Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C(ON[C:16](=[O:39])[C@H:17]([N:22]([P@:30]([CH3:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH:19]([CH3:21])[CH3:20])C1C=CC=CC=1.C(OCC)(=[O:42])C>>[CH3:38][P:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:17]([C:16]([OH:39])=[O:42])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:31]
Reactant: CC(C)C[C@H](C(=O)NOCc1ccccc1)N(Cc1ccccc1)[P@@](C)(=O)c1ccccc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)C[C@H](C(=O)O)N(Cc1ccccc1)P(C)(=O)c1ccccc1

Procedure:
N-Benzyloxy-2(R)-[[(R)-methylphenylphosphinyl]benzylamino]-4-methylpenta-namide and N-benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methyl-pentanamide: N-(R/S-Methylphenylphosphinyl)-N-benzyl-D-leucine (1.5 g, 4.17 mmol) is dissolved in N-dimethylformamide and cooled to 0° C. To this is added sequentially hydroxybenzotriazole hydrate (1.69 g, 12.5 mmol), N-methylmorpholine (1.37 mL, 12.5 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC, 959 mg, 5 mmol)). After stirring 10 minutes, O-benzylhydroxylamine hydrochloride (666 mg, 4.17 mmol) is added and the reaction is allowed to stir for 3 hours, warming to room temperature. Two diastereomers are observed by TLC. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organics are combined, washed with water and brine, dried over sodium sulfate, and concentrated to give an oil. The diastereomers are then isolated by silica gel flash chromatography (1:1 hexane:ethyl acetate) to give N-benzyloxy-2(R)-[[(R)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide: Rf =0.25 (1:1 hexane:ethyl acetate; 31P NMR (CD3OD) d 43.89; and N-benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide Rf =0.15 (1:1 hexane:ethyl acetate).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]([NH:17][C:18]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:18]([NH:17][C:15](=[O:16])[CH2:14][O:13][C:12]2[CH:11]=[CH:10][CH:31]=[C:30]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:29]=2)=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COc1cccc(Br)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)COc1cccc(-c2ccoc2)c1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
210 mg (10.7 mmol) of 3-furan boronic acid, 500 mg (7.13 mmol) of methyl 2-{[(3-bromophenoxy)acetyl]amino}-5-chlorobenzoate, 144 mg (0.713 mmol) of tetrakis(triphenylphosphine)palladium(0), and 613 mg (10.7 mmol) of cesium carbonate were heated under reflux for 6 hours in THF (5 mL). After the completion of the reaction, ethyl acetate was added thereto, and the mixture was stirred for 1 hour and filtered using a silica gel pad. After the filtrate was condensed, the obtained crude product was separated and purified by silica gel column chromatography. IPE was added to the resulting solids, followed by collection by filtration, washing with IPE, and drying under reduced pressure at 50° C. for 5 hours, thereby giving 286 mg of methyl 5-chloro-2-({[3-(furan-3-yl)phenoxy]acetyl}amino)benzoate (yield: 59%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in dichloromethane (15 parts) are added trityl chloride (1.05 equivalents) and triethylamine (1.05 equivalents) under nitrogen at 0° C. After stirring at room temperature for 24 hours, the reaction mixture is poured onto diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated in vacuum to give 2-(2-tritylamino-4-thiazolyl)malonic acid diethyl ester. Yield: 98.2%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:9][CH:10]=1)[CH3:2]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCCCCCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1

Procedure:
In a first step, (2-amino-thiazol-4-yl)-acetic acid ethyl ester is coupled to dodecanoyl chloride as described in the method of Example 334 to provide (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester as a crude solid. In a second step, the crude solid of (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester was deprotected using LiOH (2-fold excess) in THF/H2O to provide the title compound as a crude solid, which was used directly without further purification or characterization.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32]1C2C(=CC=CC=2)CC[CH:33]1C(O)=O.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([N:11]([CH2:10][CH:9]2[CH2:33][CH2:32][C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH2:8]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:30][CH2:29]1
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CC2CCc3ccccc3C2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].C(OCC)(=O)C.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNC
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N(C)C
Reaction time: 4 h
Yield: 92 %

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 0.515 g, 2.06 mmol) was dissolved in ethyl acetate (8 mL, 0.08 mol). Dimethylamine (0.4 mL, 0.008 mol) was added next. The reaction was left to stir for 4 hours. The reaction was extracted with 0.5 M HCl, washed with water and brine, and the organic layer dried over magnesium sulfate. The ethyl acetate was evaporated and the crude product 1.3.Af was obtained in 92% yield. MS analysis (m−1)=257.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[CH:7]=1.OS(O)(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([Cl:9])[C:6](=[O:8])[C:7]=1[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=2)[NH:23][CH:22]=1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Reactant: COc1ccc2[nH]ccc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]cc(C3=C(Cl)C(=O)C=C(Cl)C3=O)c2c1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of 2,5-dichloro-1,4-benzoquinone (0.242 g, 1.37 mmol) in THF (3 mL) was added H2SO4 (35 μL, 0.68 mmol) at room temperature. To this mixture was added 5-methoxyindole (0.100 g, 0.68 mmol). After the reaction mixture was stirred for 1 hour at room temperature under nitrogen protection, DDQ (0.232 g, 1.02 mmol) was added. After stirring for 2 hours, the mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with sat. NaHCO3 (3×20 mL) and brine (20 mL), and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford 2,5-dichloro-3-(5-methoxy-1H-indole-3-yl)-[1,4]benzoquinone (0.211 g, 96%) as blue needles from benzene/hexane. Melting Point 195–196° C. 1H NMR (CDCl3): 6.78 (1H, d, J=2.4 Hz), 6.93 (1H, dd, J=2.1, 8.4 Hz), 7.23 (1H, s), 7.34 (1H, d, J=9.0 Hz), 7.54 (1H, d, J=3.0 Hz), 8.62 (1H, br s). 13C NMR (d6-acetone): 55.2, 103.8, 106.7, 112.4, 112.8, 126.5, 130.9, 131.0, 131.4, 133.4, 139.8, 143.7, 154.8, 177.8, 178.0. IR (KBr): 3328, 3043, 2924, 2855, 1675, 1638, 1543, 1484, 1260, 1227 cm−1. Anal. Calcd. for C15H9Cl2NO3: C, 55.93; H, 2.82; N, 4.35. Found: C, 55.72; H, 2.99; N, 4.24.
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C([Cl:33])C=C(C(OO)=O)C=1>ClCCl.C(OCC)(=O)C>[Cl:33][C:14]1[CH:13]=[CH:12][C:11]2[C:10]([S:7]([NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:9])=[O:8])=[CH:19][C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cccnc2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (272 mg, 0.73 mmol) and mCPBA (max 77% by weight, 364 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium sulfite solution followed by brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in POCl3 and heated at 80° C. for 1 hour. The reaction mixture was concentrated before being partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and purified on silica gel (rf=0.42 in 2:1 hexanes:ethyl acetate) to give 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [CH2:1](N1CCC(NC2C=CC=C(F)C=2)(C#N)CC1)[C:2]1C=CC=CC=1.C(C(C(Cl)=O)C(Cl)=O)C.N1C(C)=CC=CC=1C.[CH2:41]([N:48]1[CH2:53][CH2:52][C:51]([N:56]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=2)[C:57](=[O:62])[CH2:58][C:59]([OH:61])=[O:60])([C:54]#[N:55])[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:41]([N:48]1[CH2:53][CH2:52][C:51]([N:56]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=2)[C:57](=[O:62])[CH2:58][C:59]([O:61][CH2:1][CH3:2])=[O:60])([C:54]#[N:55])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: N#CC1(Nc2cccc(F)c2)CCN(Cc2ccccc2)CC1
Reactant: N#CC1(N(C(=O)CC(=O)O)c2cccc(F)c2)CCN(Cc2ccccc2)CC1
Agent: CCC(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CC(=O)N(c1cccc(F)c1)C1(C#N)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-benzyl-4-[(3-fluorophenyl)amino]piperidine-4-carbonitrile (Intermediate 1A.1-1, 9.0 g, 29.1 mmol) in dichloromethane (150 ml) were added ethyl malonyl chloride (4.9 ml, 37.8 mmol) and 2,6-lutidine (5.1 ml, 43.6 mmol). The reaction was allowed to stir at rt for 2.5 h. Additional ethyl malonyl chloride (1.1 ml, 8.7 mmol) was added, and the reaction was allowed to stir for 30 min. The reaction was diluted with dichloromethane and washed with water and brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to yield a 1:1 mixture of desired ester ethyl 3-[(1-benzyl-4-cyanopiperidin-4-yl)(3-fluorophenyl)amino]-3-oxopropanoate and its acid 3-[(1-benzyl-4-cyanopiperidin-4-yl)(3-fluorophenyl)amino]-3-oxopropanoic acid (quant).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[CH2:10][O:9]1)([O-:3])=[O:2].C(O)(=O)C(O)=[O:17].O1CCOCC1>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:17])[CH2:10][OH:9])([O-:3])=[O:2]
Reactant: O=C(O)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1OCC1CO1
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OCC(O)CO
Yield: 13 %

Procedure:
To a stirred solution of 38 parts of 2-(2-nitrophenoxymethyl)-oxirane in 10 parts of ethanedioic acid and 300 parts of 1,4-dioxane are added 100 parts of water. The whole is stirred and refluxed for 2 days. The reaction mixture is evaporated and the residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and recrystallized from 2,2'-oxybispropane, yielding 29.5 parts (13%) of 3-(2-nitrophenoxy)-1,2-propanediol; mp. 96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH2:9]([NH:8][C:5]1[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1)[CH2:10][CH3:11]
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccc(F)cc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(F)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-(4-fluorophenyl)benzoxazole (108 mg, 0.30 mmol) and 1,2,4-benzenetricarboxylic anhydride (57 mg, 0.30 mmol) the title compound was obtained. (74 mg, 46%). 1H NMR (DMSO) δ 13.63(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.12(d, 1H), 8.08(m, 2H), 7.81(m, 3H), 7.68(dd, 1H), 7.47(dd, 1H), 7.32(t, 2H), 7.03(d, 1H), 3.34(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 536.2 m/z (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:16]1[O:17][C:18]([CH3:21])=[N:19][N:20]=1)[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29]C1C=CC(OCCCCCCC=O)=CC=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Ce+3].[Cl-].[Cl-].CN1NC=CO1>>[CH2:22]([O:29][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:16]2[O:17][C:18]([CH3:21])=[N:19][N:20]=2)[OH:15])=[CH:7][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CCCCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: Cc1nnc(C(O)CCCCCCOc2ccccc2)o1
Agent: CN1NC=CO1
Agent: [Ce+3]
Agent: [Cl-]
Product: Cc1nnc(C(O)CCCCCCOc2ccc(OCc3ccccc3)cc2)o1
Yield: 55 %

Procedure:
The synthesis was carried out analogous to the preparation of 64.1 using 62.2 (0.1 g, 0.32 mmol), cerium chloride (0.44 g, 1.6 mmol) and 63 (0.42 g, 1.6 mmol). Purification by flash column chromatography on silica gel gave pure 64.2 (0.077 mg, 55% yield) as a white solid (m p 98-100° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.Cl.NO.[N:38]1C=CC=CC=1.C(O)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]#[N:38])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: c1ccncc1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C#N)cc1
Yield: 67.1 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), hydroxylamine hydrochloride (0.14 g), pyridine (0.26 g) and ethanol (20 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.40 g, 68%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: O.O.[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14].[Cl:16]N1C(=[O:23])N(Cl)C(=O)N(Cl)C1=O>CO.O>[OH2:3].[OH2:23].[O:3]=[C:4]1[C:9]([Cl:16])=[C:8]([CH3:10])[NH:7][CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cc1cc(=O)c(OCC(=O)O)c[nH]1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: O
Solvent: CO
Product: Cc1[nH]cc(OCC(=O)O)c(=O)c1Cl

Procedure:
2-(4-oxo-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate (2.2 g) was dissolved in a mixture of methanol (120 ml) and water (170 ml) under heating on a water bath. The solution was stirred at 65° to 70° C. and trichloroisocyanuric acid (1.1 g) was added thereto. The resultant mixture was stirred for 65° to 70° C. for 1.5 hours. The reaction mixture was left to cool to room temperature with removal of the water bath and filtered. The obtained precipitates were washed with water and dried. The resultant crystals (2.0 g) were dried at 100° C. for 6 hours in vacuo over phosphorus pentoxide to give crystals of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate, mp 240° to 242° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:20])C.C([NH2:24])=O.C[O-].[Na+]>CN(C=O)C.CO>[Cl:20][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=2)[C:6]=1[CH2:5][C:4]([NH2:24])=[O:3]
Reactant: NC=O
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
(2-Chloro-7-dimethylaminomethyl-naphthalen-1-yl)-acetic acid ethyl ester (2.70 g, 8.82 mmol) and formamide (1.17 ml, 29.57 mmol) are dissolved under an atmosphere of argon in dry DMF (25 ml). The solution is heated to 105° C., and NaOMe (1.64 ml of a 5.4 M solution in MeOH, 8.82 mmol) is added dropwise during 10 minutes. After 1 hour at 105° C., TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT, diluted with water, and adjusted to a pH of 6-7 by the addition of 1 M NaHSO4 solution. The mixture is concentrated and purified by FCC (CH2Cl2/EtOH/NH3 conc. 90:9:1) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.01 (s, 6H), 3.48 (s, 3H), 4.02 (s, 3H), 6.9-7.0 (br, 1H), 7.41-7.47 (m, 2H); 7.47-7.85 (br, 1H), 7.75-7.88 (m, 2H), 7.80 (d, J=12.1 Hz, 1H). ES+−MS: 277.3, 279.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].N1CCCC1.[CH3:13][C:14]1[C:15]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1>C(O)C>[CH3:13][C:14]1[C:15]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[C:5]2[NH:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[C:22]=2[CH:23]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Solvent: C1CCNC1
Solvent: CCO
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
A mixture of 2,4-imidazolidinedione (101 mg, 1.0 mmol), pyrrolidine (0.04 mL, 0.5 mmol) and 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde (336 mg, 1.0 mmol) in ethanol (15 mL) was heated under reflux for 24 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with saturated aqueous NH4Cl (60 mL), saturated NH4Cl (70 mL), saturated aqueous NaCl (60 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a yellow solid that was purified by column chromatography, using a Biotage 40S cartridge, eluting with ethyl acetate/hexane (3:7). The title compound was isolated as a yellow solid (270 mg, 65%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].O>CS(C)=O>[F:20][C:21]1[CH:28]=[C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reaction time: 8 h
Yield: 48.7 %

Procedure:
9.17 g (49.3 mmol) of tert-butyl piperazine-1-carboxylate and then 6.81 g (49.3 mmol) of potassium carbonate, respectively, are added to 7 g (49.3 mmol) of 2,4-difluorobenzaldehyde diluted in 60 ml of dimethylsulfoxide. The solution is carried at 60° C. for 8 hours and then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue obtained is purified by silica gel chromatography (eluent: 7:3 cyclohexane/ethyl acetate) to yield 7.4 g (48%) of tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16]O)[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1.CCN(S(F)(F)[F:24])CC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][F:24])[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C1COCC(CO)(c2cc(Br)cnc2Cl)N1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cc(Br)cnc2Cl)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 5-(5-bromo-2-chloro-pyridin-3-yl)-5-hydroxymethyl-morpholin-3-one (547 mg, 1.70 mmol) in THF (13.6 ml) was added at 0° C. within 5 min a solution of DAST (1.01 ml, 7.65 mmol) in THF (7.2 ml), the reaction mixture was stirred at room temperature for 6 h. The mixture was cooled to 0° C., halfsaturated aq. Na2CO3 was added and the mixture was extracted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as colorless solid.