Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[O:23][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=c1cc(I)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(Oc2c(F)cccc2F)cnn1C1CCCCO1
Temperature: 120 °C
Yield: 48.3 %

Procedure:
A solution of 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (204 mg, 0.67 mmol) in anhydrous N,N-dimethylformamide (8.5 mL, 0.08M) was treated with 2,6-difluorophenol (0.09 g, 0.69 mmol) and potassium carbonate (0.20 g, 1.45 mmol). The reaction was heated at 120° C. overnight. At this time, the reaction was diluted with water (25 mL) and extracted with methylene chloride (3×25 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (25 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 24 g, 20% to 40% ethyl acetate/hexanes) afforded 5-(2,6-difluoro-phenoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (99.7 mg, 49%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.56 (m, 2H), 1.57-1.76 (m, 2H), 1.88-2.01 (m, 1H), 2.01-2.16 (m, 1H), 3.53-3.63 (m, 1H), 3.90-3.98 (m, 1H), 5.82 (dd, J=10.5, 1.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 7.34-7.43 (m, 2H), 7.43-7.55 (m, 1H), 8.23 (d, J=2.7 Hz, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:17]([CH2:19][N:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]1=[O:30])#[N:18].[OH-].[Na+]>O>[C:17]([CH2:19][N:20]1[C:25]2[CH:26]=[C:27]([N+:1]([O-:4])=[O:2])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]1=[O:30])#[N:18]
Reactant: O=[N+]([O-])O
Reactant: N#CCN1C(=O)COc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Fuming (α 1.52) nitric acid (1.3 ml) is added dropwise to 0° C. to acetic anhydride (11.3 g), and thereafter a catalytic amount of concentrated sulfuric acid is added. To the solution is added portionwise at 0° C. 4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-one (1.88 g). The mixture is stirred at 0° C. for 20 minutes, treated dropwise with a cold solution which is made by dissolving sodium hydroxide (10 g) in water (87.5 ml) and cooled to 0° C., stirred at 0° C. for 30 minutes to finish the reaction, and extracted with methyl isobutyl kotone. The extract is washed with water, dried, and evaporated. The resultant solid is recrystallized from ethanol to obtain an end product 4-cyanomethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (1.3 g). mp. 173° C.
Reaction SMILES: COC(=O)CSCC1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C3C=CC=CC=3OC)[CH:15]=2)[NH:10]C(C)(C)C=1.Br[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH:38]=2)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].SCCC(OC)=O>>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=[C:30]2[CH2:29][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]acetic acid methyl ester 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 25 μL of methyl 3-mercaptopropionate reacted to give 14 mg of the title compound as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:14][C:15]([OH:17])=[O:16])=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A suspension of 4-nitro-2-fluorobenzaldehyde (3.16 g, 18.7 mmol), malonic acid (2.14 g, 21 mmol) pyridine (catalytic) and ethanol (10 mL) was heated to reflux for 6 hours. The suspension became a clear solution upon heating. Upon cooling to room temperature solids formed and were isolated by filtration. The solids were washed with cool (15° C.) ethanol and then with 1N HCl and dried, giving 3.32 g 4-nitro-2-fluorocinnamic acid (90% yield).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:23]=3[Br:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Brc1ccc(Br)c(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(Br)ccc3Br)CC2)c(OC)nc1C
Yield: 66 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,5-dibromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.O>CN(C=O)C>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][N:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
8.1 Phenol (25 mmol) is dissolved in DMF (30 ml) and NaH (1.1 eq., 60% suspension in liquid paraffin) is added at 0° C. 5-Bromo-2-nitro-pyridine (1.0 eq.) in DMF (20 ml) is added and stirred 16 h at RT. The reaction solution is poured into water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 2-Nitro-5-phenoxy-pyridine is obtained after column chromatography (heptan/ethyl acetate) as a brown oil in a yield of 78%; HPLC (method A): 1.95 min; LC-MS: 1.678 min, 217.15 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[CH3:10][C:11]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12].N1C=CN=C1.[Na+].[Cl-]>CN(C)C=O.O>[CH3:13][C:11]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1)([CH3:10])[CH3:12]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CC1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(C#N)CC1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution maintained at 10° C., under nitrogen, of 11 g (87.8 mmoles) of 4-hydroxycyclohexanecarbonitrile (prepared according to Praefcke K. and Schmidt D., Z. Naturforsch (1980) 35b, 1451-4) in 50 ml of N,N-dimethylformamide, there is added dropwise 26.6 g (96.8 mmoles) of 1,1-dimethylethyldiphenylsilyl chloride, then by portions, 13.1 g (190 mmoles) of imidazole. Stirring is continued at room temperature during 3 days, before pouring the reaction mixture in water saturated with NaCl. The product is extracted with a hexane-ether (1:1) mixture. The organic phase is washed with a N HCl solution, then with water saturated with NaCl, before drying and concentration. The residue is purified by chromatography on a column of silica in dichloromethane to give 26.5 g (yield=85.9%) of a colorless thick oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(CBr)cc1F
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)c(F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,4-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>CC1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:3]1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=O)C(C)C1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 152 parts of 3-methyl-1-(phenylmethyl)-4-piperidinone in 900 parts of methylbenzene were added dropwise 218 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux. After cooling, the reaction mixture was washed with water and hydrochloric acid, dried, filtered and evaporated. The residue was distilled, yielding 120.5 parts (83%) of ethyl 3-methyl-4-oxo-1-piperidinecarboxylate; bp. 98°-105° C. at 1 mm pressure (intermediate 26).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([N:17]3[CH2:26][CH2:25]C4N=CC=CC=4C3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.[F:38][C:39]([F:50])([F:49])[C:40]1[N:44]2CCN[CH2:48][C:43]2=[N:42][N:41]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([N:17]3[CH2:48][CH2:43][N:44]4[C:40]([C:39]([F:50])([F:49])[F:38])=[N:41][N:42]=[C:25]4[CH2:26]3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2nc(N3CCc4ncccc4C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Product: Cc1cc2nc(N3CCn4c(nnc4C(F)(F)F)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid except using 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride instead of 5,6,7,8-tetrahydro-1,6-naphthyridine, dihydrochloride, hydrate. LCMS-ESI+: calc'd for C26H25ClF3N5O3S: 580.1, 582.1 (M+H+); Found: 580.2, 582.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 7.72-7.45 (m, 4H), 7.41 (s, 1H), 5.16 (s, 1H), 5.09 (s, 2H), 4.38 (t, J=5.4 Hz, 2H), 4.11 (t, J=5.5 Hz, 2H), 2.51 (s, 3H), 0.95 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>C(OCC)C>[ClH:22].[C:16]1([C:10]2([CH2:13][CH2:14][OH:15])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: OCCC1(c2ccccc2)CCNC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (13.0 g, 44.6 mmol) and a solution of hydrochloric acid in dioxane (22.3 mL, 4M, 89.2 mmol). Heat to 50° C. After 1 hour, cool and add diethyl ether to give a solid. Collect the solid by filtration to give, after drying, the title compound: mp; 161°-163° C. [α]2D0 =+11.8 (c=0.563, methanol). Elemental Analysis calculated for C12H17NO·HCl: C 63.29; H 7.97; N 6.15; Found: C 63.21; H 7.86; N 6.05.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:24](=[O:26])[CH3:25])=[N:13][CH:14]=2)[O:5]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52.5 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.3 g, 1.36 mmol) was dissolved in dichloromethane (5 mL) and 4-dimethylaminopyridine 17 mg, 0.136 mmol) was added, followed by triethylamine (0.38 mL, 2.73 mmol) then acetic anhydride (0.153, 1.5 mmol). The mixture was stirred at room temperature for 3.5 h then diluted with dichloromethane and washed with NH4Cl (sat aq) then brine. The organic layer was dried (MgSO4), filtered and concentrated. Chromatography eluting with ethyl acetate gave the desired product (187 mg, 52% yield). 1H-NMR (300 MHz, CDCl3) δ 9.3 (s, 1H), 8.6 (s, 1H), 8.2 (d, 1H), 8.05 (d, 1H), 2.2 (s, 3H), 1.2 (s, 12H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:16])=[O:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccc([N+](=O)[O-])c(C(=O)O)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOc1ccc([N+](=O)[O-])c(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of the compound prepared in Example 424 (1.8 g) in N,N-dimethylformamide (25 mL) was treated with potassium carbonate (1.76 g), followed by iodomethane (2.65 mL). The mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue diluted with water, crude precipitated solids were collected by filtration, 2.14 g. These solids were taken in dichloromethane and purified by column chromatography on silica gel (5-25% ethyl acetate in hexanes) to provide the title compound (1.16 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32]3[O:33][C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[C:30]=4[N:31]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1cccc2oc(S(C)(=O)=O)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1cccc2oc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)nc12
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 4-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) was added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl-4-{4′-[(4-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00-7.80 (m, 8 H), 7.30 (d, 1 H), 7.05 (d, 2 H), 3.30 (s, 2 H), 2.50 (s, 3 H), 1.10 (s, 6 H); LC-MS ret. time 3.77 min (method 2), m/z 429.2 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]=[CH:6]1.[I-:25].[Na+]>C(#N)C>[I:25][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10](=[O:24])[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]=[CH:6]1
Reactant: O=c1c2c(ncn2CCCCl)c2cccnc2n1-c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1c2c(ncn2CCCI)c2cccnc2n1-c1ccccc1
Yield: 71.5 %

Procedure:
To 200 ml of acetonitrile were added 18 g (0.052 mol) of Compound 68 obtained in Example 68 and 12 g (0.078 mol) of sodium iodide, and the mixture was refluxed for 24 hours. In the course of refluxing, 7.8 g (0.052 mol) of sodium iodide was added to the mixture. After cooling, the solvent was evaporated under reduced pressure and water was added to the residue. Then, extraction was carried out with chloroform, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a crude product. Recrystallization from ethyl acetate-nhexane gave 16 g (yield 73%) of Compound 69.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:8])[N:5]2[C:21](=[O:46])[CH:22]([NH:23][C:24](=[O:45])[CH:25]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[C:31](=[O:37])[C:30]3=[O:38])=[O:28])[C@H:4]2[C:3]1=[O:47].C(Cl)Cl.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[OH:47][CH:3]1[C@@H:4]2[CH:22]([NH:23][C:24](=[O:45])[CH:25]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[C:31](=[O:37])[C:30]3=[O:38])=[O:28])[C:21](=[O:46])[N:5]2[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:8])[CH:2]1[CH3:1]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)C(C)C(O)[C@H]23)c2ccccc2)C(=O)C1=O
Yield: 100.2 %

Procedure:
2-Naphthylmethyl 2-methyl-1-oxo-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate (36 mg., 0.056 mmole) in 3.6 ml. of methylene chloride at -78° C. was reduced with tetrabutylammonium borohydride (3.6 mg., 0.014 mmoles). After a 1 hour reaction time at -78° C., tlc (ethyl acetate) indicated conversion was complete. Isolation according to Example 3 (without chromatography) afforded 2-naphthylmethyl 1-hydroxy-2-methyl-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate [36 mg.; Rf 0.13 (ethyl acetate)].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.CO[CH:21]1[CH2:25][CH:24]([CH:26]=O)[CH:23](OC)[O:22]1.O>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:21]=[CH:25][C:24]([CH:23]=[O:22])=[CH:26]2)=[N:2]1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Yield: 21.6 %

Procedure:
Compound 2 (0.30 g, 1.3 mmol) was dissolved in acetic acid (5.0 mL) and 2,5-dimethoxy-4-tetrahydrofurancarbaldehyde (0.36 mL, 2.6 mmol) was added, followed by heating under reflux for 3 days. The reaction mixture was added with water and filtered through Celite, extracted with ethyl acetate and the organic layer was concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain Compound 167 (88 mg, 22%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a7) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:32][CH2:31][O:30][CH3:29])[C:10](=[N:12][C:13]([C:15]34[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]5)[CH2:16]3)[CH2:24]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCn1c(=NC(=O)C23CC4CC(CC(C4)C2)C3)sc2cc(S(C)(=O)=O)ccc21

Procedure:
The product from Example 62A, sodium hydride (60% solution in mineral oil) and 2-bromoethyl methyl ether were processed as described for Example 17B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61-1.80 (m, 6 H), 1.87-1.94 (m, 6 H), 1.99-2.07 (m, 3 H), 3.24 (s, 3 H), 3.26 (s, 3 H), 3.78 (t, J=5.4 Hz, 2 H), 4.63 (t, J=5.3 Hz, 2 H), 7.82-7.91 (m, 1 H), 7.93-8.03 (m, 1 H), 8.46 (d, J=1.7 Hz, 1 H); MS (ESI+) m/z 449 (M+H)+; Anal. Calculated for C22H28N2O4S2: C, 58.90; H, 6.29; N, 6.24. Found: C, 58.86; H, 6.30; N, 6.25.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O1COCO[CH2:23]1.C(O)(=O)C>O>[C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:23]2)([OH:17])=[O:16]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C

Procedure:
In a 3000-1 glass lined reactor, 550 Kg of oleum containing 25% of SO3 are charged under vacuum and good aspiration, then, consecutively, under stirring, 56 Kg of terephthalic acid at 20-23° C. and 26 Kg of 1,3,5-trioxane at 15-20° C. are added thereinto. The reactor is heated at 130-133° C. for 4 hours, then the mixture is cooled to 20-23° C. and 118 Kg of glacial acetic acid are couled portionwise thereinto at a temperature not higher than 25° C. At the end of this operation, 1000 Kg of water are added portionwise, whereby the temperature is maintained not higher than 43-45° C. by circulation of water in the jacket. The mixture is stirred for about 1 hour at 20-23° C., then the product is centrifugated, squeezed and abundantly washed with water in order to remove the larger amount of sulfuric acid from the mother liquors and to obtain 100-105 Kg of 5-carboxyphthalide as a well squeezed, wet raw-product. In a 3000-1 stainless steel reactor the product thus obtained is suspended in 680 Kg of deionized water and a solution of 60 Kg of sodium bicarbonate in 540 Kg of deionized water is then slowly added to said suspension to a pH of 7.0-7.2. To the solution thus obtained, lightly cloudy, 10 Kg of Celite® are added, the solid is filtered off and the solution, at a temperature of 22-25° C., is brought to pH=3 with 32% hydrochl 20-22° C. and centrifugated. The product is well squeezed, abundantly washed with deionized water and dried under vacuum to give 41-43.7 Kg of 5-carboxyphthalide.