Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.CS([Cl:43])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][Cl:43])=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO)c2Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CCl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(2,4-dichloro-3-hydroxymethylphenyl)2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (148 mg), triethylamine (0.11 ml) and anhydrous dimethylformamide (1 ml) was added a 1M solution of methanesulfonyl chloride in dimethylformamide (0.77 ml) under ice-water cooling. The mixture was stirred at ambient temperature for 4 hours and partitioned between chloroform and saturated aqueous solution of sodium hydrogen carbonate. The organic layer was isolated, dried over magnesium sulfate and evaporated in vacuo to give a brown oil. The residue was purified by preparative thin layer chromatography (chloroform-methanol) to give 1-(2,4-dichloro-3-chloromethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (120 mg) as an amorphous powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:17](=[O:33])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)[C:36]([OH:38])=[O:37]>C(Cl)Cl>[O:37]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:6][N:8]3[CH2:13][CH2:12][CH:11]([NH:14][C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=5)[N:18]([CH2:26][C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)[C:17](=[O:33])[CH:16]=4)[CH2:10][CH2:9]3)=[CH:24][C:19]=2[O:38][CH2:36]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(=O)n(Cc3ccncc3)c3ccc(Cl)cc23)CC1
Solvent: ClCCl
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)ccc2n1Cc1ccncc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4-(6-Chloro-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydroquinolin-4-ylamino)-piperidine-1-carboxylic acid t-butyl ester (1.22 g, 2.6 mmol) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred for 15 minutes before evaporating under reduced pressure. The crude amine was dissolved in acetone (25 mL), treated with cesium carbonate (1.26 g) and stirred for 15 minutes prior to addition of piperonyl chloride (50% wt solution in DCM, 1.4 mL). The mixture was heated to 50° C. for 8 hours at which time LC/MS analysis indicated the reaction was complete. The reaction was diluted with ethyl acetate and washed with 1 N NaOH. The organic layer was dried with sodium sulfate and concentrated to give the crude product which was purified by silica chromatography using DCM and methanol eluent to give the title compound (0.91 g). 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (2H, m), 2.23 (2H, m), 2.67 (2H, m), 3.19 (2H, m), 3.67 (1H, m), 3.81 (2H, s), 5.44 (3H, br s), 5.81 (1H, s), 5.95 (2H, s), 6.77 (1H, d, J=7.91 Hz), 6.93 (1H, m), 7.04 (4H, m), 7.30 (1H, m), 7.81 (1H, m), 8.48 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[C:32]1([S:38]([CH2:41][CH2:42][C:43](O)=[O:44])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][CH2:41][S:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:40])=[O:39]
Reactant: O=C(O)CCS(=O)(=O)c1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCS(=O)(=O)c1ccccc1)O[C@@H](Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 68.6 %

Procedure:
((S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide) (150 mg, 0.357 mmol), EDC (103 mg, 0.535 mmol), 3-(phenylsulfonyl)propanoic acid (84 mg, 0.393 mmol), and DMAP (65.4 mg, 0.535 mmol) in DCM (30 ml) were stirred at RT for 4 hours. The reaction mixture was washed with HCl 1N (2×) and NaHCO3 sat. sol. (2×); the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by trituration with iPr2O (10 ml). Further triturations with petroleum ether (15 ml) and Et2O (20 ml) were performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)ethyl)pyridine
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[NH:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[NH2:8][C:9]1[N:13]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(N)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
Ethyl bromoacetate (3.50 mL, 31.87 mmol) was added to a solution of 2-amino-4,5-diphenylimidazole (7.50 g, 31.87 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (4.80 mL, 31.87 mmol) in anhydrous tetrahydrofuran (150 mL). The mixture was heated to about 75° C. for about 2 hours and at about 65° C. for about 16 hours before it was cooled to room temperature and treated with brine. After about 15 minutes, ethyl acetate was added and the organic phase was separated, washed with saturated sodium bicarbonate solution and brine prior to drying and solvent concentration to one quarter volume. The precipitate which formed on concentration of the solvent was collected by suction-filtration. There was isolated 3.67 g (36%) of the title compound as an off-white solid. An additional 2.56 g (25%) of the title compound was isolated from the filtrate on concentration, m.p. 173°-175° C.; 1H NMR (CD3SOCD3) δ 7.46-7.36 (m, 3H), 7.32-7.29 (m, 2H), 7.25-7.21 (m, 2H), 7.17-7.04 (m, 2H), 7.03-6.99 (m, 1H), 5.78 (s, 2H), 4.36 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H); 13C NMR (CD3SOCD3) ppm 170.07, 151.51, 137.08, 133.74, 133.02, 132.50, 130.74, 130.01, 129.59, 128.55, 127.26, 127.06, 124.83, 62.62, 45.71, 15.69; IR (KBr, cm-1) 3410, 3390, 3062, 2980, 1744, 1660, 1562, 1476, 1340, 1240, 1222, 1212, 1026, 772, 700; MS m/z (MH+) calcd 322.1556, obsd 322.1555.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:16](N)=[NH:17]>CCO>[CH:5]1[N:4]=[C:3]2[C:7]([N:17]=[CH:16][NH:1][N:2]2[CH:6]=1)=[O:9]
Reactant: N=CN
Reactant: CCOC(=O)c1nccn1N
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1nc[nH]n2ccnc12
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of ethyl 1-amino-1H-imidazole-2-carboxylate (800 mg, 5.16 mmol, 1.0 eq) and formamidine acetate (2.68 g, 25.78 mmol, 5.0 eq) in EtOH (100 mL) was stirred at reflux overnight. The resulting mixture was cooled to RT. The solid was collected by filtration, rinsed with EtOH (3×2 mL) and petroleum ether (2 mL×3), and then dried in vacuo to afford imidazo[1,2-f][1,2,4]triazin-4-ol (400 mg, 50.2% yield).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:13])[C:4](=[O:12])[C@H:5]([CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])[NH2:6].C(N(CC)CC)C.S=[C:22]1[CH2:26][S:25][C:24](=[O:27])[NH:23]1>C(O)C>[CH3:2][N:3]([CH3:13])[C:4](=[O:12])[C@H:5]([CH2:7][S:8]([CH3:11])(=[O:9])=[O:10])[NH:6][C:22]1[CH2:26][S:25][C:24](=[O:27])[N:23]=1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)[C@@H](N)CS(C)(=O)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To a solution of N,N-dimethyl-3-(methylsulfonyl)-L-alaninamide hydrochloride (923 mg) and triethylamine (1.07 mL) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (533 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]3[C:10]([CH:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=O)[O:23][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[C:11]1[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]1[CH3:21].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][O:2][C:3]1[C:8]2[C:9]3[C:10]([CH:22]([CH2:24][CH2:25][N:27]([CH3:29])[CH3:28])[O:23][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[C:11]1[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]1[CH3:21]
Reactant: COc1cccc2c1-c1ccc3c(c1C(CC(=O)N(C)C)O2)C(C)=CC(C)(C)N3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc2c1-c1ccc3c(c1C(CCN(C)C)O2)C(C)=CC(C)(C)N3

Procedure:
A solution of Example 63 in diethyl ether was reduced at room temperature with lithium aluminum hydride to provide the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]([CH:20]([CH3:24])[C:21]([OH:23])=O)[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]([CH:20]([CH3:24])[C:21]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:23])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
214 mg (purity 73%, 0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoic acid (racemate) and 83 mg (0.43 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 113 mg (purity 70%, 35% of theory)
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])[C:13]([NH:19][S:20]([CH:23]3[CH2:25][CH2:24]3)(=[O:22])=[O:21])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:12]1[C:13]([NH:19][S:20]([CH:23]2[CH2:24][CH2:25]2)(=[O:22])=[O:21])=[C:14]([O:17][CH3:18])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2
Reactant: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2[nH]ncc2c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A solution of 5-cyclopropanesulfonylamino-4-(2-fluoro-4-iodo-phenylamino)-6-methoxy-indazole-1-carboxylic acid tert-butyl ester (217 mg, 0.36 mmol) in DCM (5 mL) was treated with TFA (2 mL) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated with diethyl ether to give the title compound as an off-white solid (102 mg, 52%). LCMS (method A): RT=10.17 [M+H]+=503. 1H NMR (DMSO-d6, 400 MHz): 12.92 (1 H, s), 8.72 (1 H, s), 7.60-7.52 (2 H, m), 7.34-7.24 (2 H, m), 6.71 (1 H, s), 6.53 (1 H, t, J=8.80 Hz), 3.84 (3 H, s), 2.53-2.46 (1 H, m), 0.84-0.73 (2 H, m), 0.72-0.66 (2 H, m).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]1(C)C=CC=CC=1.C(OC)(OC)OC.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:9][O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COC(OC)OC
Solvent: O
Product: COC1=CC(=O)CCC1

Procedure:
In a 21 three-necked flask, 100 g (0.89 mol) of cyclohexane-1,3-dione are initially charged and dissolved in 300 ml of methanol, 1000 ml of toluene and 97.6 ml of trimethyl orthoformate, 5 g of p-toluenesulphonic acid dihydrate are added and the mixture is heated under reflux for 2 h. After cooling, the mixture is washed 4× with in each case 200 ml of 10% strength NaOH and the organic phase is dried over sodium sulphate and concentrated on a rotary evaporator. This gives 73.4 g of a light-brown oil which is used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[N:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[N+]=[N-].C[O-].[Na+].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:10]=[C:9]2[C:6]([CH:7]=[C:14]([C:15]([OH:17])=[O:16])[NH:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
A solution of 4-cyanobenzaldehyde (1.27 g, 9.69 mmol) and ethyl azidoacetate (5 g, 38.76 mmol) in methanol (6 ml) was added dropwise over 0.16 h to a stirred solution of sodium methoxide (2.143 g, 39.7 mmol) in methanol (24 ml) at −8° C. The reaction was stirred with ice cooling for a further 3 h before being poured into ice/water (500 ml). The precipitate was filtered, washed with water and dried in vacuo. A sample of the residue (0.55 g) was dissolved in xylene (15 ml) and added dropwise to refluxing xylene (35 ml) over 0.75 h. After a further 1.5 h reflux the mixture was cooled and the precipitate filtered, washed with a small amount of xylene and dried in vacuo. The residue was dissolved in aqueous methanol (20 ml, 1:1) and sodium hydroxide (1 equivalent) added. The mixture was stirred at room temperature for 18 h, concentrated to half volume and poured into water (50 ml). The resultant solution was washed with ethyl acetate (50 ml) and the aqueous layer acidified with 2N HCl. The precipitate was filtered, washed with water and dried in vacuo to afford the title compound as a pale yellow solid (0.209 g, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([O:15][CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CNc2ccc(Cl)cc2)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1OC
Yield: 40.4 %

Procedure:
A mixture of 1.9 g of 4-(4-chloroanilinomethyl)-2-methoxyphenol, 2.11 g of ethyl 2-bromo-2-methylpropionate 1.5 g of potassium carbonate and 29 ml of methyl isobutyl ketone is refluxed for 24 hours. To the mixture is further added 705 mg of ethyl 2-bromo-2-methylpropionate and the resulting mixture is further refluxed for 3 hours. The insolubles are filtered off and the filtrate is washed with water, dried and concentrated under reduced pressure. The residual oil is purified by column chromatography, using 60 g of silica gel and benzene as a developer, to give 1.1 g of ethyl 2-[4-(4-chloroanilinomethyl)-2-methoxyphenoxy]-2-methylpropionate, mp 73° to 74° C. Infrared absorption spectrum (nujol) 3400, 1735 cm-1. N.M.R.spectrum (CDCl3, δ) ppm 6.45-7.33 (7H, m), 4.25 (2H, q, J=7 Hz), 4.20 (2H, s) 3.79 (3H, s), 1.59 (6H, s), 1.30 (3H, t, J=7 Hz)
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[CH:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:26][CH:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:16][CH2:15]2)=O)=CC=1)([O-])=O>O1CCCC1.O>[CH:13]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:16][CH2:15]1)=[NH:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CC(C(=O)N4CCN(C=NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(C=N)CC4)C3)[C@H](C)[C@H]12
Yield: 25.6 %

Procedure:
98 mg of 4-nitrobenzyl (1R,5S,6S)-2-(2-[4-(N-4-nitrobenzyloxycarbonylformimidoyl)piperazin-1-yl-carbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl-thio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 5 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 250 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 1(b), to give 12 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:19][CH3:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid (3.00 g, 12.74 mmol) and cesium carbonate (6.23 g, 19.11 mmol) in acetonitrile (70 mL) was added iodoethane (5.1 mL, 63.7 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Choromatography on silica gel (biotage, 5% EtOAc in hexane) afforded 3.5 g of ethyl 3-bromo-4-chlorobenzoate (97%). 1H NMR (300 MHz; CDCl3) 1.40 (t, 3H); 4.37 (q, 2H); 7.52 (d, J=8.1 Hz, 1H); 7.91 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H); 8.28 (d, J=1.8 Hz, 1H).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:16])[CH:12]=2)[O:7][CH2:6]1)C.Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])N.C(O)(=O)C>C(O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:18]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:16])[CH:10]=[CH:9][C:8]=3[O:7][CH2:6][C:5]=2[CH:4]=[N:2]1)[CH3:25]
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CO2
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cn1ncc2c1-c1cc(C)ccc1OC2
Yield: 40 %

Procedure:
A solution of crude 3-Dimethylaminomethylene-6-methyl-chroman-4-one b (1.34 g, 6.16 mmol), ethyl hydrazinoacetate hydrochloride (0.95 g, 6.16 mmol), and a catalytic amount of acetic acid were heated at refluxed in absolute ethanol (10 mL) for overnight. The reaction mixture was concentrated and the residue was purified by column chromatography to get the pure compound c (675 mg; 40% yield, for two steps): LC MS (Method B): 273 (M+1); 1H NMR (400 MHz, CDCl3/TMS):δ 7.37 (s, 1H), 7.02-7.01 (m, 2H), 6.90 (d. J=8.5 Hz, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 4.22 (q, J=7.6 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:19][C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:9]=2[CH2:8][CH2:7]1)[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[CH:19]=1)[CH3:2]
Reactant: CCOC(=O)CC1CCc2c(oc3ccc(Cl)cc23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc2c(c1)oc1ccc(Cl)cc12

Procedure:
A mixture of 7.23 g. of 8-chloro-1,2-dihydro-3(4H)-dibenzofuranacetic acid ethyl ester, 11.8 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 150 ml. of benzene was stirred at reflux temperature for 18 hours under an atmosphere of nitrogen, and then cooled. The solid was removed by filtration and washed with benzene. The filtrate and washings were combined and concentrated under reduced pressure to yield 14.1 g. of dark oil, which was dissolved in methylene chloride and filtered through 143.5 g. of alumina II (neutral) in a column 60 mm. in width and 65 mm. in lenght. The eluate was evaporated to 3.28 g. of yellowish solid, which was crystallized first from a mixutre of ether-pentane, and then from ether alone to give 1.35 g. of 8-chloro-'-dibenzofuranacetic acid ethyl ester having a melting point of 90°-91°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)C.CC(C)=O.[OH-].[Na+]>C1COCC1>[O:16]1[C:15]2([CH2:20][CH2:21][CH:12]([CH2:11][CH2:10][OH:9])[CH2:13][CH2:14]2)[O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 3 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Third Step: 20.0 g of lithium aluminum hydride (LAH) and 800 mL of THF were added to a reactor under nitrogen atmosphere, and stirred at 3° C. 190.0 g of the compound (12) dissolved in 200 mL of THF was added dropwise thereto at a temperature range of from 0 to 7° C. over 2 hours, followed by further stirring at 0° C. for 3 hours. After confirming that the reaction had been completed by GC analysis, a mixture of 60 mL of THF and 60 mL of acetone was added dropwise thereto at 0° C. over 30 minutes, and 100 mL of a 2N sodium hydroxide aqueous solution was further added dropwise thereto at 10° C. over 30 minutes. A white solid thus deposited was filtered off, and 300 mL of toluene and 1,000 mL of brine were added to and mixed with the filtrate. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with brine, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 152.7 g of 2-(1,4-dioxaspiro[4,5]dec-8-yl)ethanol (13) as a colorless liquid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl:12][CH2:13][CH2:14][CH2:15]I.O>O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: ClCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCCCl
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilylacetylene (12.0 g., Aldrich) in dry tetrahydrofuran (100 ml.) was stirred at 0°, under a current of nitrogen and n-butyllithium (76.5 ml. of 1.6M solution in hexane) was added dropwise. The solution was stirred for 30 minutes and a solution of 1-chloro-3-iodopropane (25.0 g.) in dry tetrahydrofuran (75 ml.) was added. The reaction mixture was allowed to warm to 20° and stirred for 18 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue distilled. 5-Chloro-1-trimethylsilylpent-1-yne was obtained as a colourless oil (12.7 g., b.p. 67°-72°, 15 mm. Hg.).