Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])=[CH:3][CH:2]=1.[CH2:20]=O.Cl.[CH3:23][NH:24][CH3:25].Cl>C(O)(C)C.C(O)C>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:23][N:24]([CH3:20])[CH3:25])=[CH:5][CH:6]=1
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)c1c(-c2ccc(C)cc2)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: Cc1ccc(-c2oc3ccccc3c2C(=O)CCN(C)C)cc1

Procedure:
To a solution of 20 grams of 2-(p-tolyl)-3-acetylbenzofuran in 80 milliliters of isopropanol was added 3.4 grams of paraformaldehyde, 9.1 grams of dimethylamine hydrochloride, and 8 milliliters of a saturated solution of hydrogen chloride in ethanol, and the mixture was heated under gentle reflux for a period of 8 hours. The solvent was evaporated under vacuum and the residue was taken up in water and ethyl ether was then added thereto to dissolve and extract the water-insoluble solids from the solution. The ether extract was then separated from the aqueous layer and the aqueous layer was made alkaline by the addition thereto of a 5% aqueous solution of sodium hydroxide. The precipitated oily base was then extracted with ethyl ether from the aqueous solution, washed with several portions of water, and dried over anhydrous sodium sulfate. A solution of hydrogen chloride in ethanol was then added to the dried ether extract and the crystals of the hydrochloride of the compound named in the heading of this example which were thus precipitated were separated by suction filtration and recrystallized by dissolving them in ethanol and precipitating them by the addition of ethyl ether to the ethanol solution. In this manner, 9.1 grams of the hydrochloride, which had a melting point of 136°-138° C, was obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:19])[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:22][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([O:19][CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:17][CH3:18])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCC(O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
1-(4′-Trifluoromethyl-biphenyl-4-yl)-butan-2-ol (0.088 g, 0.30 mmol) and 4-hydroxy-benzoic acid ethyl ester (0.062 g, 0.37 mmol) are dissolved in toluene (2 mL) under an inert atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.114 g, 0.45 mmol) is added, followed by tributyl-phosphane (0.1 mL, 0.45 mmol) at 0° C. The reaction is stirred for eighteen hours at room temperature, diluted with ethyl acetate, filtered and concentrated. Column chromatography on silica gel with 0-40% ethyl acetate/hexane gradient gives 0.050 g (0.11 mmol, 38%) of title compound.
Reaction SMILES: [N:1]([C:4]1C=CC(C(OC)=O)=[CH:6][CH:5]=1)=[C:2]=[O:3].[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][NH:20][CH2:19]2)#[N:15].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)CN1>>[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:25][C:33]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:3])[CH2:19]2)#[N:15]
Reactant: N#Cc1ccc2c(c1)CNC2
Reactant: c1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccc(N=C=O)cc1
Product: N#Cc1ccc2c(c1)CN(C(=O)NCCCCc1ccccc1)C2

Procedure:
The title compound was prepared as described in Example 1A, substituting 4-phenylbutyl isocyanate for methyl 4-isocyanatobenzoate and 5-cyanoisoindoline for isoindoline. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82 (s, 1H), 7.74 (dd, J=7.9, 1.5 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.24-7.31 (m, 2H), 7.08-7.22 (m, 3H), 6.38 (t, J=5.6 Hz, 1H), 4.59-4.64 (m, 4H), 3.06-3.13 (m, 2H), 2.58 (t, J=7.5 Hz, 2H), 1.53-1.68 (m, 2H), 1.36-1.51 (m, 2H); MS (ESI(+)) m/e 319 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)[C:16]2[N:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])[N:20]=2)[C:10]2[CH:49]=[C:50]([CH3:57])[C:51]([C:53]([F:56])([F:55])[F:54])=[CH:52][C:9]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[F:48][C:45]([F:46])([F:47])[C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=1)[CH2:34][N:15]([C@H:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:52]=[C:51]([C:53]([F:54])([F:55])[F:56])[C:50]([CH3:57])=[CH:49][C:10]1=2)[C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[N:20]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.12 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL). After stirring at room temperature for 1 h, quench the reaction with concentrated sodium carbonate (10 mL), and dilute with water (10 mL) and dichloromethane (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum, to provide the title compound as a colorless foam. MS (ES+): 712 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH:37]=O.C(OCC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:37][C:36]1[C:35]([F:34])=[CH:42][CH:41]=[CH:40][C:39]=1[F:43]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1c(F)cccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(=Cc1c(F)cccc1F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (Aldrich No. 37, 635-3; 6.7 g, 20 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (Aldrich No. 13, 900-9; 3.3 mL, 22 mmol) were dissolved in methylene chloride (11 mL) and stirred at room temperature for 15 min, and then cooled to <−30° C. A solution of 2,6-difluorobenzaldehyde (1.9 mL, 20 mmol) in methylene chloride (25 mL) was added to the reaction mixture dropwise over 20 min. The reaction mixture was stirred for another 20 min, and then allowed to warm up to room temperature for 30 min. The reaction mixture was then poured into ethyl ether (300 mL) and washed with 1 N HCl, brine and dried over MgSO4. Rotary evaporation gave crude 2-benzyloxycarbonylamino-3-(2,6-difluorophenyl)acrylic acid methyl ester which was purified by chromatography on a Medium Pressure Liquid Column (MPLC) eluting with 20% ethyl acetate/80% hexane to give pure product (5 g, 72% yield, liquid).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:3].C(N(CC)CC)C.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>O1CCCC1>[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([S:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:29])=[O:28])[CH2:6][CH2:5]1)=[O:3]
Reactant: NC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a suspension of 4-aminocarbonylpiperidine (12.8 g, 100 mmol) in dry tetrahydrofuran (250 μL) containing triethylamine (20.2 g, 200 mmol) stirring at room temperature under argon, was added 1-naphthalenesulfonyl chloride (25 g, 110 mmol). After 16 h the solvent was evaporated under vacuum, and a solution of 25% methanol in diethyl ether (250 mL) was added to the residue. The resulting mixture was stirred for 2 h before the solid was filtered. The solid was washed with diethyl ether (50 mL twice), then water (50 mL twice), followed by diethyl ether (50 mL twice) again before drying under vacuum. This provided 4-aminocarbonyl-1-(1-naphthylsulfonyl)piperidine (27.9 g, 88% yield) as a white solid.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)=[NH:17]
Reactant: N#Cc1ccccc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N=C(Nc1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Trimethylaluminum (2M in hexanes, 100 ml, 200 mmol) was added dropwise to a solution of 4-chloro-phenylamine (18.2 g, 143 mmol) in toluene (550 ml) under a N2 atmosphere at 0° C. The reaction mixture was warmed to room temperature and stirred for 3.5 hours. A solution of 2-chlorobenzonitrile (23.6 g, 171 mmol) in toluene (140 ml) was added and the reaction mixture was heated at 80° C. for 17 hours, during which time it became homogeneous. The reaction mixture was then cooled to room temperature and poured over a slurry of silica gel in CHCl3/methanol (2:1). After filtration, the filter cake was washed with a mixture of CH2Cl2/MeOH (2:1). The combined filtrates were concentrated in vacuo, and the solid yellow residue was triturated with hexanes/ether (2:1). The product I-5a (25.1 g, 66%) was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]([C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[C:15]([N:16]4[CH2:21][CH2:20][C:19](/[CH:23]=[CH:24]/[CH:25]=[CH2:26])([CH3:22])[CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23](/[C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([C:42]5[CH:41]=[C:40]([Cl:39])[CH:45]=[CH:44][C:43]=5[OH:49])[CH:7]=[CH:6][CH:5]=4)[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]=2[C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:21][CH2:20]1)=[CH:24]\[CH:25]=[CH2:26]
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 73.9 %

Procedure:
To a microwave tube was added (S,E)-methyl 2-(2-(3-bromophenyl)-7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.172 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (44.5 mg, 0.258 mmol), and 2.0 M aqueous K2CO3 (0.086 mL, 0.172 mmol) in dioxane (2 mL) and water (0.5 mL). The reaction was sparged with nitrogen for 1 minutes, treated Pd(PPh3)4 (19.87 mg, 0.017 mmol) then sparged for 1 min. The reaction tube was sealed and then heated at 90° C. in a microwave tube for 1 h. LCMS analysis showed 40% completion. Additional 10 mg of Pd(PPh3)4 added and heated at 90° C. for another 2 h. The reaction was concentrated, diluted with water (15 mL) and extracted wtih EtOAc. The EtOAc layer was washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by biotage (0%-40% EtOAc in hexanes) to isolate 80 mg (74%) of the product as off-white foam. 1H NMR (500 MHz, CDCl3) δ 8.09 (br. s., 1H), 8.06 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 6.39 (dt, J=16.9, 10.2 Hz, 1H), 6.17 (dd, J=15.4, 10.4 Hz, 1H), 6.07 (s, 1H), 5.88 (d, J=15.3 Hz, 1H), 5.33 (br. s., 1H), 5.19 (d, J=17.2 Hz, 1H), 5.04 (d, J=9.6 Hz, 1H), 4.50-2.50 (m, 4 H), 3.75 (s, 3H), 2.64 (s, 3H), 1.93 (d, J=12.9 Hz, 1H), 1.87-1.73 (m, 2H), 1.67 (br. s., 1H), 1.29-1.24 (m, 12H). LCMS (M+1)=629.08.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]([CH2:14]O)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([F:18])=[C:9]([O:16][CH3:17])[CH:10]=2)[N:5]=1)[CH3:2].O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:14][C:13]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:16][CH3:17])=[C:8]([F:18])[CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: CCNc1nc2cc(F)c(OC)cc2cc1CO
Solvent: ClCCl
Product: CCNc1nc2cc(F)c(OC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-ethylamino-7-fluoro-6-methoxyquinolin-3-yl)methanol SMA 44090 (278 mg, 1.11 mmol) in dry CH2Cl2 (30 mL) at 0° C. under N2 in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (1.60 mL, 22.1 mmol) and the mixture was stirred for 3 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then diluted with CH2Cl2 (30 mL) and concentrated back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-N-ethyl-7-fluoro-6-methoxyquinolin-2-amine hydrochloride SMA 44096 as a yellow solid (348 mg, quantitative yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O.C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([OH:43])=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)O)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cooled TFA (2.0 mL) was added to tert-butyl 2-(cis-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (160 mg, 0.28 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was neutralized with ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (46.9 mg, 0.091 mmol, 32.5%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[C:10]=1[OH:25])=[O:8])([OH:3])=[O:2].C([O-])(O)=O.[Na+].ClC1C=C(CC2C=CC=CC=2O)C(O)=C(C=1)CC1C(O)=C(C=CC=1)C(O[CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:63]([NH:64][C:65](=[O:74])[CH2:66][O:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:62](=[O:75])[N:53]2[C:54]=1[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=O>>[Cl:15][C:13]1[CH:12]=[C:11]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[C:10]([OH:25])=[C:9]([CH:14]=1)[C:7]([C:6]1[C:5]([OH:29])=[C:4]([CH:28]=[CH:27][CH:26]=1)[C:1]([O:3][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:63]([NH:64][C:65](=[O:74])[CH2:66][O:67][C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:62](=[O:75])[N:53]2[C:54]=1[C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])=[O:2])=[O:8]
Reactant: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(Cc3cc(Cl)cc(Cc4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Reactant: O=C(O)c1cccc(C(=O)c2cc(Cl)cc(C(=O)c3ccccc3O)c2O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(C(=O)c3cc(Cl)cc(C(=O)c4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Yield: 90 %

Procedure:
Compound 18 (7.33 g, 8.99 mmol) was prepared from 16 (5.30 g, 9.99 mmol), 15 (4.13 g, 10.0 mmol), and NaHCO3 (2.52 g, 30.0 mmol) in 90% yield by the same method used for the preparation of 17. For 18: mp 138-140° C.; 1H NMR (DMSO-d6) d 1.50 (s, 9 H, 3×CH3), 3.72, 3.83 (AB, Jgem=19 Hz, 2 H, CH2S), 4.60 (s, 2 H, OCH2CO), 4.99, 5.29 (AB, Jgem=15 Hz, 2 H, CH2O), 5.18 (d, J=5.0 Hz, 1 H, HC(6)), 5.79 (dd, J=5.0 and 9.5 Hz, 1 H, HC(7)), 6.20 (br, 3 H, 3×OH), 6.90-7.50 (m, 14 H, 4×ArH), 8.30 (d, J=9.5 Hz, 1H, NH); IR (nujol): 3290-3370 (OH, NH), 1792 (β-lactam), 1750 (ester), 1730 (ester), 1688 (amide), 1620 (C═O) cm−1. Anal. (C41H35N2 O12SCI) C, H, N, S, Cl.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]#[N:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[ClH:25].[CH3:26][OH:27]>>[ClH:25].[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23](=[NH:24])[O:27][CH3:26])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C#N)C3)ccc21
Reactant: CO
Agent: Cl
Product: CCn1c2ccccc2c2cc(CN3CCCC(C(=N)OC)C3)ccc21
Temperature: -5 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 100-mL 3-necked round-bottomed flask was charged with 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbonitrile (1.31 g, 4.05 mmol, 1.00 equiv, 98%) from Example 13 in anhydrous MeOH (20 mL). Then, this was treated with HCl gas. The resulting solution was allowed to stir at −5° C. for 3 hours, followed by at −20° C. for overnight. Resulting precipitate was collected by filtration and dried to afford methyl 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbimidate hydrochloride as white solid (1.44 g, 92%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)(=[O:18])=[O:17]
Reactant: Cc1cc2c(cc1CCO)COC2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1CCOS(C)(=O)=O)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-1(3H)-one (1.20 g, 6.25 mmol) and TEA (2.5 g, 25 mmol) in DCM (100 mL) was added MsCl (1.40 g, 12.5 mmol) at 0° C. The mixture was stirred at ambient temperature overnight, then was washed with water and brine. The organic layer was dried and concentrated to dryness. The resulting 2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl methanesulfonate was used for the next step without any purification.
Reaction SMILES: [F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C:11](=[O:12])[CH2:10][C@H:9]([O:13]C2CCCCO2)[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(O)(=O)C.C1COCC1.O>[F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C:11](=[O:12])[CH2:10][C@H:9]([OH:13])[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(F)(F)C(=O)CCC[C@H]1C(=O)C[C@H](OC2CCCCO2)[C@@H]1C/C=C\CCCC(=O)OC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCC(F)(F)C(=O)CCC[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)OC

Procedure:
The diketone (42) (0.188 g) was dissolved in a mixed solvent of acetic acid, THF and water (3:1:1, 25 ml) and the resultant mixture was kept at 40° C. for 3.5 hours. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the titled compound (43).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1)([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)C(C)C)C>O1CCCC1.ClCCl>[C:15]([NH:19][C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of tert-butyl-1-homopiperazine carboxylate (0.25 g, 1.25 mmol) and N-tert-butyl-3-(chloromethyl)benzamide (0.470 g, 1.25 mmol) in tetrahydrofuran (4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.88 mmol). The resultant mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, diluted with dichloromethane (50 mL) and washed with saturated ammonium chloride (aqueous) and brine. The organic phase was dried (sodium sulfate), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica (using a solvent gradient of dichloromethane/methanol) to afford the title compound (0.435 g) as a white solid. MS (ESI) m/z 389.9 [M+H]+
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH3:27]I>O1CCOCC1>[CH2:7]([O:6][P:4]([C:9]([CH3:27])([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CI
Reactant: CCOC(=O)CC(C)(C)CC(C(=O)OCC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CC(C)(C)CC(C)(C(=O)OCC)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl 2-diethylphosphono-4,4-dimethyladipate (3.6 parts) (See Example 9) was added dropwise to a suspension of sodium hydride (0.6 parts, 50% in oil) in dry dioxan (100 parts by volume) contaning methyliodide (14.2 parts) over 2 hr. at room temperature. The resulting solution was stirred at room temperature for 18 hr. then heated to reflux for 2 hr., cooled, the solids removed by filtration and the filtrate concentrated in vacuo. Distillation of the residual oil gave 3 parts of diethyl 2-diethylphosphono-2,4,4-trimethyladipate, boiling at 137°-8° C./0.03 mm having a 31P chemical shift of -26 ppm and having the following elemental analysis by weight.