Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][CH:14]([CH2:15]2)[C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:6][CH:5]=1)([O-])=O>COCCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]([CH2:16]2)[C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:8][CH:9]=1
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Agent: [Pd]
Solvent: COCCO
Product: Nc1ccc(C23CC(C2)C(=O)NC3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 5.0 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 250 ml of 2-methoxyethanol are hydrogenated at 45° in the presence of 0.5 g of 5% palladium-on-carbon and worked up. The title compound is obtained which, after recrystallisation from 2-methoxyethanol, melts at 265° with decomposition.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[CH2:11]([NH:13][CH2:14][CH2:15][CH3:16])[CH3:12].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:11]([N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)[CH2:14][CH2:15][CH3:16])[CH3:12]
Reactant: OCc1ccc(CCl)cc1
Reactant: CCCNCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CC)Cc1ccc(CO)cc1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
A mixture of 5 g of [4-(chloromethyl)phenyl]methanol, 5.56 g of N-ethylpropan-1-amine, 5.29 g of potassium iodide and 4.41 g of K2CO3 in 200 ml of acetonitrile is left to stir at AT for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 3.5 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:23])[C:11]2[CH:17]=[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:23])[C:11]2[CH:17]=[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCCCC3
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCCCC3
Yield: 96.7 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.23 mL, 2.1 mmol) was added to a stirred solution of chloride 187 (178 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 188 (204 mg, 95%) as a yellow solid: mp (MeOH) 149-152° C.; 1H NMR δ 7.96 (s, 1H, H-11), 7.31 (s, 1H, H-5), 5.84 (br s, 1H, NH), 3.52-3.57 (m, 2H, CH2N), 2.85-2.90 (m, 4H, H-6, H-10), 2.58 (br t, J=6.0 Hz, 2H, CH2N), 2.28 [s, 6H, N(CH3)2], 1.79-1.85 (m, 2H, H-8), 1.65-1.74 (m, 4H, H-7, H-9); 13C NMR δ 159.0, 153.4, 148.0, 142.1, 129.0, 125.0, 118.8, 57.6, 45.1 (2), 38.7, 36.8, 36.2, 32.0, 28.7, 28.4. Anal. calcd for C16H23N5O.½H2O: C, 61.9; H, 7.8; N, 22.6. Found: C, 62.0; H, 7.8; N, 22.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14])([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[F:11][C:10]([F:12])([F:13])[C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:14])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1N

Procedure:
2-Nitro-4-trifluoromethyl-phenylamine was purchased from Aldrich. It was reduced with tin (11) chloride dihydrate in ethanol to give 4-trifluoromethyl-benzene-1,2-diamine (Scheme 3). The diamine was reacted with hexaketocyclohexane octahydrate to give [(HATNA)(CF3)3]. The product contains two isomers (from HPLC). The product is a yellow solid. It is soluble in common organic solvent including dichloromethane, THF and hot methanol. It was purified by flash chromatography on silica gel eluting with dichloromethane.
Reaction SMILES: P([O:5][CH2:6][C@@:7]1([CH2:22][N:23]=[N+:24]=[N-:25])[O:11][C@@H:10]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:21])(O)(O)=O>O>[N:23]([CH2:22][C@:7]1([CH2:6][OH:5])[O:11][C@@H:10]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:21])=[N+:24]=[N-:25]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN=[N+]=[N-])(COP(=O)(O)O)O2)c(=O)[nH]c1=O
Solvent: O
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reaction time: 0.33 h

Procedure:
Sufficient water is added to 100 g of egg-yolk phospholipids to bring the total volume to 1 liter. The mixture is stirred with a homomixer. Then, the mixture is homogenized with an emulsifier under a pressure of 300 kg/cm2 for 30 minutes, whereby an aqueous phospholipid dispersion is obtained 4'-Azidomethylthymidine 5'-monophosphate (20 g) and sodium chloride (18 g) are dissolved in enough water to bring the total volume to 1 liter. The aqueous phospholipid dispersion (850 mL) and the 4'-azidomethylthymidine 5'-monophosphate solution (850 mL) are mixed. The aqueous dispersion thus obtained is filtered through a membrane filter (pore size 0.45 m in diameter). The filtrate is sterilized at 120° C. for 20 minutes and then allowed to stand at -20° C. for 20 hours in a freezer. The frozen dispersion thus obtained is thawed by allowing it to stand at room temperature. An aqueous suspension of 4'-azidomethylthymidine 5'-monophosphate entrapped in phospholipid spherules is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]([NH2:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[C:18](/[C:22](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14]
Reactant: NC(=O)C#Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: NC(=O)/C=C(/c1ccccc1)c1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 75 °C
Yield: 19.9 %

Procedure:
A mixture of 3-{3-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), iodobenzene (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.1 mL EtOAc (degassed) was heated at 75° C. for 16 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with H2O/brine mixture, brine, dried with anhydrous Na2SO4 and rotary evaporated. The crude material was chromatographed eluting with EtOAc/CHCl3 to give the higher Rf material as an off-white solid. The solid was recrystallized from EtOAc/hexane to give the title compound as a white solid (7.5 mg, 20%). 1H NMR (CD3CN) δ: 8.54-8.58 (m, 1H), 7.89 (s, 1H), 7.71 (d, J=3.2 Hz, 1H), 7.14-7.39 (m, 10H), 6.78-6.82 (m, 1H), 6.39 (s, 1H), 6.14 (br. s, 1H), 5.79 (br. s, 1H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.ClC1C=C(Cl)C=CC=1[C:38]1[N:39]=[C:40]([CH3:56])[C:41]([NH:45][CH:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:49][CH2:48][CH2:47]2)=[N:42][C:43]=1[CH3:44].[CH3:57][C:58]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=1B(O)O>>[CH3:65][O:64][C:62]1[CH:61]=[CH:60][C:59]([C:38]2[N:39]=[C:40]([CH3:56])[C:41]([NH:45][CH:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[CH2:49][CH2:48][CH2:47]3)=[N:42][C:43]=2[CH3:44])=[C:58]([CH3:57])[CH:63]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1NC1CCCc2ccccc21
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: COc1ccc(-c2nc(C)c(NC3CCCc4ccccc43)nc2C)c(C)c1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-(2,4-dichlorophenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and 2-methyl-4-methoxy phenyl boronic acid, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.81, 2.01, 2.06, 2.13, 2.22, 2.77, 3.71, 4.38, 5.39, 6.70, 7.09, 7.31; 13C NMR (CDCl3) δ 20.07, 20.47, 20.54, 22.09, 29.96, 30.28, 48.94, 55.68, 111.58, 116.05, 126.64, 127.57, 129.43, 129.60, 131.24, 132.37, 135.83, 138.31, 138.56, 138.74, 140.69, 147.04, 150.92, 159.51; HRMS (ESI+) for C24H27N3O1 m/z cald 374.2232 (M+H)+ found 374.2226
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].O=P(Cl)(Cl)Cl>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1O
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Temperature: 80 °C

Procedure:
The crude 5-nitro-2-trifluoromethyl-pyridin-4-ol (3.4 g, 16.3 mmol) was treated with PCl5 (5.2 g, 24.97 mmol) and POCl3 (7 mL, 24.49 mmol). The resulting mixture is heated at 80° C. for 18 h, cooled and poured into ice-cold water, and extracted with CH2Cl2. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 4-Chloro-5-nitro-2-trifluoromethyl-pyridine as an yellow oil. 1H NMR (300 MHz, CDCl3): δ 9.17 (s, 1H) 7.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([O:19][CH3:20])=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([O:19][CH3:20])=[C:10]([CH2:14][CH2:15][C:16]([Cl:25])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: COc1c(CCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 5.1 g of 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid in 25 ml of thionyl chloride was refluxed for 21/2 hours and the excess thionyl chloride was distilled off. The residue was taken up in benzene and was evaporated to dryness to obtain 5.6 g of 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionyl chloride which was used as is for the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=2)[CH2:10][O:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:5][N:4]=[N:3]1.Cl>C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=2)[CH2:10][O:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1cc(COCC2(c3ccccc3)CCNCC2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (7.0 mg, 0.01 mmol) was dissolved in a minimum amount of ethyl acetate, followed by addition of 4 N hydrochloric acid (0.5 mL). The mixture was stirred under nitrogen for 1 h. After removing the solvents, the crude mixture was precipitated in diethyl ether and filtered to afford 4.0 mg (88%). 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 7.33 (s, 1H), 7.27-7.29 (m, 2H), 7.20 (m, 1H), 4.49 (s, 2H), 4.06 (s, 3H), 3.48 (s, 2H), 2.93-2.96 (m, 2H), 2.74-2.77 (m, 2H), 2.20-2.22 (m, 2H), 1.89-1.94 (m, 2H). Mass spec.: 432.20 (MH)+. Accurate mass spec.: m/z 432.1994 [MH]+, Δ=4.4 ppm.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1)C(=O)O
Yield: 50 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, the title compound was obtained in 50% yield as a pale yellow solid. MS: (M−H)− 471.1.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:24])[NH:11]2
Reactant: c1ccc(-c2ccccc2-c2cccc3[nH]ccc23)cc1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2ccccc2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To the suspension of 4-biphenyl-2-yl-1H-indole (1.18 g, 4.4 mmol) in t-BuOH: ethanol: acetic acid (28 mL: 17 mL: 9 mL) was added pyridinium tribromide (4.39 g, 13.7 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (22 mL). Zinc dust (1.63 g, 25 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 0.93 g (74%) of 4-biphenyl-2-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:20][CH3:21])[C:15](OCC)=[O:16])=[C:4]([CH3:24])[CH:3]=1.CO.O.[NH2:28][NH2:29]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:20][CH3:21])[C:15]([NH:28][NH2:29])=[O:16])=[C:4]([CH3:24])[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(OC)c1ccccc1COc1ccc(Cl)cc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(C(=O)NN)c1ccccc1COc1ccc(Cl)cc1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To 1.05 g (3 mmol) of ethyl 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetate was added 6 ml of methanol and 0.75 g (15 mmol) of hydrazine monohydrate and stirred at 60° C. for 16 hours. After completion of the reaction, 100 ml of brine was added and extracted twice with 70 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure to give 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetic acid hydrazide (0.93 g, 92.6%) as colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6](/[C:9](=N/OC)/[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].C(O)(=O)C(C)=[O:31]>Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:31])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CC(=O)C(=O)O
Reactant: CCc1ccc(/C(COc2ccc(CC3SC(=O)NC3=O)cc2)=N/OC)nc1
Agent: Cl
Product: CCc1ccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reaction time: 2 h

Procedure:
A stirring solution of 5-(4-{[(2Z)-2-(5-ethylpyridin-2-yl)-2-(methoxyimino)ethyl]oxy}benzyl)-1,3-thiazolidine-2,4-dione (81 mg, 0.20 mmol; Supplier=Kalexsyn; Lot=1003-TTP-194) in 6M HCl (2 ml) and pyruvic acid (0.5 ml) was heated at 75° C. After 2 h at 75° C. HPLC showed reaction was complete. Neutralized with sat'd NaHCO3 and extracted with EtOAc. Extract dried (Na2SO4), filtered and evaporated in vacuo to give 45 mg (60%) pale yellow oil. 1H-NMR (DMSO-d6): δ12.02 (brs, 1H), 8.64 (s, 1H), 7.91 (m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 5.66 (s, 2H), 4.87 (dd, J=9.2, 4.3 Hz, 1H), 3.31 (m, 1H), 3.05 (dd, J=14.1, 9.1 Hz, 1H), 2.74 (q, J=7.7 Hz, 2H), 1.23 (t, J=7.7 Hz, 3H). HPLC (3.860 min., 100area % @ 210 and 254 nm. MS (ESI−) for C19H18N2O4S m/z 371.3 (M+H)+; m/z 369.4 (M−H)−
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38](O)=[O:39])=[CH:35][C:34]=2[CH:41]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([NH:1][C@@H:2]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:3]([NH:5][CH2:6][C:7]([N:9]3[CH2:10][CH2:11][N:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14]3)=[O:8])=[O:4])=[O:39])=[CH:35][C:34]=2[CH:41]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.5 %

Procedure:
To a suspension of (2S)-2-amino-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]-3-(2-pyridyl)propanamide (18 g) and 5-chloro-1-benzofuran-2-carboxylic acid (8.8 g) in N,N-dimethyl-formamide (180 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (9.44 g) and N-hydroxybenzotriazole (6.66 g) at 0° C. The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution and the resulting solid was collected by filtration. The solid was washed successively with saturated aqueous sodium hydrogencarbonate solution and water. The solid was crystallized from water:ethanol (1:9 (v/v)) to give the title compound (23 g) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10][CH3:11].C([Li])CCC.CON(C)[C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]>C1COCC1.CCCCCC>[CH3:11][O:10][CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][C:6]([C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[CH:7][CH:2]=1
Reactant: C=CCCCCCCCCC(=O)N(C)OC
Reactant: COC=Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(=O)c1ccc(C=COC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-bromo-(2-methoxyethenyl)benzene (2.13 g) in THF (20 ml) at -78° is added dropwise a 2.5M solution of n-butyllithium in hexane (4.2 ml). The temperature is not allowed to rise above -55°. After 90 min, a solution of N-methoxy-N-methyl-10-undecenamide (2.3 g) in THF (5 ml) is added dropwise, and the mixture stirred an additional 60 min at -78°. The mixture is not allowed to warm, but is immediately quenched by the addition of 10% aqueous citric acid. The mixture is extracted with dichloromethane, and the extracts are dried, filtered, and concentrated. The crude product is chromatographed with 1:1 dichloromethanehexane, to provide 1-(4-(2-methoxyethenyl)phenyl)-10-undecen-1-one as a colorless solid.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=O.C([CH2:20][C:21]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:22])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:20]/[C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(/C=C/c1ccc(O)c(O)c1)Nc1ccccc1C(=O)O
Yield: 83 %

Procedure:
Piperidine (0.39 mL, 4.0 mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (0.55 g, 4.0 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.74 g, 3.3 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dihydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.82 g, 83%) was obtained as a brown crystalline solid; mp 204-206° C.; lit. [24] 204-206° C.; δH (500 MHz, DMSO-d6) 6.50 (d, J=15.5 Hz, 1H, CH═CHCO), 6.77 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.00 (dd, J5′,6′=8.0, =2.0 Hz, 1H, H6′), 7.08 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.14 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.44 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 9.11 (s, 1H, OH), 9.52 (s, 1H, OH), 11.25 (s, 1H, NH).
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH3:41])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3nccs3)[C@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3nccs3)[C@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [C:1](SCC)(=[S:3])[CH3:2].[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10]1.C(N(CC)CC)C>CN(C=O)C>[F:28][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:1](=[S:3])[CH3:2])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=1
Reactant: CCSC(C)=S
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl dithioacetate (0.0708 ml, 0.747 mmol) is added to 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol) and triethylamine (0.0946 ml, 0.679 mmol) in DMF (3 ml) and is stirred at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give a white solid (0.21 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.59 (s, 2H), overlapping 3.84 (dd, J=6.6, 9.1, 2H) and 3.92 (t, J=4.7 Hz, 2H), 4.19 (t, J=9.1 Hz, 1H), 4.92-5.05 (m, 1H), 7.43 (dd, J=2.2, 8.5 Hz, 1H), 7.58 (dd, J=2.2, 14, 1H), 7.69 (t, J=8.5, 1H), 10.4 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 182-3; MS (m/z): [M+H]+=383.