Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C=CC=1)OCC1C=CC=CC=1C1SC(NC(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)C)CCC)=NC=1)#N.[C:38]([C:40]1C=C[CH:72]=[CH:71][C:41]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[S:54][C:53]([NH:55][C:56](=[O:70])[C@@H:57]([NH:61][C:62](=[O:69])[C@@H:63]([OH:68])[C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:58][CH2:59][CH3:60])=[N:52][CH:51]=1)#[N:39].C(C1C=C(O)C=CC=1)#N.C(C1C=CC=CC=1O)#N>>[OH:68][C@@H:63]([C:64]([CH3:67])([CH3:65])[CH3:66])[C:62]([NH:61][C@@H:57]([CH2:58][CH2:59][CH3:60])[C:56]([NH:55][C:53]1[S:54][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][O:42][C:41]2[CH:40]=[CH:38][N:39]=[CH:72][CH:71]=2)=[CH:51][N:52]=1)=[O:70])=[O:69]
Reactant: CCC[C@H](NC(=O)[C@@H](O)C(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2ccccc2C#N)s1
Agent: CCC[C@H](NC(=O)[C@@H](O)C(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2cccc(C#N)c2)s1
Agent: N#Cc1cccc(O)c1
Agent: N#Cc1ccccc1O
Product: CCC[C@H](NC(=O)[C@@H](O)C(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2ccncc2)s1

Procedure:
Compounds No. 61 ((2S)-N-(5-{2-[(3-cyano-phenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}pentanamide) and No. 69 ((2S)—N-(5-{2-[(2-cyanophenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino}pentanamide) may be prepared according to the method described in Example 7, replacing 4-hydroxypyridine with 3-cyanophenol or 2-cyanophenol, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O-:10])=O.[CH3:11][NH:12][CH3:13].[CH2:14]([OH:16])C>>[CH3:14][O:16][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]([N:12]([CH3:13])[CH3:11])=[O:10]
Reactant: CNC
Reactant: O=C([O-])Cc1ccccn1
Reactant: CCO
Product: COC(C(=O)N(C)C)c1ccccn1

Procedure:
A mixture of 18.1 g. of methyl 2-methoxy-2-(2-pyridylacetate and 10 g. of dimethylamine in ethanol is stirred at room temperature for 26 hours. The mixture is concentrated, dissolved in chloroform and extracted with brine. The organic phase is dried over magnesium sulfate and filtered and the solvent is removed under reduced pressure to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:14][N:13]=1>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:6])[C:3]([NH:11][C:12]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:14][N:13]=1)=[O:4]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
N,N-Dimethylcarbamoyl chloride (7.91 g) and aluminum chloride (9.80 g) are added to toluene (100 ml), and the mixture is stirred at room temperature for 30 minutes. To this mixture is added 3-amino-5-t-butylisoxazole (9.81 g), and the resulting mixture is refluxed for 6 hours with stirring. After cooling, the reaction mixture is mixed with water, stirred at room temperature and shaken with toluene. The organic layer is evaporated to remove the toluene, whereby 1,1-dimethyl-3-(5-t-butyl-3-isoxazolyl)urea (14.63 g) is obtained. Yield is 98.9%. Melting point of the colorless crystalline product is 119 to 120.5° C. (after recrystallization from benzene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:26])=[CH:22][C:23](Cl)=[O:24]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:23](=[O:24])[CH:22]=[C:21]([CH3:26])[CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.58 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.67 ml of 3,3-dimethylacryloyl chloride in 7 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid was recrystallized from methyl cellusolve to give 0.97 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-3-methyl-2-butenamide: mp=300-301° C., mass spectrum (m/e): 396, 398.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]2[N:35]([CH:36]=1)[C:18]1[N:19]([C:28]3[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:20](=[O:27])[C:21]3[C:26]([C:17]=1[N:16]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3>ClCCl>[Cl:34][C:31]1[N:30]=[CH:29][C:28]([N:19]2[C:18]3[N:35]4[CH:36]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=[CH:14][C:15]4=[N:16][C:17]=3[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:27])=[CH:33][CH:32]=1
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Formic acid (5.0 equiv., 1.390 mmol, 0.064 g) was added to a cooled (0° C.) solution of acetic anhydride (2.0 equiv., 0.552 mmol, 0.050 g) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 1 h. Compound 53 (1.0 equiv., 0.276 mmol, 0.100 g) was added and the resulting suspension was stirred at room temperature for 6 h. The precipitate was filtered off and successively washed with isopropanol and isopropyl ether affording N-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-formamide (57) (0.060 g, yield=56%, purity (LC)=96%).
Reaction SMILES: [Mg].[CH2:2](Cl)[CH:3]=C.[C:6]([CH:9]1[C:14]([CH3:16])([CH3:15])[CH:13]2[CH2:17][CH:10]1[CH2:11][CH2:12]2)(=[O:8])[CH3:7].[NH4+].[Cl-].[CH3:20]COCC>>[CH2:7]([C:6]([CH3:20])([CH:9]1[C:14]([CH3:16])([CH3:15])[CH:13]2[CH2:17][CH:10]1[CH2:11][CH2:12]2)[OH:8])[CH:2]=[CH2:3]
Reactant: CC(=O)C1C2CCC(C2)C1(C)C
Reactant: C=CCCl
Reactant: CCOCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: C=CCC(C)(O)C1C2CCC(C2)C1(C)C
Reaction time: 1 h

Procedure:
The magnesium turnings are placed into a 1 liter, 3 neck reaction flask, followed by 200 cc of anhydrous ether. Approximately 6 cc of allyl chloride is added to initiate formation of the Grignard reagent. When the reaction is initiated, the remaining allyl chloride is added dropwise over a 2 hour period, with moderate reflux. After the addition, reflux is continued for 1 hour; at which time 28.5 g 2-acetyl-3,3-dimethylnorbornane is introduced over a 20 minute period. The reaction is very exothermic during this addition. At the end of the addition, refluxing is continued for 1 hour. The work up is carried out by hydrolyzing with NH4Cl solution, filtering and separating the layers. The organic layer is washed with two 200 cc portions of water, dried over MgSO4, filtered and concentrated to give 34 grams of oil which is distilled to give 26 g of product, b.p. 90-105° C at 1-2 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]#[N:7]
Reactant: N#Cc1ccc(Cl)c(F)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)c(F)c1

Procedure:
A solution of 4-chloro-3-fluoro-benzonitrile (236 mg, 1.52 mmoles), piperazine (784 mg, 9.1 mmoles) and potassium carbonate (276 mg, 2 mmoles) in acetonitrile (5 mL) was heated to 100° C. overnight. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% 2N methanolic ammonia in DCM) to provide the title compound. MS(APCI+) m/z 206 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[CH3:13][N:14]([CH3:16])[NH2:15]>>[CH3:13][N:14]([CH3:16])[NH:15][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([Cl:1])=[C:3]([Cl:12])[CH:4]=1
Reactant: CN(C)N
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Product: CN(C)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
Reaction of 1,2,4-trichloro-5-nitrobenzene with 1,1-dimethylhydrazine as described in Example I gave the desired product, m.p. 138° - 143° C.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:44])=[C:27]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28]2>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:44])=[C:27]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:20][CH:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:2])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28]2
Reactant: CN1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1ccc(C)c2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-methyl-piperidin-4-ylamine and rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=460.8 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][C@@H:11]([OH:13])[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C@H:11]1[CH2:10][CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCO[C@@H](c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](c2ccccc2)C1
Yield: 62.6 %

Procedure:
A solution of cis-2-phenyltetrahydro-2H-pyran-4-ol (1 g) in DCM (20 mL) was cooled in an ice-salt water bath and treated with DIEA (2.2 g) and methanesulfonyl chloride (0.7 g) for 2 hours. The mixture was diluted with DCM (50 mL) and washed with water and brine. The organic layer was dried and concentrated. Preparative TLC provided 0.9 g of cis-2-phenyl-tetrahydro-2H-pyran-4-yl methanesulfonate.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C(OC(OCC)OCC)C.[C:37]([C@@H:42]([C@H:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])O)[OH:43])([O:39][CH2:40][CH3:41])=[O:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:49]([O:48][C:46]([C@H:44]1[C@H:42]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:43][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[O:26]1)=[O:47])[CH3:50]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(OCC)OCC
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C3O[C@@H](C(=O)OCC)[C@H](C(=O)OCC)O3)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of 0.706 g of 4'-(6-acryloxyhexyloxy)biphenyl-4-carboxaldehyde, 1 ml of orthoformic acid triethyl ester, 0.7 ml of diethyl L-tartrate, 27 mg of BHT, 6.8 mg of 4-toluenesulphonic acid monohydrate and 10 ml of toluene was allowed to stand for 1 hour at room temperature, then heated for 2.5 hours to boiling, the solvent being distilled off and replaced by fresh toluene. After the addition of 3 drops of triethylamine and cooling, it was diluted with diethyl ether, washed with water, dried over sodium sulphate, filtered and concentrated at 40° C. in vacuo. The oily residue was chromatographed on 45 g of silica gel with hexane/ethyl acetate 4:1. Recrystallisation from ethyl acetate resulted in 0.18 g (4R,5R)-2-[4-(6-acryloxyhexyloxy)biphenyl-4-yl]-1,3-dioxolane-4,5-dicarboxy acid diethyl ester; boiling point (C-I) 65° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:15](CC(C4C=C5C(C=CN5S(CCC)(=O)=O)=CC=4)=O)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+:39]([CH2:48][CH2:49][CH2:50][CH3:51])([CH2:44][CH2:45][CH2:46][CH3:47])CCCC)CCC.[O:52]1CCC[CH2:53]1>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:15]([C:53]([C:46]4[CH:45]=[C:44]5[C:50]([CH:49]=[CH:48][NH:39]5)=[CH:51][CH:47]=4)=[O:52])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: CCCS(=O)(=O)n1ccc2ccc(C(=O)Cc3c[nH]c4ncc(OC5CCCC5)cc34)cc21
Agent: [F-]
Product: O=C(c1ccc2cc[nH]c2c1)c1c[nH]c2ncc(OC3CCCC3)cc12
Temperature: 60 °C
Reaction time: 19 h

Procedure:
To (5-Cyclopentyloxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-[1-(propane-1-sulfonyl)-1H-indol-6-yl]-methanone (62, 0.065 g, 0.14 mmol) dissolved in tetrahydrofuran (5.10 mL, 0.0628 mol), 1.00 M tetra-n-butylammonium fluoride in tetrahydrofuran (0.475 mL) was added. The resulting solution was allowed to stir at 60° C. under an atmosphere of nitrogen. After 19 hours, the reaction was quenched with water, and the two layers were separated. The organic layer was extracted with 50% sat. NaHCO3 (in water), followed by sat. bicarbonate, 1N HCl, and brine. The organic layer was dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by HPLC to give 1.7 mg of compound P-0040. MS (ESI) [M+H+]+=346.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14](Cl)[CH:15]([Cl:20])[C:16]([Cl:19])([Cl:18])[Cl:17])[C:11](=[O:22])[N:10]([CH3:23])[C:9]1=[O:24].[F:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].C(N(CC)CC)C.Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[F:25])[CH:15]([Cl:20])[C:16]([Cl:19])([Cl:18])[Cl:17])[C:11](=[O:22])[N:10]([CH3:23])[C:9]1=[O:24]
Reactant: CN1C(=O)C(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C1=O
Reactant: Nc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CN1C(=O)C(=NC(Nc2ccccc2F)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C1=O
Reaction time: 0.17 h

Procedure:
In this example 0.02 mol of 1-(2-fluorophenyl)-3-methyl-5-(1,2,3,3,3-pentachloropropyl)imino-1,3-diazolidine-2,4-dione is dissolved in 20 ml of acetonitrile and then 0.02 of mol of 2-fluoroaniline is added. After about 10 minutes, triethylamine is added to neutralize the byproduct HCl produced by the reaction. The mixture is stirred for five hours and 20 ml of ethyl ether is then added. The mixture is filtered and the filtrate evaporated under high vacuum affording 1-(2-fluorophenyl)-3-methyl-5-(1-2'-fluorophenylamino-2,3,3,3-tetrachloropropyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25][CH2:26][C:27](O)=[O:28])[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl.[CH2:37]([NH2:39])[CH3:38].[Cl-].[NH4+]>C(N(CC)CC)C.ClCCl>[CH2:37]([NH:39][C:27]([CH2:26][NH:25][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:10]([NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:14]=1)=[O:11])=[O:28])[CH3:38]
Reactant: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NCC(=O)O
Reactant: CCN
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
To a 25 ml flask was added 2-((S)-3-(4-fluorophenyl)-1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylamino)acetic acid 103.2 (145 mg, 0.36 mmole), 50% propylphosphoric anhydride in ethyl acetate (348 mg, 0.55 mmole), 0.2 ml of triethylamine and 3 ml of dichloromethane. After 20 min, ethylamine hydrochloride (60 mg, 0.73 mmole) was added to the mixture. The reaction was stirred at room temperature for 4 days. The solution was poured into saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 103.3 (69 mg, 44% yield) as colorless amorphous. LCMS ESI (pos.) m/e: 425 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.58 (dd, J=17.9, 6.2 Hz, 2H), 7.63 (dd, J=19.5, 6.2 Hz, 2H), 7.25 (dd, J=9.2, 6.0 Hz, 2H), 7.05 (t, J=7.7 Hz, 2H), 6.82 (s, 1H), 5.79 (brs, 1H), 3.81 (s, 3H), 3.46 (dd, J=8.6, 4.7 Hz, 1H), 3.31-3.17 (m, 3H), 3.21 (d, J=2.8 Hz, 2H), 2.92 (dd, J=14.1, 8.6 Hz, 1H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1([NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39].FC(F)(F)C(O)=O>C1COCC1.C(OCC)(=O)C>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:40][C:9](=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH:3]([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1
Reactant: COC(CC=CC=CC(=O)O)c1ccc(N(C)C)cc1
Reactant: Nc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(CC=CC=CC(=O)Nc1ccccc1N)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of carboxylic acid 16 (207 mg, 0.753 mmol) in anhydrous THF (10 mL) was added 1,1′-carbonyldiimidazole (128 mg, 0.790 mmol) at rt, and the mixture was stirred overnight. To the resulting solution was added 1,2-phenylenediamine (570 mg, 5.27 mmol), followed by trifluoroacetic acid (52 μl ), and the reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated NaHCO3 solution (5 mL) and then water (10 mL), dried (MgSO4), and concentrated. Purification by flash silica gel chromatography (50% ethyl acetate in toluene) afforded the title compound 20 (115 mg, 42% yield): 1H NMR (300 MHz, CDCl3) δ 7.44 (br. s, 1H), 7.01-7.29 (m, 5H), 6.70-6.78 (m, 4H), 6.09 (m, 2H), 5.90 (d, J=15.0 Hz, 1H), 4.10 (br. t, J=6.6 Hz, 1H), 3.89 (br. s, 2H), 3.18 (s, 3H), 2.95 (s, 3H), 2.66 (m, 1H), 2.50 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 40.5, 41.6, 82.8, 112.3, 118.1, 119.4, 121.7, 124.4, 125.1, 127.0, 127.6, 128.6, 130.0, 140.0, 140.8, 142.5, 150.2, 164.7.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>CO.O>[OH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(C)O

Procedure:
The same procedure of Example 5 is repeated with the only differences that 1.95 g of ethyl 3-oxo-butyrate were weighed and dissolved in MeOH/H2O 19/1 (v/v) and the catalyst of Example 15 was utilized. At the end of the reaction, the ethyl 3-hydroxybutyrate resulted to be equal to 91%, while the ethyl 3-dimetoxybutyrate resulted equal to 9%. The stereoinduction was <99% in favour of the antipode (S).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][C:20]=2[C:24]#[N:25])=[CH:15][CH:14]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:28][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:26])[F:27])=[CH:18][CH:17]=2)=[C:20]([C:24]#[N:25])[N:21]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
LiHMDS (1.0 M in THF, 4.5 mL, 4.5 mmol) was added dropwise to a solution of Example 56C (0.980 g, 4.11 mmol) in THF (13 mL) at −78° C. After 30 min solid hexachloroethane (0.974 g, 4.11 mmol) was added in one portion. The reaction was allowed to warm to room temperature while stirring overnight during which a solid formed. The mixture was diluted with hexanes and water, and filtered. The filtrate was diluted with EtOAc, and the phases separated. The organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in toluene, loaded on silica gel, and eluted with 1 column length of hexanes and then 0% to 30% EtOAc:hexanes to afford 0.51 g (46%) of the title compound as a yellow milky oil. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.2, 2H), 7.81 (d, J=8.3, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)(=[O:3])[CH3:2]>C(O)C.O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)NCCNc1ccc(N)cn1
Yield: 43.8 %

Procedure:
A suspension of 2-(2-acetamidoethylamino)-5-nitropyridine (4.0 g, 17.86 mmol) in ethanol-water (3:1, 160 ml) was shaken with 10% palladium on charcoal (400 mg) under an atmosphere of hydrogen for 5 h then filtered through Celite™ and the filtrate concentrated. The residue was subjected to column chromatography (silica, 3-10% methanol-CH2Cl2) to afford the title compound (1.52 g) as an air-sensitive deep mauve gum. MS (ES+) 195 (MH+). δH (d6DMSO) 7.89 (1H, br s), 7.45 (1H, d, J 2.5 Hz), 6.82 (1H, dd, J 2.5, 8.7 Hz), 6.28 (1H, d, J 8.7 Hz), 5.60 (1H, br s), 4.34 (2H, br s), 3.16 (4H, m) and 1.79 (3H, s).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:8]([CH3:10])=O)[CH:2]([CH3:4])[CH3:3].[C:22]1(=[O:45])[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])[C:25](=[O:40])[C:24]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:23]12>>[CH3:10][C:8]1[NH:38][C:36]([CH3:37])=[C:35]([C:34]([O:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:22](=[O:45])[C:23]3=[CH:44][CH:43]=[CH:42][CH:41]=[C:24]3[C:25]2=[O:40])=[O:39])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:21]
Reactant: C/C(N)=C/C(=O)OCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC(C)C
Product: CC1=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC(C)C)=C(C)N1

Procedure:
Prepared by a method analogous to that of Example 1(a) from 7.0 g (24 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid isobutylester and 8.0 g (24 mmol) of 3-amino-crotonic acid-(6-phthalimidohexyl)ester. 14.6 g (quantitative) of an orange yellow oil which is used for further reactions without purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1

Procedure:
5-(4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy) benzylidene)-2,4-thiazolidinedione (2.4 g) in dioxan (150 ml) was hydrogenated in the presence of 10% palladium-charcoal (4.8 g) for 3 h. at room temperature and atmospheric pressure. A further portion of catalyst (2.4 g) was added and the hydrogenation continued for a total of 20 h. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The residue was chromatographed on silica gel with 3% methanol-dichloromethane as eluant to afford the title compound as a foam, which collapsed at 78° C.