-2- methylpropan-1-ol, 0.6 g of BOP, 1 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.12 g of the expected product in the form of white crystals. M.p.=218° C.
Reaction SMILES: C(S[C:9]1[N:14]=[N:13][C:12]2[CH2:15][CH2:16][N:17]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][C:11]=2[CH:10]=1)C1C=CC=CC=1.O.[NH2:28][NH2:29]>C(O)C>[C:19]([N:17]1[CH2:16][CH2:15][C:12]2[N:13]=[N:14][C:9]([NH:28][NH2:29])=[CH:10][C:11]=2[CH2:18]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: O=C(c1ccccc1)N1CCc2nnc(SCc3ccccc3)cc2C1
Solvent: O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 4.0 g of 3-benzylmercapto-6-benzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 1.5 g of hydrazine hydrate in 10 cc of 95% ethanol is heated in an autoclave at a bath temperature of 150° for 16 hours. The oil obtained after concentrating the reaction mixture in a vacuum, is divided between chloroform and a small amount of water, and the organic phase is concentrated to a red oil. The title compound is obtained by crystallization from dimethyl formamide. M.P. 220°-223° (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:38][C:39]=1[CH2:40]C)[C:6]([NH:8][C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)=[O:7].[H-].[Na+].[CH3:50]N(C)C=O.CI>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:38][C:39]=1[CH3:40])[C:6]([N:8]([CH3:50])[C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)=[O:7]
Reactant: CN(C)C=O
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2CC)c(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Yield: 41 %

Procedure:
To a mixture of diethyl (E)-2-[3-({3-methoxy-4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil compound. To remove remaining trifluoroacetic acid, water was added to the oil compound, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-{3-[{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (20.8 mg, yield 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1.[CH3:15][O:16]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]=1[CH:15]=[O:16]
Reactant: COc1ccc2ccc(OC)cc2c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2ccc(OC)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 2,7-dimethoxynaphthalene 2 (65 mmol; 12.26 g) is dissolved in 150 cm3 of anhydrous dichloromethane under an inert atmosphere. TiCl4 (91 mmol; 10cm3) is added by syringe, at 0° C., followed by dropwise addition, by means of a dropping funnel, of α,α-dichloromethyl methyl ether (99 mmol; 9 cm3) in solution in 40 cm3 of the same solvent. Stirring is continued at 0° C. for 1 h and then at room temperature for 4 h 30. The reaction medium is poured onto an ice/3N HCl mixture (250 cm3), stirred vigorously and then extracted with CH2Cl2. The organic phase is washed with water and then with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and evaporated. The residue is taken up in ether, the solution is filtered and the filtrate is evaporated to dryness. 2,7-Dimethoxynaphthaldehyde 3 is isolated pure in the form of a beige-colored powder.