Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:30])[CH:15]=[CH:16][CH:17]([C@@:19]1([CH3:29])[O:23][C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[O:21][C:20]1=[O:28])[OH:18].Cl[C:34]([O:36][CH3:37])=[O:35].C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][Si:2]([CH3:1])([CH3:31])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:30])[CH:15]=[CH:16][CH:17]([C@@:19]1([CH3:29])[O:23][C@H:22]([C:24]([CH3:26])([CH3:25])[CH3:27])[O:21][C:20]1=[O:28])[O:18][C:34]([O:36][CH3:37])=[O:35]
Reactant: C[C@H](C=CC(O)[C@@]1(C)O[C@H](C(C)(C)C)OC1=O)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)OC(C=C[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C)[C@@]1(C)O[C@H](C(C)(C)C)OC1=O

Procedure:
A 1.24 g amount of (5R,2S)-5-{(4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1, 3-dioxolan-4-one and 1.0 g of 4-dimethylaminopyridine were dissolved in 15 ml of dichloromethane in a 50 ml eggplant-shaped flask. The solution was stirred under ice-cooling while slowly adding 315 μl of methyl chloroformate, then was stirred at the same temperature for 15 minutes and at room temperature for 1.5 hours. A 100 ml amount of ethyl acetate and 30 ml of water were added for separation, and extraction was performed from the aqueous layer by 50 ml of ethyl acetate. The organic layer was washed by a saturated aqueous solution of potassium hydrogensulfate, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline and was dried over anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate=19/1 to 9/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 1.388 g (98%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(O)c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(OCc2ccccc2)c1C=O
Temperature: 25 °C

Procedure:
A mixture of commercially available 2-hydroxy-6-methoxybenzaldehyde (1.000 g; 6.57 mmol), benzyl bromide (2.867 g; 16.43 mmol), and K2CO3 (2.960 g; 21.42 mmol) in anh. acetone (33 ml) was refluxed, under nitrogen, for 5.5 h. After cooling to rt, volatiles were removed under reduced pressure, and the residue was dissolved in water and AcOEt. The separated aq. layer was further extracted with AcOEt (2×), and the mixed organic layers were washed with brine, dried dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=8/2) afforded 2-(benzyloxy)-6-methoxybenzaldehyde. LC-MS (conditions E): tR=0.68 min.; [M+H]+: 243.27 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:24])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH:15]=[CH:16][N:17]4[CH2:20][CH2:21][OH:22])=[CH:13][C:12]=3[F:23])[C:3]=12.C([BH3-])#N.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:24])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH2:20][CH2:21][OH:22])=[CH:13][C:12]=3[F:23])[C:3]=12
Reactant: Cn1cc(-c2cc3c(ccn3CCO)cc2F)c2c(Br)ccnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1cc(-c2cc3c(cc2F)CCN3CCO)c2c(Br)ccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of 2-(6-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-1H-indol-1-yl)ethanol (D40) (780 mg, 2.009 mmol) in 5 mL of acetic acid cooled in an ice bath was added sodium cyanoborohydride (189 mg, 3.01 mmol). The ice bath was removed and the reaction mixture was left to stir at RT for 1 hour. The reaction mixture was once again cooled in an ice bath then quenched and basified by the slow addition of 2N sodium carbonate aqueous solution. The aqueous layer was extracted with DCM (3×50 mL), the organic layers were combined, passed through a hydrophobic frit and concentrated. The crude was purified by column chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane to afford the title compound (614 mg). LCMS (A): m/z (M+H)+390/392, C18H17BrFN3O requires 389/391 (acidic).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=[N:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: COCCCc1cc(C=NC2CC2)c(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCc1cc(CNC2CC2)c(Cl)cn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-(3-methoxy-propyl)-pyridine-4-carbaldehyde (21.0 g, 98.2 mmol) and cyclopropylamine (13.8 mL, 196 mmol) in MeOH (450 mL) was stirred at rt overnight. NaBH4 (4.83 g, 128 mmol) was added at 0° C., and the mixture was stirred at rt overnight. Ice was added, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc, and this mixture was washed with aq. 1M NaOH. The aq. layer was extracted back with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5→1:4→1:3→1:1→3:1→EtOAc) yielded the title compound (11.8 g) and [5-chloro-2-(3-methoxy-propyl)-pyridin-4-ylmethylene]-cyclopropyl-amine (10.7 g). This unreacted imine was dissolved in MeOH (20 mL), and this sol. was cooled to 0° C. NaBH4 (3.20 g, 84.6 mmol) was added, and the mixture was stirred at rt overnight. NaBH4 (3.20 g, 84.6 mmol) was added again, and the mixture was stirred for 3 days. Ice was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and the resulting mixture was washed with aq. 1M NaOH. The aq. phase was extracted back with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→1:2→1:1→EtOAc) yielded the title compound (9.40 g). The fractions of the title compounds were mixed together (21.2 g, 85%). LC-MS: tR=0.55 min; ES+: 296.16.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:26][O:27][C:28](=[O:29])[C:30]1[CH:35]=[CH:34][C:33]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]3[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2Cl)cc1

Procedure:
In analogy to Example 151, step 8, 5-[2-(2,3-dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=528.2 [M−H+].
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][N:7]([C:17](=[O:43])[CH2:18][N:19]([C:21](=[O:42])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=1)[CH3:20])[CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:41][O:40][C:25]1[CH:24]=[C:23]([CH2:22][C:21]([N:19]([CH2:18][C:17]([N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:6][CH2:5][C:4]([OH:44])=[O:3])=[O:43])[CH3:20])=[O:42])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]
Reactant: CCOC(=O)CCN(CCCN1CCCC1=O)C(=O)CN(C)C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC(=O)N(C)CC(=O)N(CCCN2CCCC2=O)CCC(=O)O)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetic acid [0.80 g, Reference Example 1] and 3-[3-(2-oxo-pyrrolidin-1-yl)-prop-l1ylamino]-propionic acid ethyl ester (0.51 g, Reference Example 2(c)] in dimethylformamide (25 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (0.80 g) and diisopropylethylamine (0.75 ml). After stirring at room temperature for 2 hours the reaction mixture was treated with water (100 ml) then extracted three times with ethyl acetate. The combined organic extracts were washed with hydrochloric acid (1M), then with brine, then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (25:1, v/v) to give 3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid ethyl ester as a colourless oil (0.76 g). The ester was dissolved in tetrahydrofuran (50 ml) and then treated with lithium hydroxide hydrate (0.065 g) in water (10 ml). After stirring at room temperature for 2 hours the mixture was concentrated to remove the tetrahydrofuran. The residual aqueous residue was washed with ethyl acetate then acidified by addition of hydrochloric acid (1M) and then extracted three times with dichloromethane. The combined organic extracts were washed with brine, then dried over magnesium sulphate and then evaporated to give 3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid as a white solid (0.58 g, Compound A), m.p.73-76° C. [Elemental analysis:- C,60.69; H,6.85; N,11.79% Calculated for C30H39N5O7.0.67H2O:- C,60.69; H,6.69; N,11.58%]. MS: 580 [MH]−. HPLC: RT=9.72 minutes (gradient elution using a mixture of acetonitrile and water 1:4 to 4:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:27]C)[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:46])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2CC)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 85 %

Procedure:
Prepared analogously to Example 25d from 1-ethyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 85% of theory, C28H31N7O3 (513.6); Rf value: 0.21 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=514; (M+H+Na)++=268.6; (M+2H)++=257.7.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H][H]>[C].[Pd]>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [Pd]
Product: CC(C)(C)C1CCC(=O)C(C(C)(C)C)C1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
300 g of 2,4-di-tert-butylphenol and 3.0 g of 5% palladium-carbon catalyst were introduced into a 500 ml autoclave and stirred therein at a reaction temperature of 180° C. under a hydrogen pressure of 20 kg/cm2. After approximately ten hours, the absorption of the theoretical amount (2.9 moles) of hydrogen was confirmed. Then the reaction mixture was cooled to room temperature and the catalyst was filtered off. 218 g of the crude 2,4-di-tert-butylcyclohexanone thus obtained was distilled under reduced pressure in a Helipack packing column of a number of theoretical plates of 5 to give 245 g of a colorless and transparent 2,4-di-tert-butylcyclohexanone (I) fraction (b.p.: 93° to 94° C./3 mm Hg). It was confirmed by gas chromatography that this product was a mixture of cisisomer (I-A) and trans-isomer (I-B) at a ratio of 83:17. The physical properties of this product were as follows:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]([S:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]3[C:31]([NH:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[O:32])(=[O:24])=[O:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:21][C:20]([S:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH2:27][C@@H:26]3[C:31]([NH:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[O:32])(=[O:23])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Solvent: ClC(Cl)Cl
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Nc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
A solution of phenyl isocyanate (38 mg) in CHCl3 (1 ml) was added to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) in CHCl3 (3 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was concentrated in vacuo to give 203 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[(N-phenyl)aminocarbonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](O)=O)=[CH:4][C:3]=2[O:2]1.B.C1C[O:18]CC1>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:18])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: C1CCOC1
Agent: B
Product: CC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0° C. was added BH3.THF (40 ml, 1.0 M in THF). The mixture was stirred at room temperature for 1h. To work up, THF was evaporated on a rotavap. The residue was treated with water (100 ml) Acidified and extracted with ether (2×100 ml). Removal of the solvent under reduced pressure gave 2-(3,4-methylenedioxy)phenyl-1-ethanol as an oil (4.7 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([CH2:15][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH:8]=[CH:9]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrCC1CCCCC1
Reactant: COc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ccn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 42 h
Yield: 90.3 %

Procedure:
To a solution of 7-methoxyindole (5.00 g, 34.0 mmol) in dimethylformamide (50 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 1.50 g, 37.4 mmol). The mixture was stirred at room temperature for 10 minutes before the addition of bromomethylcyclohexane (5.20 ml, 37.4 mmol). The resulting mixture was stirred at room temperature for 42 hours and then partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic layers were washed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo. The crude intermediate was purified by flash column chromatography eluting with 0-10% (v/v) ethyl acetate in n-heptane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole (7.48 g, 30.7 mmol). Chloroacetyl chloride (8.66 ml, 109 mmol) was added dropwise over a period of 1.5 h, to a stirred solution of pyridine (2.20 ml, 27.2 mmol) and 1-(cyclohexyl)methyl-7-methoxy-1H-indole (6.60 g, 27.2 mmol) in toluene (50 ml) at 55° C. The resulting mixture was heated at 55° C. for a further 0.5 h then allowed to cool to room temperature. Water (60 ml) and methanol (10 ml) were added. The organic layer was separated and concentrated under reduced pressure to afford a dark brown residue. The residue was purified by column chromatography eluting with 5% (v/v) ethyl acetate in n-heptane. The solid obtained was repeatedly recrystallised from ether to give 2-chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]ethanone as a white solid (1.40 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]([CH3:24])[CH2:22][NH2:23]>>[OH:20][CH:21]([CH3:24])[CH2:22][NH:23][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CC(O)CN
Product: CCc1cc(-c2cncc(C(=O)NCC(C)O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-hydroxy-propylamine to afford the title compound. MS: m/e=316 (M+H).
Reaction SMILES: C([NH:11][CH2:12][CH:13]([N:15]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C)(OCC1C=CC=CC=1)=O.[C:32]([OH:35])(=[O:34])[CH3:33]>C(O)C.[Ni]>[C:17]([OH:19])(=[O:18])[CH3:16].[C:32]([OH:35])(=[O:34])[CH3:33].[C:28]([O:27][C:25]([CH2:24][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]([NH2:11])[CH3:32])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(CNC(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of N-carbobenzyloxy-N′,N′-bis-(t-butoxycarbonylmethyl)-propylenediamine 35 (5.3017 g, 12.144 mmol) in ethanol (75 mL) was filtered through a bed of Raney nickel into a solution of acetic acid (2.1 mL, 3 equiv) in ethanol (75 mL). The filtrate was degassed with nitrogen and treated with 10% palladized charcoal (0.4 g). The mixture was hydrogenated at 50 psi on a Parr apparatus for 16 h and then the catalyst was filtered off on a bed of celite. The filtrate was concentrated in vacuo and the residue flushed with chloroform (150 mL). The crude product was carried on without further purification.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](/[CH:9]=[CH:10]\[S:11][C:12]2[C@H:13]([CH3:26])[C@@H:14]3[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]3[C:16]=2[C:17]([O-:19])=[O:18])=[CH:7][N:8]=1)(=[O:3])[NH2:2].[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[C:1]([C:4]1[S:5][C:6](/[CH:9]=[CH:10]\[S:11][C:12]2[C@H:13]([CH3:26])[C@@H:14]3[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]3[C:16]=2[C:17]([O:19][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])=[CH:7][N:8]=1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3cnc(C(N)=O)s3)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(S/C=C\c3cnc(C(N)=O)s3)[C@H](C)[C@H]12

Procedure:
In the same manner as in Example 81, 78 mg of the title compound was prepared from 74 mg of sodium (1R,5S,6S)-2-[[(Z)-2-(2-carbamoylthiazol-5-yl)ethen-1-yl]thio]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 62 and 0.031 ml of iodomethyl pivalate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[Cl:16]C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:16])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(Cl)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 4-chlorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O.O1CCCC1>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14 g (69 mmol) of methyl 6-hydroxynaph-thalene-2-carboxylate in 90 ml of dimethylformamide and 90 ml of tetrahydrofuran are introduced into a round-bottomed flask and under a nitrogen stream. 3.3 g (82 mmol) of sodium hydride at 60% are added in small portions. When the gas emission has ceased, 8.7 ml (76 mmol) of 2-methoxyethoxymethyl chloride are added and the reaction medium is stirred for 3 hours at room temperature. It is then poured into ice-cold water and extracted with ether. The organic phase is dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (80/20) mixture and 17 g (85%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CC(C)(C)[O-]
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
(S)-N-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X above by the treatment of (S)-N-Boc-2-formyl-pyrrolidine (470 mg, 2.36 mmol) (Example 87A above) with potassium tert-butoxide (340 mg, 3.07 mmol) and diazomethyl-phosphonic-acid-diethylester (550 mg, 3.07 mmol) (also prepared according to Method X). The product was obtained after silica gel column chromatography with 10% Et2O in hexanes. (Yield 200 mg, 43%).