Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:37]=[C:38]2[NH2:41])=[CH:33][CH:32]=1>>[NH2:41][C:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([F:30])[CH:40]=2)[C:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c3cc(F)ccc23)OC1(C)C
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cnc(N)c5cc(F)ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure A for Suzuki coupling, 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide and 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine were reacted to give 185. LCMS: M+H+=565.3
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:18][N:17]([C:30](=[O:45])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC3C=CC=CC=3)=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[C:1]1([C@H:11]([NH:13][CH2:14][C@@H:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[CH2:18][N:17]([C:30](=[O:45])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)OCc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reaction time: 16 h

Procedure:
A 310 mg portion of benzyl 6-{(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate was dissolved in 2 ml of methanol and 2 ml of THF, mixed with 2 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred for 16 hours. The reaction solution was washed with diethyl ether, 1 M hydrochloric acid was added to the water layer until its pH became 2.0, and then this was extracted with chloroform. After washing this with saturated brine, the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. By purifying the thus obtained residue by a silica gel column chromatography (chloroform-methanol), 6-{(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoic acid was obtained. The thus obtained compound was dissolved in 2 ml of 4 M hydrogen chloride/1,4-dioxane solution and then concentrated under a reduced pressure. THF and diethyl ether were added to the residue, the thus obtained precipitate was collected by filtration, and the filtered product was dried under a reduced pressure to obtain 200 mg of 6-{(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoic acid hydrochloride as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:5]3[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]=3)[CH2:20][CH2:19]2)=[O:23])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3)CC2)n1
Reaction time: 20 h
Yield: 67.3 %

Procedure:
A mixture of 1-[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (80.0 mg, 0.255 mmol), 4-chlorobenzylamine (32.0 mg, 0.255 mmol), EDCI (49.0 mg, 0.255 mmol), HOBt (35.0 mg, 0.255 mmol) and N-methylmorpholine (26.0 mg, 0.255 mmol) in CH2Cl2 (5 mL) was stirred for 20 h (reaction progress monitored by LCMS). The solvent was removed under vacuum, and the residue was purified by preparative HPLC to yield 75 mg of the title compound as a white solid. MS (ES+): m/e 437.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12](=[O:16])[N:13]([CH3:15])[CH2:14][C:8]=2[CH:7]=1.CS[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12](=[O:16])[N:13]([CH3:15])[CH2:14][C:8]=2[CH:7]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCN)cc2CN(C)C1=O
Reactant: CSC1=NCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1Cc2ccc(OCCCNC3=NCCN3)cc2CN(C)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A mixture of methyl (±)-8-[3-amino-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.3 g, 1 mmol), 2-methylthioimidazoline (0.46 g, 2 mmol), diisopropylethylamine (0.42 mL, 2 mmol) and dimethylacetamide (3 mL) was heated to 100° C. under argon. After 2 hr, the reaction was concentrated under vacuum and the residue was partitioned between CHCl3 and H2O. The organic phase was dried (MgSO4) and concentrated, and the residue was purified by preparative HPLC to give the title compound (0.24 g, 51%) as a yellow oil: MS (ES) m/e 389.4 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10](O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)C.[OH-].[K+].[C:18](=[S:20])=[S:19]>>[SH:19][C:18]1[S:20][CH2:10][CH:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]=1
Reactant: S=C=S
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: SC1=NC(Cc2ccccc2)CS1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
A total of 75 mmoles of Phe in 225 mmoles of ethanol containing 300 mmoles of carbon disulfide and 75 mmoles of solid potassium hydroxide is added with stirring while maintaining the temperature below 40° C. The temperature is then raised to 40° C. and the reaction mixture held in a closed vessel for 12 hours. At the end of this period, the alcohol and carbon disulfide are removed by rotary evaporation. The residue is suspended in a small amount of cold water, and the product recrystallized from the water-ethanol mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([C:15]([OH:17])=O)=[CH:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][N:19]1[C:23]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])=[CH:22][N:21]=[C:20]1[CH3:31].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:18][N:19]1[C:23]([C:24]2[CH:25]=[C:26]([NH:27][C:15]([C:9]3[C:10]4[NH:11][C:12]5[C:4](=[CH:3][C:2]([F:1])=[CH:14][CH:13]=5)[C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:17])[CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]=[C:20]1[CH3:31]
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Reactant: O=C(O)c1cccc2c1[nH]c1ccc(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(-c2cccc(NC(=O)c3cccc4c3[nH]c3ccc(F)cc34)c2)n1C
Reaction time: 40 h
Yield: 59.1 %

Procedure:
To a suspension of 6-fluoro-9H-carbazole-1-carboxylic acid (37 mg) and 3-(1,2-dimethylimidazol-5-yl)aniline (43 mg) in dichloromethane (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg) and 4-dimethylaminopyridine (11 mg), and the mixture was stirred for 40 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with a silica gel column chromatography eluting with 2-3% methanol/dichloromethane to give N-[3-(1,2-dimethylimidazol-5-yl)-phenyl]-6-fluoro-9H-carbazole-1-carboxamide (38 mg, 51.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.Cl.C1C=CC2N([OH:35])N=NC=2C=1.[CH2:36]([N:38]([CH2:41]C)[CH2:39]C)[CH3:37].CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[N:8]([C:37](=[O:35])[CH2:36][N:38]([CH3:41])[CH3:39])[CH2:7][CH2:6]2
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(O)c32)cc1
Reactant: CCN(CC)CC
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C(=O)CN(C)C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
To a suspension of 6,7-dimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (103 mg, 0.312 mmole) in dichloromethane (2 ml) were added N,N-dimethylglysine hydrochloride (52.2 mg, 0.374 mole) and HOBt (57.3 mg, 0.374 mmole) at room temperature under nitrogen. Then triethylamine (56.5 μl, 0.405 mmole) and EDCI (71.7 mg, 0.374 mmole) were added to the mixture at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hours and at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The combined extracts were successively washed with a saturated aqueous sodium hydrogencarbonate solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from methanol to give the desired compound (78.4 mg) as colorless crystals.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(OCC)(=[O:24])C.C(=O)([O-])[O-].[K+].[K+].Cl.[C:35]([Cl:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>O>[ClH:43].[ClH:1].[C:35]([N:12]1[CH2:13][CH2:14][N:9]([C:8](=[O:24])[C:7]2[CH:6]=[C:5]([O:4][CH3:3])[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:11]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)c3cccnc3)CC2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1 g), ethyl acetate (50 ml), water (50 ml) and potassium carbonate (3 g) is added, with stirring at room temperature, nicotinoyl chloride hydrochloride (1 g). After stirring for 30 minutes, further nicotinoyl chloride hydrochloride (1 g) is added to the mixture, followed by stirring for another one hour. The ethyl acetate layer is separated, washed with an aqueous solution of sodium bicarbonate and water, successively, and dried, then the solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of ethanol and ethyl acetate. To the mixture is added a 1N hydrogen chloride - ethyl acetate solution (10 ml). The mixture is diluted with ethyl ether, then precipitating powder is collected by filtration to yield 1-(nicotinoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine dihydrochloride (0.8 g) as colorless powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.Cl[C:14]1[CH:24]=[C:18]2[N:19]([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=1>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=[C:14]([O:10][CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)[CH:24]=[C:18]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cccc(C(F)(F)F)c1
Product: CN1CCCn2c1cc(OCc1cccc(C(F)(F)F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][C:17]([CH3:19])=[CH2:18])[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:19][I:29])([CH3:18])[CH2:16][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: II
Reactant: C=C(C)Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
In 200 ml of a mixed solvent of diethyl ether-water (3:1) was dissolved 10.0 g of 4-acetoxy-3,5-di-t-butyl-2-(2-methyl-2-propenyl)phenol synthesized according to the procedure described in JP 7-330759/95 and combined with 5.3 g of sodium bicarbonate and 12.0 g of iodine, and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was combined with a saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to give 13.2 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([S:12](Cl)(=[O:14])=[O:13])=[C:5]2[CH3:16].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>N1C=CC=CC=1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:12]([C:6]2[N:7]([CH3:11])[C:8]3[C:4]([C:5]=2[CH3:16])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)(=[O:14])=[O:13])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: Cc1c(S(=O)(=O)Cl)n(C)c2ccc(F)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Yield: 65.9 %

Procedure:
This compound was prepared in analogy to Example 1 starting from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonyl chloride (0.25 g) and 2-amino-5-bromobenzotrifluoride (2.3 g) in pyridine (5 ml) for 18 h at 35° C. to obtain the title compound (0.293 g) as a yellow solid. MS (ISN): 551.4, 549.3 (M−H)−
Reaction SMILES: O[CH:2]([N:7]1[CH:10]([S:11][CH2:12][C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]([NH:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]1=[O:41])[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.S(Cl)([Cl:50])=O>O1CCCC1.O1CCOCC1>[Cl:50][CH:2]([N:7]1[CH:10]([S:11][CH2:12][C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]([NH:21][C:22]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:8]1=[O:41])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccccc1

Procedure:
1-(1-Hydroxy-1-methoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-phenylprop-2-ynylthio)azetidin-2-one (395mg) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (14ml) and the solution, under nitrogen, was cooled to -10°. Pyridine (176mg) in dry dioxan (1ml) was then added, followed by the dropwise addition of thionyl chloride (0.153ml) in dry dioxan (4ml) over 2-3 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added and was decanted from any solid. The organic solution was evaporated to give 1-(1-Chloro-1-methoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-phenylprop-2-ynylthio)azetidin-2-one as an amorphous solid (419mg), after drying overnight in vacuo. νmax (CHCl3) 1770 (broad, β-lactam and ester) cm-1.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Br:17]CC(O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][CH2:16][C@@H:15]1[CH2:1][O:3][C@@H:4]([CH2:5][P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[O:14]1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Reactant: OCC(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@@H]1OC[C@@H](CBr)O1)OCC
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (15.00 g, 59.0 mmol) and 3-bromo-1,2-propanediol (11.00 g, 71.0 mmol, 1.2 eq.) in toluene (60 mL) was added pTSA (few cristals). The mixture was stirred at reflux for 72 hr and was cooled to room temperature. A saturated solution of sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude material was pure by TLC and NMR and gave 17.93 g of the compound in a 96% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH:22]=[C:21]([CH:24]([OH:26])[CH3:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.C(N(CC)CC)C>[C:24]([C:21]1[CH2:22][CH2:23][N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH:20]=1)(=[O:26])[CH3:25]
Reactant: CC(O)C1=CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of oxalyl chloride (5.8 ml) in dichloromethane (100 ml) were added dropwise dimethyl sulfoxide (9.44 ml), a solution of 1-benzyl-4-(1-hydroxyethyl)-1,2,3,6-tetrahydropyridine (13.7 g) in dichloromethane (30 ml) and triethylamine (44.2 ml ) under nitrogen atmosphere at -70° C. Then, the reaction mixture was allowed to warm at ambient temperature and precipitate was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (350 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give 4-acetyl-1-benzyl-1,2,3,6-tetrahydropyridine (9.63 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH2:10][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC#Cc1ccc(Br)cc1)C(=O)OC1CCCC1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)OC(=O)N[C@@H](C/C=C\c1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 82.4 %

Procedure:
A mixture of cyclopentyl(2S)-5-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]pent-4-ynoate (750 mg, 1.719 mmol), quinoline (41 μl, 3.44 mmol), 5% Pd on CaCO3 (500 mg) was purged with nitrogen. EtOH (60 ml) was added and the mixture was stirred under an atmosphere of H2 at room temperature for 21 hrs. Because of incomplete reaction, the mixture was filtered through Celite, treated with fresh catalyst (500 mg) and stirred under an atmosphere of H2 at room temp for a further 18 hrs. The mixture was filtered through Celite and the filtrate evaporated in vacuo to afford the crude product as a colourless oil. Column purification using 5% EtOAc/isohexane afforded the product (640 mg, 1.416 mmol, 82% yield) as a clear colourless oil. LCMS purity 97%: m/z 439 [M+H]+. 1H NMR showed 8 wt % trans-alkene.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O-:10])=[O:9])[N:6]=1.[C:12]1([CH:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:26](N(CC)CC)[CH3:27].[I-].[K+]>CN(C)C=O>[C:12]1([CH:18]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O:10][CH2:26][CH3:27])=[O:9])[N:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C(=O)C(=O)[O-])cs1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(c2ccccc2)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 53, the desired compound was prepared from 10.1 g of 2-aminothiazol-4-ylglyoxylate, 10.0 g of diphenylmethyl chloride, 10 ml of triethylamine, 10 ml of dimethylformamide and 1.0 g of potassium iodide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: C([O:3][C:4](=[O:30])[C@H:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26]C(=O)C)[NH:6][C:7](=[O:18])[CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])C.[OH-].[Na+]>CO>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][C@@H:5]([C:4]([OH:30])=[O:3])[NH:6][C:7](=[O:18])[CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1ccccc1OC(C)=O)NC(=O)CNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CNC(=O)c1ccccc1)N[C@@H](Cc1ccccc1O)C(=O)O

Procedure:
7.69 g (0.02 M) of o-acetoxyhippuryl-L-phenylalanine ethyl ester was dissolved in 50 ml of methanol and to this solution was added 70 ml of a 0.1 N aqueous solution of NaOH, and then this solution was treated by repeating the same procedure as Procedure 1 supra to obtain o-hydroxyhippuryl-L-phenylalanine.