Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)cn(C(=O)OC(C)(C)C)c23)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)c(C(=O)OCc4ccccc4)n(C(=O)OC(C)(C)C)c23)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
A solution of 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (200 mg, 0.41 mmol) in THF (10 ml) was cooled to −78° C., and t-BuLi (1 ml, 1.7 M in pentane) was added. After stirring at −78° C. for 20 minutes, 0.15 ml of benzyl chloroformate was added and the reaction was allowed to warm up to room temperature for 30 minutes. Water was slowly added, followed by EtOAc. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting residue was purified by flash chromatography to give 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a yellow solid (100 mg, 39%). MS: (M+H)+ 626.4.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][NH:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:48]4[CH3:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@H]1CCCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC[C@@H]2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-(+)-2-methylpiperidine (Aldrich) to give the title product. LC-MS (ES+) 746 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)[CH:12]=[CH:11]1)(C)(C)C.C(Cl)Cl.[BH3-][C:33]#[N:34].[Na+].[C:36]([OH:39])(=O)[CH3:37]>C(OCC)(=O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[C:18]3[C:13]([CH2:12][CH2:11][N:10]3[CH2:9][C@@H:8]([NH:7][CH2:37][C:36]([N:10]3[CH2:18][CH2:13][CH2:12][C@H:11]3[C:33]#[N:34])=[O:39])[CH3:27])=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2ccc3ccn(C[C@H](C)NC(=O)OC(C)(C)C)c3c2)cc1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(c2)N(C[C@H](C)NCC(=O)N2CCC[C@H]2C#N)CC3)cc1
Reaction time: 4 h

Procedure:
(S)-{2-[6-(4-Methoxy-phenyl)-indol-1-yl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (1.80 g) was dissolved in acetic acid (25 mL) and CH2Cl2 (10 mL) and cooled to 0° C. NaCNBH3 (1.41 g) was added in portions and the resulting mixture was allowed to stir for 4 hours. The reaction mixture was diluted with ethyl acetate and extracted with concentrated NaOH solution. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (gradient of ethyl acetate in hexanes) to give the title compound as a brown oil (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH:37]1([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][CH2:9][C:10]([N:45]2[CH2:46][CH2:47][N:42]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:43][CH2:44]2)=[O:12])=[CH:13][CH:14]=1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCN(C2CCCC2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
To a mixture of 3-(4-chlorobenzoyl)propionic acid (31.9 g, 150 mmol), DMF (200 ml), and N-hydroxybenzotriazole (40.6 g, 301 mmol) was added a solution of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.8 g, 150 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 1.5 hour, and a solution of 1-cyclopentylpiperazine (23.2 g, 150 mmol) in DCM (100 ml) was added. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was distributed between ethyl acetate (1.0 I) and a saturated, aqueous NaHCO3 solution (1.0 I). Phases were separated, the organic layer was dried (MgSO4), and concentrated, and the residue was redissolved in 1 molar aqueous hydrochloric acid (150 ml). The solution was concentrated, and the residue was dried by coevaporation with ethanol. Recrystallization of the residue from ethanol yielded 31.1 g (54%) of the title compound. Concentration of the mother liquor gave additional 19.4 g (34%) of product.
Reaction SMILES: [O:1]([C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:20])[CH2:17]C=C)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl[C:25]([F:30])([F:29])[C:26](O)=O.[CH3:31]OCCOCCOC>>[O:1]([C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:20])[CH2:17][CH:26]2[CH2:31][C:25]2([F:30])[F:29])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)Cl
Reactant: C=CCC(=O)OCCOc1ccc(Oc2ccccc2)cc1
Reactant: COCCOCCOC
Agent: [Na]
Product: O=C(CC1CC1(F)F)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
14.8 g of 3-butenoic acid 2-(4-phenoxyphenoxy)-ethyl ester are dissolved in 30 ml of diethylene glycol dimethyl ether (diglyme), and the solution is heated to +165° C. with stirring. A solution of 15.25 g of the sodium salt of chlorodifluoroacetic acid in 30 ml of diglyme is then added dropwise at that temperature over a period of 8 hours. The mixture is stirred for a further one hour at +165° C. and then cooled to room temperature. The reaction mixture is filtered, the residue is washed with 20 ml of diglyme and the filtrate is concentrated completely by evaporation and then taken up in 40 ml of diethyl ether, washed twice with 20 ml of water each time and dried over sodium sulfate. The solvent is concentrated by evaporation and the oily residue is then purified by column chromatography on silica gel with hexane/ethyl acetate (9:1), yielding 12.1 g of 2-(2,2-di-fluorocyclopropyl)-acetic acid 2-(4-phenoxyphenoxy)-ethyl ester in the form of a colourless oil having a refractive index of nD22 : 1.5309.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH:23][CH2:24][CH:25](OCC)OCC)=[O:22].O.C(=O)([O-])O.[Na+]>C(O)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:25]=[CH:24][NH:23][C:21]1=[O:22]
Reactant: CCOC(CNC(=O)Nc1ccccc1[C@@H]1CN(C)Cc2c(Cl)cc(Cl)cc21)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2-n2cc[nH]c2=O)C1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-(2,2-diethoxyethyl)urea (65 mg) was dissolved in formic acid (0.4 ml) and stirred at room temperature for 2 hours. Subsequently, the mixture was admixed with water and neutralized with saturated sodium hydrogencarbonate solution. After extracting three times with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered, concentrated and purified by means of preparative chromatography. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was taken up with aqueous HCl and freeze-dried.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.[CH3:18][CH:19]([O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=1)[CH2:20][CH3:21].[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34].CCOCC>CN(C=O)C.O>[CH2:33]([NH:35][C:36](=[O:37])[O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([O:22][CH:19]([CH3:18])[CH2:20][CH3:21])=[CH:24][CH:25]=1)[CH3:34]
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCNC(=O)OCCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C

Procedure:
Dibutyltin diacetate (0.004 ml) is added to a solution of the above alcohol (0.42 g, 2.0 mmol) in 1.5 ml of DMF and the mixture is chilled in an ice bath. Ethyl isocyanate (0.18 ml, 2.2 mmol) is then added and the mixture is allowed to warm slowly to RT. The mixture is then poured into ether and water containing 10% potassium dihydrogen phosphate. The aqueous phase is extracted with ether, and the combined organic phases are washed with water and with brine, dried, filtered and the solvent is removed in vacuo to give O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate (compound 30, Table A).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20](N(OC)C)=[O:21])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Temperature: -15 °C

Procedure:
To a cooled (−15° C.), stirred suspension of lithium aluminum hydride (4.355 g, 114.743 mmol) in diethyl ether (500 mL) was added dropwise a solution of 3-{[methoxy(methyl)amino]carbonyl}-1-piperidine-carboxylic acid tert-butyl ester (25.000 g, 91.795 mmol) in THF (150 mL) over 30 min. The reaction mixture was quenched with aqueous 1N potassium hydrogen sulfate (300 mL), and extracted with a 1:1 mixture of diethyl ether and ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 3-formyl-piperidine-1-carboxylic acid tert-butyl ester, which was used for the next steps without further purification. (22.56 g, yield; quant.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][NH:32]C(=O)OC(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:32][CH2:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:25]1[C:22]([C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=3[N:10]=2)=[O:6])=[CH:3][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NCC1CCCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl piperidin-2-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17.
Reaction SMILES: Br.Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][NH2:25])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Cl:26][CH2:27][C:28](Cl)=[O:29].O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][NH:25][C:28](=[O:29])[CH2:27][Cl:26])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: Cc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 5-chloro-2-(3-aminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone dihydrobromide (0.5 g) in dimethylformamide (3 ml), chloroacetyl chloride (0.2 g) is dropwise added under ice cooling, and the resultant mixture is stirred. The reaction mixture is allowed to stand at room temperature overnight, mixed with water (3 ml), neutralized with aqueous sodium bicarbonate and shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous saline solution in order, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from ethyl acetate/n-hexane to give 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.35 g) as crystals melting at 140° to 141° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([F:17])[F:16])[C:9]=1[CH3:18].S(S([O-])=O)([O-])(=O)=[O:20].[Na+].[Na+].C(O)(C)(C)C.[OH2:33]>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([F:16])[F:17])[C:9]=1[C:18]([OH:20])=[O:33]
Reactant: Cc1c(Cl)cccc1OC(F)F
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1c(Cl)cccc1OC(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Potassium permanganate (1.64 g) was added portionwise over a period of 4 hours to a stirred mixture of 1-chloro-3-[(difluoromethyl)oxy]-2-methylbenzene (0.999 g) in t-butanol/water (20 ml, 1:1) heated at 100° C. The reaction mixture was heated for a further 4 hours—total heating time was 8 hours. The reaction mixture was allowed to cool to room temperature and then allowed to stand overnight. Aqueous sodium metabisulphite solution (5%) was added dropwise until the purple colour disappeared and the resultant mixture was filtered. The filtrate was adjusted to pH 10 using aqueous sodium carbonate solution and extracted with ether (100 ml). The aqueous portion was acidified using aqueous hydrochloric acid (2M) to pH 1 and then extracted with ether (100 ml). The ether layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and evaporated. The title compound was obtained as a colourless oil (0.538 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][CH2:52][N:51]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][CH2:52][N:51]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1CCC(C[C@@H]2C[C@H](S)CN2C(=O)OCC=C)C1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CCN(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 49.7 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (790 mg, 1.6 mmol), (2R,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-3-ylmethyl)-4-mercaptopyrrolidine (560 mg, 1.6 mmol) and N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (480 mg, yield: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([NH2:11])=[CH:6][C:3]=1[CH2:4][OH:5].[C:12]1(=[O:22])[O:17][C:15](=O)[CH:14]2[CH2:18][CH2:19][CH:20]=[CH:21][CH:13]12.[O:23]1CC[CH2:25][CH2:24]1>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:4][O:5][C:24]([CH3:25])=[O:23])=[CH:6][C:7]([N:11]2[C:12](=[O:22])[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[C:15]2=[O:17])=[C:8]([F:10])[CH:9]=1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: Nc1cc(CO)c(Cl)cc1F
Reactant: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 4.9 g (0.028 mole) of 2-chloro-4-fluoro-5-aminobenzyl alcohol, 4.25 g (0.028 mole) of tetrahydrophthalic anhydride, and 100 ml of tetrahydrofuran was refluxed overnight. The solvent was evaporated under reduced pressure, leaving a thick, black oil. To this residue was added 100 ml of acetic acid, and the mixture was heated at 100° C. for several hours. The solvent was evaporated under reduced pressure and was replaced with 200 ml of ethyl acetate. This solution was washed three times with 150 ml of a saturated, aqueous solution of sodium bicarbonate and three times with 150 ml of 10% hydrochloric acid. The solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving 8.80 g of a viscous, black oil. This oil was passed through a column of silica gel, eluting with ethyl acetate/heptane (7/13). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 6.3 g of N-[4-chloro-2-fluoro- 5-(methylcarbonyloxymethyl)phenyl]-3,4,5,6-tetrahydrophthalimide as a thick, amber oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2cccn2)cc1Cl)N1Cc2cccn2Cc2ccccc21

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.2 g, degreased with hexane), pyrazole (0.20 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m/z: 389.2 (M+H)+, 777.1 (2M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-piperazinone (1.802 g, 18 mmol, CAS [5625-67-2], commercially available e.g. from Sigma-Aldrich) and triethylamine (3.01 mL, 21.60 mmol) were dissolved in Dichloromethane (DCM) (100 ml) at 0° C. 2-Chloro-3-(trifluoromethyl)benzoyl chloride (4.81 g, 19.80 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added portionwise and the solution was stirred at room temperature for 48 hr. The solution was diluted with Dichloromethane (400 ml), was washed with 1N HCl (100 ml), water (100 ml), saturated sodium bicarbonate solution (100 ml), water (3×100 ml), and brine (100 ml), was dried over anhydrous magnesium sulfate, and was concentrated to a crude solid (5.92 g). The crude product was purified by flash chromatography (Biotage SP4, 40+M, 0% to 25% methanol/Dichloromethane as eluent) to afford crude product (5.01 g), that was recrystallised from toluene to afford pure 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (4.54 g, 14.80 mmol). LC/MS [M+H]+=307, 309, retention time=1.74 minutes (5 minute method).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].[OH2:18]>N1C=CC=CC=1>[C:1]([O:11][C:2]([CH3:10])([CH3:3])[CH3:1])(=[O:18])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
To a solution of terephthaloylchloride (2.00 g, 9.85 mmol) in dry pyridine (25.0 mL) was added tert-butyl alcohol (803 mg, 10.8 mmol). After 16 hours at 85° C. water (75.0 mL) was added and the solid filtered. The solid was dissolved in diethyl ether (40 mL) and washed with saturated sodium bicarbonate (2×75 mL). The organic phase was then dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1.15 g (Y: 42%) of the title compound; 1H-NMR (CDCl3): δ8.01 (s, 4H), 1.60 (s, 18H).