Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][NH:2][C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:9]
Reactant: CCOC(=O)C(CN)c1ccccc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NCC(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Ethyl 3-amino-2-phenylpropanoate hydrochloride (4.38 g, 19.13 mmol) was suspended in methylene chloride (80 mL) and triethylamine (5.86 mL, 2.2 eq.). The mixture was cooled to 0° C. and treated dropwise with ethyl 3-chloro-3-oxopropanoate (2.69 mL, 1.1 eq.). The reaction was kept at room temperature for one hour, diluted with methylene chloride, washed with 1 N HCl and then with 5% NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude material was chromatographed on silica gel, eluting with hexane/ethyl acetate 1/1, to give 3-(2-ethoxycarbonyl-acetylamino)-2-phenyl-propionic acid ethyl ester (4.24 g, Y=72%) as an oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[NH:6][C:5](=O)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Cl)n2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-6-(4-trifluoromethylphenyl)-1H-pyridin-2-one (51.5 g, 168 mmol) and phosphoryl chloride (50 mL) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (53.4 g, 98%). MS (ISN) 384.1 [(M+OAc)−], 386.0 [(M+2+OAc)−]; mp 39-40° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([NH:73][C:74]1[S:75][CH:76]=[C:77](/[C:79](=[N:83]/[O:84][CH2:85][C:86]([O:88][CH:89]([C:96]2[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=2)[C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)=[O:87])/[C:80](O)=[O:81])[N:78]=1)([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClC.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:80](=[O:81])/[C:79](/[C:77]4[N:78]=[C:74]([NH:73][C:54]([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=5)[C:67]5[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=5)[S:75][CH:76]=4)=[N:83]\[O:84][CH2:85][C:86]([O:88][CH:89]([C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)[C:90]4[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=4)=[O:87])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=C(CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Agent: CCl
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethyl-thio)-3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg: 1.06 mMol.) and (Z)-2-(2-tritylaminothiazol-4-yl)-2-(diphenylmethoxycarbonylmethoxyimino)acetic acid (728 mg: 1.11 mMol.) in chloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml: 2.46 mMol.), phenyl dichlorophosphate (0.19 ml: 1.27 mMol.), and the mixture is stirred at -30° C. for 30 minutes. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=10:1) to give 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(diphenylmethoxycarbonylmethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.07 g) as yellow foam. Yield: 73%.
Reaction SMILES: Cl[C:2]([O:4][CH:5](C)[CH2:6][Cl:7])=[O:3].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].[C:20](=O)([O-])[O-].[Ca+2]>O1CCOCC1>[N+:17]([C:11]1[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[NH:9][C:2](=[O:3])[O:4][CH2:5][CH:6]([Cl:7])[CH3:20])([O-:19])=[O:18]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: CC(CCl)OC(=O)Cl
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CC(Cl)COC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
85 g (0.54 mole) of α-methyl-β-chloroethyl chloroformate are added dropwise to 77 g (0.5 mole) of 4-amino-3-nitrophenol and 27 g of calcium carbonate in 250 ml of dioxane at 70° C. After 2 hours at 90° C., the inorganic salts are filtered off hot and the filtrate is concentrated completely. The desired intermediate product is thereby obtained in the form of a reddish oil and is used as such in the following stage.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][I:21]>C1C=CC=CC=1>[I-:21].[CH3:20][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CI
Solvent: c1ccccc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (30 g, 0.114 mol) in benzene (200 mL) was added methyl iodide (11 ml, 0.1756 mol) dropwise, and the solution stirred at room temperature for 15 min under a nitrogen atmosphere. The sub-title compound formed as a colourless solid, which was filtered and then dried. Yield: 30 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(CC)CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(C(F)(F)F)cn2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A degassed (argon) solution of 152 mg (0.50 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]), 124 mg (0.55 mmol) 2-bromo-5-(trifluoromethyl)pyridine and 0.21 ml (1.5 mmol) Et3N in 5 ml acetonitrile was treated with 18 mg (0.03 mmol) of PdCl2(PPh3)2 and 3 mg (0.03 mmol) of CuI. After stirring for 3 h at room temperature the reaction mixture was partitioned between cold aqueous 10% KHSO4 and ether (three times). Washing of the organic layer with aqueous 10% NaCl solution, drying (Na2SO4) and evaporation of the solvents, followed by flash chromatography (SiO2, n-heptane/EtOAc 95:5 to 9:1) yielded 170 mg of the title compound as yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]4=[O:16])[CH2:12][CH2:13]3)=[O:7])=[CH:25][CH:26]=2)[CH:29]=[CH:33][CH:32]=[CH:31]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CC(=O)O
Product: O=C(c1ccc(-n2cccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1

Procedure:
1-[1-(4-Aminobenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg) and 2,5-dimethoxytetrahydrofuran (0.19 ml) are refluxed with heating for 2 hours in acetic acid. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane to give 1-{1-[4-(1-pyrrolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (228 mg) as light gray powder, m.p.: 153°-156° C.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2].[BH4-:12].[Na+:13].[H][H]>COCCOCCOC>[N+:1]([C:4]1[N:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]([B-:12]([N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[N:6]2)([N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[N:6]2)[N:5]2[C:4]([N+:1]([O-:3])=[O:2])=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[N:6]2)[N:5]=1)([O-:3])=[O:2].[Na+:13]
Reactant: [BH4-]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1n[nH]c([N+](=O)[O-])n1
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1nc([N+](=O)[O-])n([B-](n2nc([N+](=O)[O-])nc2[N+](=O)[O-])(n2nc([N+](=O)[O-])nc2[N+](=O)[O-])n2nc([N+](=O)[O-])nc2[N+](=O)[O-])n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Under anhydrous conditions and a stream of dry nitrogen, 6.36 g (40.0 mmol) 3,5-dinitro-1H-1,2,4-triazole and 37.8 mg (10.0 mmol) sodium borohydride were loaded into a dry 250 mL three-necked round bottom flask that was equipped with a TEFLON™ coated stirring bar, an addition funnel and a reflux condenser. While stirring, 50 mL of anhydrous 1-methoxy-2-(2-methoxyethoxy)ethane (diglyme) was carefully added through the addition funnel. Immediately, hydrogen gas was evolved and the reaction mixture turned yellow-orange. When the addition was complete, the addition funnel was replaced by a stopper. The mixture was heated to 50° C. for three hours and then to 110° C. for an additional 24 hours. The obtained orange solution was allowed to cool to ambient temperature and all volatiles were pumped-off in vacuo. Subsequent evacuation to a constant weight over a period of 48 hours resulted in a yellow solid of sodium tetrakis(3,5-dinitro-1H-1,2,4-triazolyl)borate, 8.5 g. Decomposition temperature: 167.6° C. (TGA, weight loss: 69.4%), density: 1.80 g/cm3 at 20° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[I:14]Cl>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1[I:14]
Reactant: ClI
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To a suspension of 1.06 g (5.31 mmol, 1.0 equiv.) of 4-amino-N-methylbenzenemethanesulfonamide in 20 mL of acetonitrile was added 0.862 g (5.31 mmol, 1.0 equiv.) of iodine monochloride. The reaction was stirred for 15 minutes at room temperature. The mixture was partitioned between 25 mL of ethyl acetate and 15 mL of 20% aqueous sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was filtered through a plug of silica gel using 40% ethyl acetate in hexane to yield 1.13 g (65%) of 4-amino-3-iodo-N-methylbenzenemethanesulfonamide
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1.[C:16](=[S:18])=[S:17].[CH3:19]O>>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[S:18])[S:17][CH3:19])[CH2:8][CH2:7]1
Reactant: S=C=S
Reactant: NCCCN1CCN(CCO)CC1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: CSC(=S)NCCCN1CCN(CCO)CC1
Reaction time: 2 h

Procedure:
To a solution of potasium hydroxide (1.5 g) in methanol (11 ml) was added 3-[4-(2-hydroxyethyl)-1-piperazinyl]propylamine (5.0 g) and thereto was added carbon disulfide (2.0 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (10 ml), washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (3.8 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling, extracted with ethyl acetate, dried over magnesium sulfate and then evaporated to give methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]dithio-carbamate (4.8 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[O:21][C:20]([C:22]([Cl:24])=[O:23])=[CH:19][CH:18]=1>C1C=CC=CC=1>[ClH:24].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:22]([C:20]3[O:21][C:17]([CH3:16])=[CH:18][CH:19]=3)=[O:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)o1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)N2CCN(CCCc3ccccc3)CC2)o1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 1 from a mixture of 1-(3-phenylpropyl)piperazine, 5-methyl-2-furoyl chloride and benzene.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.CS(O[CH:15]1[CH2:18][N:17]([C:19]([C:21]2[O:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:25]=2)=[O:20])[CH2:16]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH:15]2[CH2:16][N:17]([C:19]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[O:20])[CH2:18]2)=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: OCc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
(4-Mercaptophenyl)methanol (2.38 g, 17.0 mmol) and 1C (5.00 g, 15.5 mmol) were mixed in DMF (80 mL). Cs2CO3 (6.05 g, 18.56 mmol) was added. The mixture was stirred at 90° C. overnight and then cooled room temperature. Ethyl acetate (150 mL) was added and the mixture was washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic phases were combined, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography eluting with ethyl acetate/heptane (20:80, 40:60 and then 60:40). There was obtained 3.5 g (61%) of 5A as a solid. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 4.64 (m, 2H), 4.69 (s, 2H), 5.10 (m, 1H), 7.34 (m, 4H), 7.53 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 368 [M−H]−.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1cc[nH]n1
Product: O=C1CCCC2=C1C(c1ccc(C(F)(F)F)cc1)n1nccc1N2

Procedure:
1,3-Cyclohexanedione, 4-trifluoromethylbenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[O:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:13][C@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[O:17][CH:18]=2)[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1coc(-c2cccs2)n1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1coc(-c2cccs2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-[(thiophene-2-yl)oxazol-4-yl]ethanamine HBr, 47, (3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol) and 1-hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL) at 0° C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90 g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)[CH3:2].CC([O-])(C)C.[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C1COCC1.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:6]1[CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=[CH:5]1)[CH3:20].[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:4]1[C:3]([CH2:1][CH3:2])=[CH:7][N:6]=[CH:5]1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CCc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cnc(CC)c1
Product: CCOC(=O)Cn1cncc1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.02 g (50 mmol) of 4-ethylimidazole are dissolved in 100 ml THF at rt under nitrogen. 5.9 g (52 mmol) KOtBu is added and the reaction is stirred for 2 h at rt. 6.3 ml (55 mmol) ethyl bromoacetate is added drop wise over a period of 30 min and the resulting mixture is stirred at rt for 2.5 h. 20 ml H2O and 130 ml AcOEt are added, the organic layer is separated and the aq. layer is washed again 2× with 100 ml AcOEt. The combined organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The reaction is purified by Flash-chromatography (silica gel, MeOH/methylen chloride) to give (4-ethyl-imidazol-1-yl)-acetic acid ethyl ester and (5-ethyl-imidazol-1-yl)-acetic acid ethyl ester, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]([O:16]CC)=[O:15])[CH2:12][CH2:11][N:10]([CH3:19])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC1C=C([C@H]2[C@@H](C(OCC)=[O:34])CCN(C)C2)C=CC=1.[OH-:39].[K+:40].CO.C>CC(O)C>[OH2:15].[OH2:34].[OH2:39].[OH2:15].[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]([O-:16])=[O:15])[CH2:12][CH2:11][N:10]([CH3:19])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[K+:40]
Reactant: CCOC(=O)[C@H]1CCN(C)C[C@H]1c1cccc(F)c1
Reactant: [OH-]
Reactant: CCOC(=O)[C@@H]1CCN(C)C[C@H]1c1cccc(F)c1
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Product: CN1CC[C@@H](C(=O)[O-])[C@H](c2cccc(F)c2)C1
Product: O
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of 26.53 parts of trans-ethyl 3-(3-fluorophenyl)-1-methyl-4-piperidinecarboxylate: cis-ethyl 3-(3-fluorophenyl)-1-methyl-4-piperidinecarboxylate (40:60), 6.52 parts of potassium hydroxide and 80 parts of methanol was stirred for 3 hours at reflux temperature. After the addition of 78 parts of 2-propanol, the reaction mixture was treated with charcoal. The whole was filtered and the filtrate was evaporated to near dryness in vacuo. The residue was treated with 7.2 parts of water and then diluted with ~210 parts of 1,1'-oxybisethane (to near cloud point). After cooling, the crystallized product was filtered off, washed with 1,1'-oxybisethane and recrystallized twice from a mixture of a minimal amount of damp 2-propanol and 1,1'-oxybisethane, yielding 26.1 parts (75%) of potassium (±)-trans-3-(3-fluorophenyl)-1-methyl-4-piperidinecarboxylate tetrahydrate; mp. 75.2° C. (interm. 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:14]=2[C:15]#[N:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(Nc2ccc(Cl)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 160 °C
Yield: 37.5 %

Procedure:
Combine 1,4-dichloro-2-nitro-benzene (0.513 g, 2.67 mmol), 2-amino-5-isopropyl-benzonitrile (0.514 g, 3.21 mmol), potassium carbonate (0.754 g, 5.45 mmol), and fine granular copper (0.031 g, 0.48 mmol) in dimethylformamide (5 ml). Heat the reaction mixture to 160° C. for 16 hours, and cool to ambient temperature. Dilute the reaction mixture with 50 ml of ethyl acetate and wash 3 times with 50 ml water and once with 50 ml of brine. Collect organic layer, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a step gradient starting with 90% hexanes: 10% ethyl acetate and going to 85% hexanes: 15% ethyl acetate to obtain 0.316 g (1.00 mmol, 37% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 316 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]([CH3:25])[N:23]=[N:24][C:20]=2[CH:19]=1>>[CH3:25][N:22]1[C:21]2[CH:26]=[CH:27][C:18]([CH2:17][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)=[CH:19][C:20]=2[N:24]=[N:23]1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: Cn1nnc2cc(CCl)ccc21
Product: Cn1nnc2cc(CN(c3ccc([N+](=O)[O-])cc3)n3cnnc3)ccc21

Procedure:
Starting Compounds: 4-[(4-nitrophenyl)amino ]-4H-1,2,4-triazole and 5-chloromethyl-1-methyl-1H-benzotriazole
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[OH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[OH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]([CH3:16])[CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(N)C(C)NC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC(NC(=O)OCc1ccccc1)C(C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
To a mixture of benzyl 3-aminobutan-2-ylcarbamate (5.3 g, 23.8 mmol), 2-hydroxybenzoic acid (3.28 g, 23.8 mmol) and imidazole (1.62 g, 23.8 mmol) in EtOAc (180 mL) at 0° C. was slowly added a solution of DCC (4.90 g, 23.8 mmol) in EtOAc (20 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with PE-EA (5:1) to afford benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 40%) as a colorless oil. Mass calculated for C19H22N2O4=342.39. found: [M+H]+=343.2.