Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Mg].[C:10]([C:12](=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2([CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C1(c2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-chloro-3-iodobenzene (14.1 g, 59.28 mmol) in diethyl ether (12 ml) was added dropwise to a mixture of magnesium turnings (1.59 g, 65.4 mmol) in diethyl ether (50 ml) at room temperature. When the Grignard reaction was complete, the resulting organomagnesium reagent was added dropwise to a stirred mixture of compound 16a (5.0 g, 17 mmol) and cuprous iodide (800 mg, 4.2 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. The reaction mixture was stirred 1 hour at 0° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate (500 ml) was added and the mixture was washed successively with saturated ammonium chloride, water and brine. The organic layer was dried and concentrated and the resulting crude material was purified by column chromatography on silica gel eluting with 4:1 hexane:ethyl acetate. This afforded tert-butyl 4-(3-chlorophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (16b) as an oil (5.2 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.26 (m, 4H), 3.99 (br.q, 2H, J=6 Hz), 3.91 (br m, 2H), 3.58 (s, 1H), 2.88 (br.m, 2H), 2.52 (ddd, 2H, J=6, 4, 3 Hz), 2.04 (m, 2H), 1.43 (s, 9H), and 1.06 (t, 3H, J=6 Hz). ES-LCMS m/z 429 (M+Na+).
Reaction SMILES: [C:1]([C:7]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:23]([NH:27][OH:28])([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:7]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:10]([CH:11]=[N+:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[O-:28])=[CH:9][C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(C)NO
Reactant: CCCCC(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCC(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 56.5 %

Procedure:
To a solution of 4-pentanoyl-3,5-di-tert-butylbenzaldehyde (17.48 g, 0.050 mol) in benzene (250 mL) was added tert-butylhydroxylamine (4.57 g, 0.0510 mol) and p-toluenesulfonic acid (0.080 g). Using a Dean-Stark trap, the resulting mixture was refluxed until no more aldehyde was detected by TLC (Rf=0.43 for product using 1:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was thoroughly washed with hexanes. The title compound was isolated (56.50% yield) as a white solid, m.p. 195.5–204.8° C.
Reaction SMILES: O[CH2:2][C:3]1([NH2:10])[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].S(Cl)([Cl:13])=O.C(Cl)(Cl)[Cl:16]>CN(C)C=O>[ClH:13].[NH2:10][C:3]1([CH2:2][Cl:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9]
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Reactant: NC1(CO)CCCNC1=O
Solvent: CN(C)C=O
Product: Cl
Product: NC1(CCl)CCCNC1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxymethyl-3-amino-2-piperidone (7 g or 0.049 mol) in anhydrous dimethylformamide (50 ml) is added one equivalent of thionyl chloride (3.6 ml). The reaction mixture is stirred at 80° C. under nitrogen. After 24 hours, another equivalent of thionyl chloride (3.6 ml) is added and stirring is continued for 2 hours. Then the solvent is stripped off under reduced pressure. Trituration of the semi-solid residue with chloroform (2×30 ml) leaves 2.1 g of crystalline analytically pure 3-amino-3-chloromethyl-2-piperidone hydrochloride: m.p. 230° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:12]=[CH:13][CH:14]=1.Cl.Cl[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35].C(OCC)(=O)C>CC(N(C)C)=O.O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(CCCCc2ccccc2O)c1
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCCCc2ccccc2OCCC2CCCN2C)c1
Yield: 47.5 %

Procedure:
1.48 g of potassium t-butoxide were added to a solution of 1.35 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7) in 20 ml of dimethylacetamide, whilst ice-cooling and stirring. 1.45 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochoride were then added to the solution, and the mixture was stirred at 55° C. for 2 hours. At the end of this time, the reaction mixture was cooled, 200 ml of ethyl acetate and 100 ml of water were added to the mixture, and the mixture was shaken. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.92 g (yield 48%) of the title compound as an oil.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[C:7]([OH:11])(C)(C)C.O.C([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=C>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C1(C)C=CC=CC=1.C(Cl)Cl>[O:18]1[CH2:19][CH2:20][CH:15]([C@@H:1]([OH:4])[CH2:7][OH:11])[CH2:16][CH2:17]1
Reactant: CC(C)(C)O
Reactant: O=C([O-])[O-]
Reactant: C=CC1CCOCC1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: OC[C@H](O)C1CCOCC1
Temperature: 0 °C

Procedure:
A 500-mL, round-bottomed flask was charged with potassium ferricyanide (III) (15.0 g, 45.6 mmol), 2,5-diphenyl-4,6-bis(9-O-dihydroquinidyl)pyrimidine ((DHQD)2-PYR) (132 mg, 0.15 mmol) and K2CO3 (6.29 g, 45.6 mmol). A 1:1 mixture of tert-butyl alcohol/H2O (150 mL) was added and the suspension was stirred under N2. A 0.25 M solution of OSO4 in toluene (0.60 mL, 0.15 mmol) was then added the mixture was cooled to 0° C. After stirring for 60 minutes, 4-vinyltetrahydro-2H-pyran (1.70 g, 15.2 mmol) was added and the mixture was stirred overnight. Solid Na2S2O5 (22.5 g) was then added and the reaction mixture was allowed to warm to ambient temperature. CH2Cl2 (150 mL) was then added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave 2.11 g of (1R)-1-tetrahydro-2H-pyran-4-ylethane-1,2-diol as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)C#N.C[Mg]Br.C([O:17][CH2:18][CH3:19])C>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([C:18](=[O:17])[CH3:19])[CH:8]=[CH:9][N:10]=1
Reactant: CCOCC
Reactant: CN(C)c1cc(C#N)ccn1
Agent: C[Mg]Br
Product: CC(=O)c1ccnc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7.4 g. (50 mmoles) of 2-dimethylaminoisonicotinonitrile in 150 ml. of diethyl ether was added dropwise 33 ml. (100 mmoles) of a 3 M solution of methyl magnesium bromide under a nitrogen atmosphere. On completion, the reaction was allowed to stir at room temperature for 16 hours, and was then quenched by the careful addition of 80 ml. of 2 N hydrochloric acid. The aqueous phase was separated and the organic phase extracted further with 2 N hydrochloric acid (2×10 ml.). The combined acid extracts were neutralized with solid sodium carbonate and extracted with chloroform (5×50 ml.). The combined chloroform extracts were dried and concentrated to a brown oil. Distillation of the residue gave 5.0 g. (61%) of the product as an oil (b.p. 110° C./1 torr). On standing the oil crystallized, m.p. 37°-42° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+].Br[C:24]#[N:25]>C(O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[N:17]=[C:24]1[NH2:25]
Reactant: Cc1cc(C)c(Nc2ncccc2N)c(C)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-n2c(N)nc3cccnc32)c(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of N2-(2,4,6-Trimethyl-phenyl)-pyridine-2,3-diamine (3.05 g, 13.4 mmol), NaHCO3 (2.03 g, 24.1 mmol) in ethanol (40 mL) at 0° C., was added a solution of BrCN (2.55 g, 24.1 mmol) in ethanol (6 mL). The resulting mixture was stirred at 0° C. for 1 h, room temperature for 8 h, and then 80° C. for 8 h. Ethanol was removed in vacuo and the residue was taken up into a separatory funnel with methylene chloride (100 mL). The mixture was washed sequentially with 1N NaOH, water and brine, then the organic layer was dried over Na2SO4. After removing solvents, a brown solid was obtained. By LC-MS, the solid was a mixture of the desired product and the unreacted starting material in a ratio of 4:1 in favor of the desired product. Mass spec.: 253.17 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].[CH2:13]([OH:15])[CH3:14].[Br:16]N1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1([Br:16])[CH2:11][CH2:10][O:9][CH:8]1[O:15][CH2:13][CH3:14])=[O:6])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(=O)C1=COCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C(=O)C1(Br)CCOC1OCC
Temperature: 7.5 °C

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (100 g) was dissolved in dichloromethane (500 ml) and Ethanol (150 ml) was added to reaction mass and then reaction mass was cooled to 5 to 10° C. N-bromosuccinimide (115 g) was added lot wise by maintaining temp below 10° C. Reaction mass was then stirred at 20-30° C. till completion of reaction. Reaction mass was washed with sodium bicarbonate solution (8%, 3×400 ml). Reaction mass was then concentrated to residue to get Ethyl-2-(3-bromo-2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 170 g).
Reaction SMILES: Cl.[Cl:2][C:3]([Cl:20])([Cl:19])[CH2:4][O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH:10]([CH3:18])[CH:9]=1)=[O:7].CN(C)C1C=CC=CC=1.[S:30]([CH:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35](O)=[O:36])([OH:33])(=[O:32])=[O:31].C(OOC(=O)O)C>ClCCl.C(N(CC)CC)C>[CH3:18][CH:10]1[CH:9]=[C:8]([C:6]([O:5][CH2:4][C:3]([Cl:2])([Cl:19])[Cl:20])=[O:7])[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:35](=[O:36])[CH:34]([S:30]([OH:33])(=[O:31])=[O:32])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:12]2[S:11]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: O=C(O)C(c1ccccc1)S(=O)(=O)O
Agent: CCOOC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(c3ccccc3)S(=O)(=O)O)[C@H]2S1

Procedure:
A suspension of 2,2,2-trichloroethyl-2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (6.9 g) in dried dichlormethane (70 ml) was homogenzied by adding triethylamine (1.48 g) and N,N-dimethylaniline (0.44 g) under stirring and ice-cooling and by stirring for 30 minutes at room temperature. A solution of triethylamine salt of mixed anhydride of 2-sulfo-2-phenylacetic acid with ethoxycarbonic acid (8.5 g) in dried dichloromethane (60 ml) was dropwise added over about 30 minutes under stirring and cooling at -20° to -25° C. to the above-mentioned solution, and the mixture was stirred for 1.5 hours at -10° to -15° C. and for 1 hour at room temperature. After the reaction, dichloromethane was removed at low temperature, and the residue was dissolved in ethyl acetate, after which the solution was washed with cooled 5% hydrochloric acid and three times with water, and then dried. The solvent was distilled off at low temperature to give 2,2,2-trichloroethyl 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylate (11.5 g), amorphous.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([N+:28]([O-:30])=[O:29])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.[OH-].[Na+]>O>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([N+:28]([O-:30])=[O:29])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCCc1nc([N+](=O)[O-])c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc([N+](=O)[O-])c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 85.6 %

Procedure:
A solution of 1.98 g of 1[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-nitroimidazole, 20 mL of trifluoroacetic acid, and 20 mL of methylene chloride was stirred at 25° for 1 hour. At this point, the solution was poured into water. The resulting mixture was adjusted to pH 3 using 10% sodium hydroxide solution and then extracted with chloroform. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol/chloroform) provided 1.49 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-nitroimidazole; m.p. 204°-205.5°. NMR (200 MHz, DMSO-d6): δ 7.71 (d, 1H); 7.56 (t, 1H); 7.43 (t, 1H); 7.32 (m, 3H); 7.15 (d, 2H); 5.63 (br s, 1H); 5.42 (s, 2H); 4.83 (s, 2H); 2.54 (t, 2H); 1.50 (quint., 2H); 1.24 (sext., 2H); 0.76 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12](I)=[C:11]([NH2:20])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)#[CH:23].C(NC(C)C)(C)C.CN(C)C=O>C(OCC)(=O)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>[NH2:20][C:11]1[N:10]=[C:9]([N:7]([CH3:8])[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12]=1[C:23]#[C:22][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C#CC1CCCCC1
Reactant: CN(C(=O)OC(C)(C)C)c1nc(N)c(I)c2c1ncn2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CN(C(=O)OC(C)(C)C)c1nc(N)c(C#CC2CCCCC2)c2c1ncn2C
Temperature: 95 °C

Procedure:
A1.12 tert-Butyl-6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate (1.0 g, 2.48 mmol), dichlorobis(triphenylphosphine)palladium (75 mg, 0.11 mmol), ethynylcyclohexane (0.3 g, 2.8 mmol), CuI (25 mg, 0.13 mmol), and diisopropylamine (5 mL) were added to N,N-dimethylformamide (7 mL). The reaction mixture was heated at 95° C. (in preheated oil bath) for 60 min. Additional ethynylcyclohexane (0.3 g, 2.8 mmol) was added to the reaction mixture and heated for another 60 min. The reaction was cooled and diluted with ethyl acetate and washed several times with water. The solvent removed under reduced pressure and the residue was chromatographed on a silica gel column (50%-70% ethyl acetate/hexane) to give 400 mg of C32.1 as a yellow solid. LCMS B: Ret time 3.15 min, (M+H)+=384.41.
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[CH3:17][CH:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])CCO>C1CCCCC1>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH:18]([CH3:17])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(CCO)CC(C)(C)C
Agent: [Na]
Solvent: CCO
Solvent: C1CCCCC1
Product: CC(CCOC(=O)c1ccc(N)cc1)CC(C)(C)C

Procedure:
Sodium metal (1 g cat.) was added to ethanol (30 mL) to give a solution which was added to a suspension of ethyl 4-aminobenzoate (175 g, 1.06 mol) and 3,5,5 trimethyl hexanol (200 g, 1.4 mol) in cyclohexane (300 mL). The suspension was heated under reflux for 24 hours with the azeotropic removal of ethanol.
Reaction SMILES: C(OC(=O)[N:7]=[C:8]([NH:47]C(OC(C)(C)C)=O)[NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][S:21][C:22]2[N:23]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:24]([C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][CH3:38])[CH:31]=3)([CH3:29])[CH3:28])=[CH:25][N:26]=2)=[C:15]([F:46])[CH:14]=1)(C)(C)C.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>C(Cl)Cl.CCOC(C)=O>[F:59][C:58]([F:61])([F:60])[C:56]([O-:62])=[O:57].[NH2:47][C:8]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][S:21][C:22]2[N:23]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:24]([C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][CH3:38])[CH:31]=3)([CH3:29])[CH3:28])=[CH:25][N:26]=2)=[C:15]([F:46])[CH:14]=1)=[NH2+:7]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCNC(N)=[NH2+])cc3F)n2-c2ccc(F)cc2)ccc1Cl
Product: O=C([O-])C(F)(F)F
Yield: 68 %

Procedure:
To a solution of tert-butyl(tert-butoxycarbonylamino)(2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethylamino)methylenecarbamate (273 mg) in DCM (1 mL) was added TFA (5 mL). After 1 h the reaction mixture was diluted with EtOAc, washed with H2O, satd NaHCO3 and brine. The combined organic layers were concentrated and purified by preparative HPLC (30-100%, CH3CN/H2O with 0.05% TFA) to yield the title compound as a white solid (112 mg, 68%, 2 steps). 1HNMR (400 MHz, CD3CN) δ 8.01 (m, 1H), 7.20-7.13 (m, 2H), 6.99-6.94 (m, 2H), 6.88-6.78 (m, 2H), 6.57 (d, J=2.1 Hz, 1H), 6.55-6.48 (m, 3H), 6.44-6.38 (m, 2H), 4.08 (t, J=5.0 Hz, 2H), 3.92 (s, 2H), 3.71 (s, 3H), 3.52 (dd, J=10.6, 5.4 Hz, 2H), 1.49 (s, 6H); MS (EI) m/z 604.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([OH:13])=O.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[NH2:19].P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([NH:19][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([NH:19][C:18]3[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:16]([C:15]([F:14])([F:27])[F:28])[CH:17]=3)=[O:13])[CH:4]=2)[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 25 %

Procedure:
Using 4-hydroxyisophthalic acid (182 mg, 1 mmol), 3,5-bis(trifluoromethyl)-aniline (687 mg, 3 mmol), phosphorus trichloride (87 μl; 1 mmol) and toluene (10 mL), the same operation as the example 16 gave the title compound (151 mg, 25.0%) as a white crystal.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][F:15])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N+:12]=[N-:13])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[Cl:23][CH:24]([Cl:30])[C:25](OCC)=[O:26]>CO>[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@H:2]([NH:1][C:25](=[O:26])[CH:24]([Cl:30])[Cl:23])[CH2:14][F:15])=[CH:10][CH:9]=1)=[N+:12]=[N-:13]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](N)CF)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To the stirred solution of (1R,2R)-2-Amino-1-(4-azido-phenyl)-3-fluoro-propan-1-ol (600 mg, 2.83 mmol) in methanol (6.5 mL) is added triethyl amine (0.57 g, 5.64 mmol) and ethyl dichloroacetate (0.88 g, 5.60 mmol). Resulting reaction mixture is stirred under nitrogen at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 0.5% methanol in dichloromethane to afford the title compound (150 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 4.40-4.41 (m, 1H), 4.24-4.26 (m, 0.5H), 4.36-4.38 (m, 0.5H), 4.52-4.54 (m, 0.5H), 4.64-4.66 (m, 0.5H), 4.84 (t, 1H, J=3.64 Hz), 5.96 (d, 1H, J=4.24 Hz), 6.49 (s, 1H), 7.05 (d, 2H, J=8.48 Hz), 7.38 (d, 2H, J=8.44 Hz), 8.58 (d, 1H, J=8.98 Hz). LC-Ms (m/z): [M−H]=318.8.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>C(OCC)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 237.3 %

Procedure:
71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to 20 g (0.5 mol) of sodium hydroxide in 250 ml of aqueous solution, and the mixture was stirred at 80° C. for 2 hours. The mixture solution was cooled by ice-water, 71.8 g (0.2 mol) of 2-furancarbonyl chloride and 24 g (0.6 mol) of sodium hydroxide in 100 ml of aqueous solution were simultaneously added thereto over approximately 1 hour. The reaction solution was slowly returned to room temperature and stirred overnight. 80 ml of ethyl acetate was added to the reaction solution and after the mixture was stirred for 1 hour, the insolubles were removed by filtration. The aqueous layer was separately collected, and 49 ml of concentrated hydrochloric acid was added thereto under ice-cooling. The precipitated crystal was collected by filtration and dried under reduced pressure to obtain 112.6 g (95%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CS(C)=O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2cccnc2)CC1
Yield: 33.6 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (15.0 g, 55.7 mmol), 1-(tert-butoxycarbonyl)piperazine (15.5 g, 83.5 mmol), diisopropylethylamine (9.70 ml, 55.7 mmol) and dimethylsulfoxide (300 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (5.74 g, 33.6%) as a solid.
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[CH3:28][CH2:29][SH:30]>>[C:1]([NH:4][CH:5]([S:30][CH2:29][CH3:28])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCS
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCSC(NC(C)=O)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BF3.Et2O (2.72 g, 19.2 mmol) and EtSH (2.38 g, 38.4 mmol) gave an aqueous reaction mixture. The solution was extracted with CHCl3 (3×100 mL). The combined CHCl3 layers were dried (Na2SO4), and then concentrated in vacuo to give the desired product as white solid.