Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1>[Cl:29][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)C1CO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2SC(c2ccccc2)C1CCl
Yield: 84 %

Procedure:
5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 1 and 1.6 g of pyridine were dissolved in 30 ml of benzene, and 3.6 g of thionyl chloride was added to the solution, followed by heating under refluxing for 1 hour. The solvent was then distilled off and water was added to the residue. The precipitated crystals were filtered, washed with methanol and recrystallized from benzene to obtain 5.1 g of 3-chloromethyl-2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 233° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22](=[O:24])=[O:23].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:27]1([CH2:26][O:23][C:22]([N:10]2[CH2:9][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])[C:14](=[O:15])[N:13]([CH3:16])[C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]2=3)=[O:24])[CH2:29][CH2:28]1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: BrCC1CC1
Reactant: O=C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC2CC2)c2ccccc21
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of 350 mg (1.2 mmol) of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester [Example 103a] in 10 ml of N,N-dimethylformamide was treated successively with about 1 g of solid carbon dioxide, 237 mg (1.7 mmol) of bromomethyl-cyclopropane, and 626 mg (1.9 mmol) of cesium carbonate. The reaction mixture was stirred in a sealed flask at 80° C. during the weekend. For the working-up, the solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of 30 ml of ethyl acetate and 10 ml of water. The organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure. For the purification, the crude compound was chromatographed on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 410 mg (87% of theory) of the (S)-3-tert-butoxycarbonylamino-5-methyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid cyclopropylmethyl ester as a white gum;
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[CH:35][C:9]2[CH2:10][N:11]([C:17]3[CH:26]=[C:25]([NH:27]C(=O)OC(C)(C)C)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:12][CH2:13][S:14](=[O:16])(=[O:15])[C:8]=2[CH:7]=1.FC(F)(F)C(O)=O>ClCCl.O>[NH2:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:11]2[CH2:10][C:9]3[CH:35]=[CH:36][C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][C:8]=3[S:14](=[O:15])(=[O:16])[CH2:13][CH2:12]2)[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCS(=O)(=O)c3cc(OCCCO)ccc3C2)nc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Nc1cc(N2CCS(=O)(=O)c3cc(OCCCO)ccc3C2)nc2ccccc12
Yield: 4.9 %

Procedure:
A mixture solution of tert-butyl {2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-yl}carbamate (359.1 mg, the crude product of the above step) and trifluoroacetic acid (1.0 mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 14.2 mg of the desired product as a white solid (yield was 4.9%). MS obsd. (ESI+) [(M+H)+] 414, 1HNMR ((400 MHz, CD3OD) δ ppm 7.82-7.67 (m, 2 H), 7.54-7.48 (m, 2 H), 7.48-7.39 (m, 1 H), 7.19-7.06 (m, 2 H), 6.30 (s, 1 H), 5.04 (s, 2 H), 4.78-4.34 (m, 2 H), 4.11 (t, J=6.32 Hz, 2 H), 3.71 (t, J=6.19 Hz, 2 H), 3.62-3.49 (m, 2 H), 2.11-1.78 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.CCOC(C)=O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1Cl)c1cccc(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g (177.5 mmol) was added to this suspension, and the mixture stirred at rt overnight. The reaction mixture was filtered through a thin pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aq solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc/hexanes yielding 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid [8.5 g, 95%, TLC Rf=0.4, 30% EtOAc/HEX.(3:7)]. 1H-NMR (DMSO-d6) δ 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18 (m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[C:19]([NH:21][C:22]([NH2:24])=[NH:23])#[N:20]>C(OCCOCCO)C>[NH2:24][C:22]1[N:21]=[C:19]([NH2:20])[C:11]2[CH2:12][CH:7]([O:6][C:5]3[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=3)[CH2:8][CH2:9][C:10]=2[N:23]=1
Reactant: O=C1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: N#CNC(=N)N
Solvent: CCOCCOCCO
Product: Nc1nc(N)c2c(n1)CCC(Oc1cccc(C(F)(F)F)c1)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.4 grams (0.013 mole) of 4-(3-trifluoromethylphenoxy)cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(3-trifluoromethylphenoxy)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)C.C[O-].[Na+].CO.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30]([CH2:5][C:4]([O:3][CH3:1])=[O:14])[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1(C)C
Yield: 52.9 %

Procedure:
To a cooled (0° C.) solution of diethylphosphonoacetic acid ethyl ester (4.4 mL, 24.2 mmol) in tetrahydrofuran (50 mL) under an atmosphere of nitrogen were added a solution of 28% sodium methoxide in methanol (4.6 mL, 26.4 mmol), and then a solution of 3,3-dimethyl-4-oxopiperidine-1-carboxylic acid t-butyl ester (5.0 g, 22.0 mmol) in tetrahydrofuran (10 mL) and stirred for 3 hours at room temperature. After the reaction was completed, the solvent was removed under a reduced pressure and water was added to the residue. The mixture was extracted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=6:1) to obtain 1.8 g (yield 32.1%) of 4-methoxycarbonylmethylene-3,3-dimethylpiperidine-1-carbxylic acid t-butyl ester (A) and 3.3 g (yield 58.9%) of 4-methoxycarbonylmethyl-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (B). Each of their physical properties is shown below.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:46]=[C:47]([OH:52])[CH:48]=[CH:49][C:50]=1[Cl:51]>>[Cl:44][C:45]1[C:50]([Cl:51])=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:52])[CH:46]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Cl)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3,4-dichlorophenol, the title compound was obtained (26%): 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H), 7.50-7.40 (m, 2H), 7.22 (td, 1H), 7.11 (s, 1H), 6.95 (d, 1H), 6.86 (s, 1H), 4.31-4.12 (br, 1H), 3.79-3.59 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 363 (M−17), 403 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl.C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH2:11]([NH:12][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[F:23])[C:14]1[CH:22]=[CH:21][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reaction time: 0.17 h
Yield: 154.1 %

Procedure:
In a solution of 0.15 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-fluoro benzoic acid in 10 ml of dichloromethane, 0.3 ml of oxalyl chloride and 2 drops of N,N-dimethylformamide were added at room temperature, and stirred at the same temperature for 10 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, the remaining white solid was dissolved in 10 ml of chloroform, and 0.3 ml of benzylamine and then 0.3 ml of triethylamine were added under cooling with ice, after the completion of the addition, continued to stir at room temperature for further 20 minutes. After the completion of the reaction, 40 ml of water was poured in the reaction mixture, and extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.14 g of the aimed product as white crystal.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:69]/[O:70][CH3:71])/[C:15]([NH:17][C@@H:18]2[C:67](=[O:68])[N:20]3[C:21]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:22]([S:25][CH2:26][C:27]4[CH:28]=[N:29][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1>C1(OC)C=CC=CC=1.ClCCl>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:69]/[O:70][CH3:71])/[C:15]([NH:17][C@@H:18]2[C:67](=[O:68])[N:20]3[C:21]([C:51]([OH:53])=[O:52])=[C:22]([S:25][CH2:26][C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CS[C@H]12)c1csc(N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cn[nH]c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
Under nitrogen atomosphere, 1 ml of trifluoroacetic acid was added slowly to a solution of 500 mg of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate in anisole (0.5 ml) and dichloromethane (1.5 ml) at 0° C. The mixture was warmed to a room temperature and stirred for 2 hours. The mixture was poured into IPE and the resulting precipitate was collected by filtration. The precipitate was dissolved in pH 6.86 buffer and chromatographed on a HP-20 (eluent: water-methanol). The eluate was lyophilized to afford 171.6 mg of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+].O.[ClH:26]>C(O)C.CCOCC>[ClH:26].[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]2)[CH:17]=1
Reactant: Cc1cccc(C2CCN(C(=O)Oc3ccccc3)CC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 11.9 g of 1-phenoxylcarbonyl-4-(3-toluyl)piperidine and 75 ml of an aqueous 50% potassium hydroxide solution in 300 ml of ethanol is heated at reflux for 24 hours and then stirred at ambient temperature for an additional 36 hours. 100 ml of water are added, the ethanol is partially removed, the resulting mixture is extracted with ether and the combined ether extracts are extracted with 1N HCl. The aqueous solution is basified with an aqueous sodium hydroxide solution, extracted with ether, the combined ether extracts are dried, and the ether is removed, leaving a dark oil. The oil is dissolved in ether and ethereal hydrogen chloride is added to produce the salt which is collected by filtration, dried and recrystallized thrice from an ethanol-water mixture to give 4-(3-toluyl)piperidine hydrochloride, mp 196°-197° C.,
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15].C[Al](C)C.[NH:26](/[C:30](/[CH3:36])=[CH:31]\[C:32](OC)=[O:33])[C:27]([CH3:29])=O>C(Cl)Cl>[CH2:13]([O:12][CH2:11][CH2:10][N:9]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:32](=[O:33])[CH:31]=[C:30]([CH3:36])[N:26]=[C:27]2[CH3:29])=[CH:7][C:2]=1[F:1])[CH2:14][CH3:15]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCCOCCN(CCOCCC)c1ccc(N)cc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCOCCN(CCOCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 2-fluoro-N1,N1-bis(2-propoxyethyl)benzene-1,4-diamine (0.50 g, 1.68 mmol) in CH2Cl2 (10 mL) was added trimethylaluminum (3.4 mL, 6.8 mmol, 2 M in toluene) slowly. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (0.32 g, 2.02 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as pale yellow oil (0.53 g, 78%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CC1C([N:8]2[C:17](=O)[C:16]3[C:11](=[CH:12]C=C[CH:15]=3)[N:10]=[C:9]2C)=CC=CC=1.[CH3:20][N:21](C=O)[CH3:22].C(Cl)[Cl:26]>CN(C=O)C.CO.C(Cl)(Cl)Cl>[CH3:12][CH2:11][N:10]=[C:9]=[N:8][CH2:17][CH2:16][CH2:15][N:21]([CH3:22])[CH3:20].[ClH:26]
Reactant: ClCCl
Reactant: Cc1ccccc1-n1c(C)nc2ccccc2c1=O
Reactant: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN=C=NCCCN(C)C
Product: Cl
Reaction time: 12 h

Procedure:
A stock solution of 567 mg (1.48 mmol) PP-HOBT in 8.5 mL DMF (approximately 0.175 M PP-HOBT in DMF) was prepared and 0.81 g (0.86 mL, 150 umol) of this PP-HOBT solution was added to each of the nine round-bottom vessels containing the products from Step B. Clear solutions were obtained for all, except where the linked amino acid was alpha amimo isobuttric acid. In the case, an additional 0.86 mL of DMF was added but still the mixture remained heterogeneous. The contents of each of the nine round bottoms “n” (where n=1 to 9) were divide into four aqual portions (approximately 37 umols each) and placed in vials. Stock solutions (0.1 M) of the carboxylic acids were then made up in 10% DMF/DCM. The appropriate stock solution (0.3 mL, 30 umol) was then added to each of the vials. A 0.1 M stock solution (20 mL) of EDC hydrochloride in DMF was prepared. This stock solution (0.4 mL, 40 umol) was then added to each of the vials which were then capped and put on a rotator for 12 hours. Normal SCX workup and evaporation of solvent afforded products as white solids or clear to light caramel resins. Each of these products was taken up in methanol/chloroform and divided into three tared vials, plus a vial for MS and HPLC characterization. After evaporation of solvent, the final weights in each vial were determined. Product identity was verified by ionspray mass spec and purity assessed by reverse phase HPLC.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:53])[CH2:40][C:41]([C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)=O)[CH3:37].C(N(CC)CC)C>ClCCCl>[CH2:36]([O:38][C:39](=[O:53])[C:40]#[C:41][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)c1ccc2ccccc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C#Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
Triflic anhydride (2.9 mL, 17 mmol) was added dropwise to a solution of triphenylphosphine oxide (4.8 g, 17 mmol) in 1,2-dichloroethane (40 mL) at 0° C. The resulting suspension was stirred for 15 minutes, followed by the dropwise addition of a solution of 3-naphthalen-2-yl-3-oxo-propionic acid ethyl ester (3.2 g, 12 mmol) in 1,2-dichloroethane (40 mL). After the addition was complete, triethylamine (4.0 mL, 29 mmol) was added and the reaction mixture was heated at reflux for 1 hr. The solution was cooled to room temperature, washed with water, and dried (MgSO4). The solvent was removed under reduced pressure, and the product was purified via column chromatography with silica eluting with hexane/ethyl acetate (9/1) to yield naphthalene-2-yl-propynoic acid ethyl ester (1.15 g, 37% yield) as a yellow oil. 1H NMR (CDCl3) δ 8.25 (s, 1H), 7.95 (m, 3H), 7.66 (m, 3H), 4.46 (m, 2H), 1.51 (t, 3H, J=8.0 Hz).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>O1CCCC1.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:33][CH2:34][N:35]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:36][CH2:37]2)=[CH:28][CH:27]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCC(O)(c2ccc(Cl)cc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was treated with 2 g (0.01 mole) of 4-(4-chlorophenyl)-4-hydroxypiperidine added in small portions. After stirring for 30 min, a few pieces of ice were added and stirring continued for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a water-like oil (5.16 g). A crystalline solid was obtained by cooling to -78° C. and recrystallization was accomplished by dissolving the residue in 5 ml of acetone and 75 ml of isopropyl ether and reducing the volume under nitrogen to 40 ml. Upon cooling, filtration yielded 3.6 g (79.1%) of fine white crystals, m.p. 127°-128.5° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:16]([O-])=O)[C:3]=1[O:19][CH3:20].[H][H]>[Pd].C1COCC1.CN(C=O)C>[NH2:16][C:4]1[C:3]([O:19][CH3:20])=[CH:2][C:7]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: COc1c([N+](=O)[O-])cc2oc(C(=O)N(C)C)cc2c1Cl
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)N(C)C)oc2cc1N
Reaction time: 18 h

Procedure:
4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide (500 mg, 1.68 mmol), TEA (184 mg, 1.83 mmol) and 10% palladium on charcoal (90 mg) were stirred at room temperature in THF-DMF (2:1) (30 mL) under an atmosphere of hydrogen for 18 h. The reaction was recharged with hydrogen then allowed to stir for an additional 18 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford a brown solid (400 mg, quant.), which was taken through to the next step with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O:20]=[C:21]([CH2:27][C:28](=[O:30])[CH3:29])[C:22](OCC)=[O:23]>>[C:28]([C:27]1[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[N:1]([C:2]2[CH:3]=[C:4]([Cl:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:22](=[O:23])[C:21]=1[OH:20])(=[O:30])[CH3:29]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: O=Cc1ccc(Cl)cc1
Product: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2), 4-chlorobenzaldehyde and ethyl 2,4-dioxovalerate at 120° C. for 1 hr. tR: 3.73 min (HPLC 1); tR: 0.74 min (LC-MS 2); ESI-MS: 393/395 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CN(C=O)C.[H-].[Na+].O([CH:18]=[CH:19][C:20](=[N:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([S:3][CH:18]=[CH:19][C:20](=[N:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSC=CC(=Nc1ccccc1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethanethiol (0.11 ml) was dissolved to DMF (3 ml), and sodium hydride (60% in oil: 60 mg) was added under ice-cooling, and stirred for 30 minutes at the same temperature. Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to DMF (2 ml), and the obtained solution was added to the above mentioned thiolate solution under ice-cooling, and stirred for two hours at the same temperature and for two hours at room temperature. Ethyl acetate (100 ml) was added to the reaction solution, and it was successively washed with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-ethylthio-N-phenylacrylimidate (0.14 g) as yellow oil.