Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]=[N:3][C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]([CH3:7])[CH3:6].[CH3:12][C:13]([NH2:19])([CH2:15][CH2:16][CH:17]=[CH2:18])[CH3:14]>C1COCC1>[CH3:12][C:13]([NH:19][C:2]([NH:3][C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]([CH3:6])[CH3:7])=[O:1])([CH3:14])[CH2:15][CH2:16][CH:17]=[CH2:18]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: C=CCCC(C)(C)N
Solvent: C1CCOC1
Product: C=CCCC(C)(C)NC(=O)N[C@H](C(=O)OC)C(C)C
Reaction time: 0.08 h

Procedure:
Methyl N-(oxomethylene)-L-valinate (2.80 g, 17.7 mmol) was added to 2-methylhex-5-en-2-amine [J. Org. Chem. (1976) 41(5) 855-863.] (2.00 g, 17.7 mmol) in THF (15 mL). After 5 minutes, the reaction mixture was evaporated to give the title compound as a solid which was triturated with hexane and isolated by filtration (2.71 g). LRMS (M+H)+=271.4.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=O.[OH-].[K+].O.NN>C(O)COCCO>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccsc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Nc1ccccc1Cc1ccsc1

Procedure:
14.8 g of 3-(amino-benzoyl)thiophene, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to the boil at reflux in 180 cc of diethylene glycol for 3 hours. After diluting the reaction mixture with ice water, extraction is effected with ether. The ether phase is washed thrice with water, is dried with sodium sulphate and concentrated. 3-(2-amino-benzyl)thiophene is obtained in the form of a light yellow oil having a B.P. of 121°-123° 10.05 mm Hg.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9]CN2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].COC1C=CC(N)=C([C:27]([F:30])([F:29])[F:28])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:16][C:17]=1[C:27]([F:30])([F:29])[F:28])=[C:2]=[S:3]
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Product: COc1ccc(N=C=S)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-methoxy-2-trifluoromethylaniline. Title compound: 1H NMR [400 MHz, (CD3)2SO]: 7.70-7.55 (m, 1H), 7.35-7.15 (m, 2H), 3.28 (s, 3H); single peak at tR=5.61 min (System 2).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]([CH2:28][C:29]1[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:10][NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH3:13]
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1cc(F)cc(F)c1)C(C)C

Procedure:
N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide (377 mg, 0.735 mmol) is stirred with 1.5 mL of trifluoroacetic acid and 3 mL of dichloromethane for 25 min. It is then concentrated on a rotary evaporator and then neutralized with several mL of saturated aqueous sodium bicarbonate. The product is taken up in ethyl ether containing about 1% methanol, washed with several more mL of bicarbonate solution and with brine, and then dried over Na2SO4. Concentration afforded a quantitative yield of the title compound as a yellow solid. HRMS (ESI) calcd for C21H34F2N4O2+H1 413.2728, found 413.2730.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Temperature: 70 °C

Procedure:
4-Formylbenzoic acid (1.50 g, 10.0 mmol), tert-butyl (2-aminophenyl)carbamate (2.08 g, 10.0 mmol), EDC (1.92 g, 10.0 nmol) and HOBt (1.35 g, 10.0 mmol) were dissolved in DMF and the solution was heated at 70° C. for 4 h. The solution was diluted with 200 mL of EtOAc and the organic solution was washed twice with 150 mL of water, then sequentially with 150 mL each of 1 N HCl, NaHCO3 (sat'd), and brine. The solution was dried over MgSO4, concentrated, then purified by flash chromatography (12-100% ethyl acetate in hexanes) to give the desired product, MS cal'd 341 (MH+), exp 341 (MH+).
Reaction SMILES: [N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N+:2]=[N-:3].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:42])[C@H:5]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Solvent: ClCCl
Product: C[C@@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Temperature: -20 °C
Yield: 82.7 %

Procedure:
To a solution of phenyl 3-azido-4-O-benzoyl-3,6-di-deoxy-2-O-pivaloyl-1-thio-β-L-galactopyranoside (β-19) (270 mg, 0.575 mmol) in 10 mL of CH2Cl2 at -78° C. is added a solution of mCPBA (159 mg of 64% material, 0.920 mmol) in 2 mL of CH2Cl2. The reaction mixture is allowed to warm to -20° C. and then quenched with TEA (500 μL, 3.59 mmol). The reaction mixture is diluted with 10 mL of CH2Cl2. washed with saturated NaHSO3 (10 mL), saturated NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (60% EtOAc/petroleum ether) to give 231 mg (83%) of 3-azido-4-O-benzoyl1,3,6-tri-deoxy-2-O-pivaloyl-1-(phenylsulfinyl)-β-L-galactopyranose (β-20) as a mixture of diastereomers: Rf 0.26 (50% EtOAc/petroleum ether).
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:9]1[C:8]2[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:22][CH:23]=3)=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: ClC1=Nc2ccccc2Oc2ccccc21
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 1 (229 mg, 1.00 mmol) in DME (3 mL) was added 4-methoxycarbonylphenylboronic acid (216 mg, 1.20 mmol), Pd(PPh3)4 (0.065 mg, 0.056 mmol) and 2 N Na2CO3(aq) (1.5 mL, 3.0 mmol). The reaction mixture was stirred for 2 h at 90° C. The solution was then cooled at room temperature and poured into AcOEt. The organic layer was washed with water, brine and dried (Na2SO4), filtered and concentrated to give a yellow oil. The residue was purified by silica gel column chromatography with EtOAc (15%) in Hexanes to afford 2 (327 mg, 99%) as a yellow foam. LRMS (ESI): (calc) 329.1. (found) 330.3 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(C)=O.O>[N:24]([C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[N+:25]=[N-:26]
Reactant: Cc1ncccc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ncccc1C(=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-methylnicotinic acid (500 mg, 3.65 mmol) in a mixture of acetone (6.6 mL) and water (3.3 mL) was added triethylamine (1.02 mL, 7.3 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (0.79 g, 7.3 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.47 g, 7.3 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (390 mg, 62%). 1HNMR (CDCl3) (δ) 8.67 (d, 1H), 8.21 (d, 1H), 7.24 (t, 1H), 2.88 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.BrC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C3CC3)C=NC=2C=1.CC1(C)C(C)(C)OB([C:53]2[CH:61]=[C:60]3[C:56]([CH2:57][C:58](=[O:62])[NH:59]3)=[CH:55][CH:54]=2)O1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@@H:11]4[CH2:12][C:13](=[O:16])[NH:14][CH2:15]4)[CH3:10])=[N:7][C:2]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][C:58](=[O:62])[NH:59]5)=[CH:55][CH:54]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reaction time: 0.25 h
Yield: 30 %

Procedure:
In a microwave reaction vessel were placed a mixture of (R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: and (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (50.0 mg, 0.14 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one: (141.9 mg, 0.55 mmol), and Pd(PPh3)4 (11.1 mg, 0.010 mmol) in dioxane (1 ml) and 2N Na2CO3 (1 ml). The mixture was sonicated for 15 sec. and degassed with nitrogen gas for 30 sec. Then it was placed in the microwave reactor at 135° C. for 15 min. The reaction mixture was directly loaded onto the pre-packed silica cartridge, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane). The fractions were collected, concentrated, and further purified by reverse phase chromatography. The fractions were collected, neutralized with sat. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 17 mg (30%) of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)indolin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 10.42 (s, 1H), 8.29 (s, 1H), 7.70 (s, 1H), 7.64 (m, 3H), 7.26 (d, J=8.0 Hz, 1H), 5.55 (m, 1H), 3.72 (m, 1H), 3.45 (m, 3H), 3.24 (m, 1H), 2.86 (m, 1H), 2.48 (m, 2H), 1.43 (d, J=6.4 Hz, 3H), 1.11 (m, 4H). MS (ESI+) m/z 418.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[S:28]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:27]([NH:26][CH3:25])=[S:28])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CN=C=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=S)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
N-{2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) and methylisothiocyanate (0.3 ml, 4.4 mmol) were dissolved in THF and the reaction mixture was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and washed with 1N HCl, 10% sodium bicarbonate, water, and brine. The solvents were removed in vacuo and the crude product was purified by flash chromatography (ethyl acetate-methanol, 97:3) to give 1-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-3-methyl-2-thiourea (265 mg, 73%) as a solid, mp 135° C.
Reaction SMILES: O(P(O[C:18]1[C@H:24]([CH3:25])[C@H:23]2[N:20]([C:21](=[O:29])[C@@H:22]2[C@H:26]([OH:28])[CH3:27])[C:19]=1[C:30]([O:32]CC1C=CC([N+]([O-])=O)=CC=1)=[O:31])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:43][N:44]([CH3:66])[C:45]([C@@H:47]1[CH2:51][C@H:50]([SH:52])[CH2:49][N:48]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:46].C(N(C(C)C)CC)(C)C.CC(C([O-])=O)=CCCCC>C(#N)C.C(OCC)(=O)C.CC(N(C)C)=O>[CH3:25][C@H:24]1[C:18]([S:52][C@@H:50]2[CH2:49][NH:48][C@H:47]([C:45]([N:44]([CH3:66])[CH3:43])=[O:46])[CH2:51]2)=[C:19]([C:30]([OH:32])=[O:31])[N:20]2[C@H:23]1[C@@H:22]([C@H:26]([OH:28])[CH3:27])[C:21]2=[O:29]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@H]12
Agent: CCCCC=C(C)C(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N(C)C)C3)[C@H](C)[C@H]12
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10 gm) Formula-A and 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-1-carboxylate (6.122 gm) Formula-B was dissolved in 60 ml acetonitrile and 3 ml dimethyl acetamide at ambient temperature. The solution was stirred under same condition for 10 minutes to get clear solution and cool to a temperature of minus −10° C. Di-isopropylethyl amine (9.15 ml) was added dropwise under stirring conditions to the above solution at −10° C. and continued the reaction for 90 minutes at the same reaction parameters. After completion of the reaction, 150 ml ethyl acetate was added in said reaction mass, the ethyl acetate layer was extracted by acidic water till to get pH 6-7 of the extracted acidic water, then dried over sodium sulphate and distilled off up to free solid. Next a 1:1 mixture of 50 ml methyl ethyl ketone and acetone was added and allowed to keep for 14 hours for crystallization at 0-5° C., finally 30 ml cold water with a small amount of seeding was added for complete crystallization. The solid was filtered and washed with 10 ml mixture of diethyl ether and ethyl acetate to obtain pure 4-Nitrobenzyl (4R,5S,6S)-3-({(3S,5S)-5-[(dimethylamino)carbonyl]-1-[(4-nitrophenoxy)carbonxyl]pyrrolidin-3-yl}thio)-6-[(1R)-1-hydorxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0].hept-2-ene-2-carboxylate (referred as protected meropenem)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C[O-].[Na+].[Na]>CO.[Cu]>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: COc1ccccc1O
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1ccc(Cl)cc1C(=O)O

Procedure:
A mixture of 2,5-dichlorobenzoic acid (9.5 g.), 2-methoxyphenol (7.4 g.) and copper bronze (1.0 g.) is added to a solution of sodium methoxide in methanol prepared from sodium (2.53 g.) and methanol (50 ml.). The excess methanol is evaporated and 1,2-dichlorobenzene (50 ml.) is added to the residue. The mixture is stirred and heated under reflux for 2.5 hours. The mixture is cooled, acidified with 3 N hydrochloric acid, filtered to remove copper bronze and extracted with chloroform. The organic layer is separated and extracted with saturated sodium hydrogen carbonate solution. The sodium hydrogen carbonate extract is acidified. The precipitate is filtered off, dissolved in toluene, and the toluene solution treated with carbon, filtered and the solvent evaporated. The solid residue is recrystallised from toluene-petroleum ether (b.p. 60°-80° C.) to give 5-chloro-2-(2'-methoxyphenoxy)benzoic acid, m.p. 115°-118° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([NH2:10])=[C:8]([Cl:11])[N:7]=[CH:6][N:5]=1.[CH2:12](I)[CH3:13]>CN(C=O)C.[Cl-].[NH4+].O>[CH2:12]([NH:10][C:9]1[C:4]([Cl:3])=[N:5][CH:6]=[N:7][C:8]=1[Cl:11])[CH3:13]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1c(Cl)ncnc1Cl
Reaction time: 18 h
Yield: 44.9 %

Procedure:
Sodium hydride (55%, 0.17 g, 4.0 mmol) was added in a single portion to a solution of (4,6-dichloropyrimidin-5-yl)amine (0.61 g, 3.72 mmol) and ethyl iodide (0.30 mL, 3.8 mmol) in dry DMF (3 mL) at room temperature. The suspension was stirred for 18 hours, then diluted with saturated aqueous ammonium chloride (5 mL) and water (20 mL). The mixture was extracted with diethyl ether (30 mL), and the extract was dried, filtered and concentrated. Flash column chromatography on silica, eluting with 10% ethyl actetate-hexanes, gave ethyl(4,6-dichloropyrimidin-5-yl)amine (0.321 g, 1.67 mmol, 45%). LC-MS (LCT2) m/z 192, 194 [M+H+], Rt 6.07 min.
Reaction SMILES: [NH2:1][C:2]1([C:15](=[O:17])[NH2:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:18][C:19]([F:24])([F:23])[CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O.C(Cl)Cl>[C:15]([C:2]1([NH:1][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1)(=[O:17])[NH2:16]
Reactant: O=CCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCCC(F)(F)F)(C(N)=O)CC1
Reaction time: 3 h

Procedure:
10 g of tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate, 4.42 g of 3,3,3-trifluoropropionaldehyde, 17.61 g of sodium triacetoxyborohydride and 4.51 ml of acetic acid are added, at AT, to 250 ml of DCM, and then the mixture is stirred for 3 hours. Water is added and the expected compound is extracted with DCM, and the organic phase is washed with a saturated solution of NaHCO3 and then with water. After drying of the organic phase, filtration and evaporation to dryness, 13 g of expected compound are obtained.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C[Si](Cl)(C)C>O1CCCC1.O>[OH:18][CH:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#CC(=O)OCC
Reactant: CC(C)CC=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C#CC(O)CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 22.5 ml) was added dropwise over 40 minutes with stirring to fresh ethyl propiolate (6.0 ml) in dry tetrahydrofuran (75 ml) under nitrogen, with the temperature being maintained below −68° by external cooling. After 30 minutes, isovaleraldehyde (6.5 ml) in dry tetrahydrofuran (15 ml) was added over 15 minutes with the temperature maintained below −69°. After one hour, trimethylsilyl chloride (10 ml) was added and the reaction was allowed to warm to room temperature. Water was added and the mixture was extracted with ethyl acetate, which was washed with brine, dried, and evaporated to give ethyl 4hydroxy-6-methyl-2-heptynoate as an oil (9.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:14][N:13]([CH2:15][C:16]([OH:18])=O)[C:12](=[O:19])[CH:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:9]1=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH:63]1[CH2:68][CH2:67][CH:66]([CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])[CH2:65][CH2:64]1>CN(C)C=O>[CH2:73]([O:72][C:70](=[O:71])[CH2:69][CH:66]1[CH2:67][CH2:68][N:63]([C:16](=[O:18])[CH2:15][N:13]2[CH2:14][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C:9]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:10]=3[CH:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]2=[O:19])[CH2:64][CH2:65]1)[CH3:74]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CC(C)CC1C(=O)N(CC(=O)O)CC(c2ccccc2Br)c2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCN(C(=O)CN2CC(c3ccccc3Br)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg of the compound from Example 6 (0.32 mol) are dissolved in 2 ml of dimethylformamide, and 147 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.39 mol) and 67 μl of diisopropylethylamine (50 mg, 0.39 mol) are added. After stirring at room temperature for 30 min, 80 mg of ethyl 4-piperidylacetate hydrochloride (0.39 mol) and a further 135 μl of diisopropylethylamine (100 mg, 0.77 mol) are added. The reaction mixture is stirred at room temperature overnight and then purified directly by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 130 mg (65% of theory) of the title compound are obtained.