Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.[CH3:28][O:29][C:30]([C:32]1[CH:36]=[C:35]([NH2:37])[NH:34][N:33]=1)=[O:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]([C:32]1[CH:36]=[C:35]2[NH:37][C:5]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:11][CH:12]=3)=[C:4]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:3](=[O:2])[N:34]2[N:33]=1)=[O:31]
Reactant: COC(=O)C(C(=O)c1ccc(OCc2ccccc2)cc1)C1CCCCC1
Reactant: COC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Yield: 16.1 %

Procedure:
A mixture of 274 mg (0.747 mmol) of 3-(4-benzyloxy-phenyl)-2-cyclohexyl-3-oxo-propionic acid methyl ester, 106 mg (0.747 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 15 mg (10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 10 mL of toluene was heated at reflux for 88 h. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (Biotage; gradient elution 2% to 20% ethyl acetate in dichloromethane) to afford 55 mg (16% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by 1H NMR; LC-MS—calcd for C27H27N3O4 [M++H]+: 458.2, found: 458.2.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)[CH:9]=2)[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:3]=1.[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([C:8]3[CH:9]=[C:10]4[C:2]([I:1])=[N:3][N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[C:5]4=[N:6][CH:7]=3)[CH:12]=2)=[O:16])[CH2:34][CH2:33]1
Reactant: CN(C)CCN1CCNCC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)O)c3)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCN1CCN(C(=O)c2cccc(-c3cnc4c(c3)c(I)nn4COCC[Si](C)(C)C)c2)CC1
Yield: 42.9 %

Procedure:
A mixture of crude 3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid (200 mg, 0.404 mmol), N,N-dimethyl-2-(piperazin-1-yl)ethanamine (76 mg, 0.485 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (185 mg, 0.485 mmol), triethyl amine (0.700 ml, 0.485 mmol) and in DMF (2 ml) was stirred at 90° C. in Personal Microwave for 1 hour. Water was then added to the mixture and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (110 mg, 43% yield) as off-white solids. MS: m/z 635.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:8]([C:7]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:3][C:4]([CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)N(C)C
Reactant: CC(C)c1ncc(C#N)c(N)n1
Product: CC(C)c1ncc(C#N)c(N=CN(C)C)n1

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-isopropyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: C1C2C(=CC=CC=2)C=[N:3][N:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]2[C:21](=O)[O:20][C:18](=[O:19])[C:17]2=[CH:23][CH:24]=1)([O-])=O.NN>C(O)(C)C>[NH2:11][C:14]1[CH:15]=[C:16]2[C:17](=[CH:23][CH:24]=1)[C:18]([OH:19])=[N:3][N:2]=[C:21]2[OH:20]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: c1ccc2cnncc2c1
Agent: NN
Solvent: CC(C)O
Product: Nc1ccc2c(O)nnc(O)c2c1

Procedure:
The synthesis of phthalazine derivatives of general formulas 13-20 may be achieved as outlined in Scheme II. In general, a mixture of 4-nitrophthalic anhydride 9 and hydrazine may be refluxed in a suitable solvent, e.g., isopropyl alcohol, to provide 6-amino-phthalazine-1,4-diol 10 in almost quantitative yield. Compound 10 may then be treated with phosphorus oxychloride and N,N-diisopropylethylamine to form 1,4-dichloro-phthalazin-6-ylamine 11. Reduction of compound 11 with a suitable reducing agent, e.g., iron, may be used to produce the amino derivative 12. Alkylation or acylation of the amino group of compound 12 using A-B-X (where, for example, A is alkyl, aryl, arylalkyl, arylheteroalkyl, B is absent, CO, SO2, and X is a suitable leaving group, such as, Cl, Br, I, OTosyl, etc.) may be used to provide the dichloro derivative of general formula 13. Treatment of compound 13 with a nucleophile of general formula R1R2NH affords two isomers of general formulas 17 and 18. Alternatively, compound 13 may be treated with NaI and HI in, e.g., acetone to obtain the di-iodo derivative 14. Compound 14 may then be reacted with an appropriate nucleophile (e.g., of general formula R1R2NH) to produce compounds 15 and 16. Compounds 15 and 16 may then be treated with CuCN to produce the corresponding cyano derivatives 19 and 20.
Reaction SMILES: [CH2:1](I)[CH3:2].CC(C)=O.[N:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:14]([N:13]1[CH2:2][CH2:1][N:10]([N:8]=[O:9])[CH2:11][CH2:12]1)[CH3:15]
Reactant: CCI
Reactant: O=NN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1CCN(N=O)CC1
Yield: 103.5 %

Procedure:
Ethyl iodide (8.13 g, 0.052 mole) was added to acetone (80 ml) containing N-nitroso piperazine (6.0 g, 0.052 mole) (prepared as described in U.S. Pat. No. 2,907,767) and anhydrous potassium carbonate (7.3 g, 0.052 mole). The mixture was heated under reflux for 24 hours, cooled, treated with water (50 ml) evaporated to 1/2 volume and extracted with ether (3×150 ml). The combined extracts were dried (K2CO3) filtered and evaporated in vacuo to yield N-ethyl-N'-nitrosopiperazine (7.71 g, 98%), as a straw coloured oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]([NH2:33])[CH3:32])[N:30]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([NH:33][CH:31]([C:29]3[N:30]=[C:26]([CH3:25])[S:27][CH:28]=3)[CH3:32])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: Cc1nc(C(C)N)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3csc(C)n3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (30 mg, 0.097 mmol), 1-(2-Methylthiazol-4-yl)-ethylamine hydrochloride (22 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (92 mg, 0.24 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol), and N,N-dimethylformamide (1.0 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to get the product as a light peach colored solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[N:14]O)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.[Pd]>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH2:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc2c(c1)CCC2=NO
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCc1ccc2c(c1)CCC2N
Reaction time: 16 h

Procedure:
A suspension of 5-n-butylindan-1-one oxime (0.50 g, 2.46 mmol) and 10% Pd/C (0.50 g) in acetic acid (50 ml) is hydrogenated at 3.5 bar for 16 hours. The reaction is filtered through a Celite™ filter pad and partitioned between ether and water. The organic phase is washed with saturated NaHCO3 then brine and dried (MgSO4). Evaporation affords the title compound. NMR δH 0.85 (t J 7.3 3H), 1.26 (sextet J 7.3 2H), 1.50 (quintet J 7.3 2H), 1.58 (m 1H), 2.10 (br s 1H), 2.40 (m 1H), 2.50 (t J 8.0 2H), 2.70 (m 1H), 2.88 (m 1H), 4.38 (t J 6 1H), 6.95 (m 3H), 7.16 (d J 8.3 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:31])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:22])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:31])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:22])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OC)c(F)c2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)c(F)c2)c1
Yield: 94.8 %

Procedure:
A solution of 138 mg (0.32 mmol) of methyl 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 3 ml of methanol is stirred for 4 hours at room temperature in the presence of 10 mg of 10% Pd/C under a hydrogen atmosphere. The palladium is filtered off and the solvents are evaporated off. The residue is chromatographed on silica gel (70/30 heptane/ethyl acetate). 130 mg of methyl 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained. Yield=94%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[C:30](OC)[CH:29]=[CH:28][C:27]=3OCOC)[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.BrCC1C2N=C(C3C=C[C:52]([O:55][CH2:56][O:57]C)=CC=3)OC=2C=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:57][CH2:56][O:55][CH3:52])=[CH:28][CH:27]=3)[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CN(Cc3ccccn3)Cc3ccccn3)cccc2o1
Reactant: COCOc1ccc(-c2nc3c(CBr)cccc3o2)cc1
Product: COCOc1ccc(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)cc1

Procedure:
4-bis(2-pyridylmethyl)aminomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F21) was prepared in a similar manner for the preparation of 4-bis(2-pyridylmethyl)aminomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F18) using 4-bromomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F15) (552 mg, 1.5 mmol) instead of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) in 98% (704 mg); 1H-NMR (400 MHz, CDCl3) δ3.52 (s, 3H), 3.93 (s, 4H), 4.19 (s, 2H), 5.26 (s, 2H), 7.11-7.18 (m, 4H), 7.29 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (d, 2H, J=7.6 Hz), 7.78 (d, 2H, J=7.6 Hz), 8.19 (d, 2H, J=9.2 Hz), 8.55 (d, 2H, J=5.0 Hz).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>S(=O)(=O)(O)O.CO>[CH2:11]([NH:15][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=C(O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCNC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Phenylacetic acid (16 g, 117.6 mmol) and methanol (60 ml) were added to a 250 ml three-necked flask, followed by addition of 5 drops of concentrated sulphuric acid. The resulting solution was heated to reflux for 6 hours. Then, the mixture was cooled to room temperature, followed by adding n-butylamine (12 ml, 121.4 mmol), and heated to reflux for another 3 hours. After the reaction was completed, it was cooled to room temperature. Most of the solvent was removed by rotary vacuum evaporation, 30 ml of water was added thereinto, and the mixture was extracted with ethyl acetate (3×80 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to yield 15.9 g of N-n-butylphenylacetamide (white solid, yield: 70.4%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:19]=[CH:18][C:7](/[CH:8]=[CH:9]/[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH:3]([C:4]1[CH:19]=[CH:18][C:7](/[CH:8]=[CH:9]/[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:20][CH3:21])=[O:2]
Reactant: COc1cc(/C=C/c2ccc(C#N)cc2)ccc1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COc1cc(/C=C/c2ccc(C#N)cc2)ccc1C=O
Yield: 99 %

Procedure:
To a solution of (E)-4-(4-(dimethoxymethyl)-3-methoxystyryl)benzonitrile (70 mg, 0.227 mmol) in aqueous THF (5 ml water/25 ml THF) was added p-toluenesulfonic acid (1 mg, 0.02 eq.) and the mixture was refluxed for 30 minutes. The mixture was concentrated under reduced pressure, extracted with EtOAc (3×), dried, and the solvent was removed in vacuum to give the desired product 99% pure by GC-MS. MS (EI+): 263 (100%, M+); 246 (40%), 232, 216, 203 (60%), 190 (65%), 176, 140, 88.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:15][C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2[S:19][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:15][C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2[S:19][C:20]=1[C:21]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[O:22]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: NCCCCn1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCn1cncn1)c1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of about 2.13 g of 1H-1,2,4-triazole-1-butanamine, dihydrochloride, about 70 ml of methylene chloride, about 30 ml of 1N sodium hydroxide and about 2.3 g of 3-chlorobenzo[b]thiophene carbonyl chloride was stirred at room temperature overnight. About five ml of 1N sodium hydroxide and about 50 ml of methylene chloride were added. The organic layer was separated, washed twice with water, dried and concentrated to an oil. The oil was crystallized from ether, giving about 2.8 g of the desired product as a yellow solid, mp 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:33][CH:34]=C)[CH2:10][N:11]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C[O:39]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:33][CH:34]=[O:39])[CH2:10][N:11]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(CN(CCCCC(=O)O)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(C(=O)N(CCCCC(=O)O)CC(CC=O)c2ccc(Cl)c(Cl)c2)c2ccccc2c1
Reaction time: 18 h

Procedure:
To a stirred slurry of N-[2-(3,4-dichlorophenyl)-4-pentenyl]-N-[(2-carboxyethyl)ethyl]-3-cyano-1-naphthamide (0.56 g) and NaIO4 (0.82 g) in 60 mL 1:1 THF:H2O was slowly added 0.55 mL OsO4 solution (4% w/w in H2O). Mixture was stired for 18 h, 10 mL sat'd Na2S2O3(aq) was added, THF was evaporated, and aqueous residue was extracted with DCM. Extracts were dried over Na2SO4, filtered, and concentrated. This gave 0.26 g of N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-[(2-carboxyethyl)ethyl]-3-cyano-1-naphtharide after purification by chromatography (5:4:1 Hexane:DCM:EtOAc); MS: m/z 511 (M+); 1H NMR (CDCl3) δ 9.79 (s), 9.56 (s), 9.55 (s), 8.26-8.19 (m), 8.00-7.82 (m), 7.79-7.20 (m), 7.00-6.90 (m), 6.81-6.72 (m), 6.68-6.55 (m), 4.45 (t), 4.30-2.78 (m), 2.60-2.25 (m), 1.40-1.12 (m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:20]2[N:21]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[S:15][CH:16]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C1(OC)C=CC=CC=1>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]([C:20]2[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[S:15][CH:16]=1
Reactant: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3n2CC(=O)O)n1

Procedure:
1.07 g of N-[4-(2,6-dimethoxy-4-methylphenyl)-2-thiazolyl]-1-(tert-butoxycarbonylmethyl)indole-2-carboxamide (prepared according to EP-A-0,432,040) are dissolved in a mixture of 2 ml of anisole and 20 ml of TFA. The reaction mixture is left for 3/4 hour at r.t. and then concentrated under vacuum. The residue is taken up in ether, and the precipitate is then filtered off and dried in an oven to obtain 1.13 g of the expected compound; m.p.=223°-224° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1.[CH2:30]([C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38]Br)[CH2:31][CH3:32]>>[CH2:30]([C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14])[CH2:31][CH3:32]
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reactant: CCCc1ccccc1OCCCBr
Product: CCCc1ccccc1OCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Yield: 80.9 %

Procedure:
The title compound (471 mg) was prepared by the method of Example 18 except that the title product of Example 1 (406 mg) was used instead of the title product of Example 2, and the title product of Example 11 (308 mg) was used instead of benzyl bromide.
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: CCOC(C)=O
Solvent: ClCCl
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: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:29]=[O:30])=[CH:23]2.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:24]([CH:29]=[O:30])=[CH:23]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
p-Toluenesulfonyl chloride (2.445 g, 12.82 mmol), N,N-dimethyl-4-aminopyridine (0.196 g, 1.603 mmol) and triethylamine (2.253 ml, 16.03 mmol) were added to a solution of 5-fluoro-1H-indole-2-carbaldehyde (0.523 g, 3.21 mmol) in dichloromethane (10 ml) and stirred at room temperature for 20 hours. After reaction, the mixture was poured into saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to give 823 mg (81% yield) of the title compound as a white crystal:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Na].Br[CH:11]=[C:12]=[C:13]([CH3:15])[CH3:14].O>C(O)C>[C:1]([CH:3]([C:13]([CH3:15])([CH3:14])[C:12]#[CH:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)=C=CBr
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C#CC(C)(C)C(C#N)C(=O)OCC
Reaction time: 20 h

Procedure:
Ethyl cyanoacetate (77.0 g.) was slowly added at 40° C. to a stirred solution of sodium (15.7 g.) in ethanol (400 ml.) and 15 minutes after the addition was completed 1-bromo-3,3-dimethylallene (100 g.) was carefully added over about 30 minutes. The mixture was then heated at the reflux temperature for a period of 2.5 hours and then kept at the ambient temperature for a further 20 hours. The mixture was then poured into an excess of water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent. The residual oil was distilled and ethyl 2-cyano-3,3-dimethylpent-4-ynoate was obtained as a colourless oil (boiling point 75°-76° C./0.1 mm Hg.).
Reaction SMILES: [I-].[CH3:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[N+:14]([CH2:18][CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[BH4-].[Na+]>CO>[CH3:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCC[n+]1cccc(-c2ccc([N+](=O)[O-])c(C)c2)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCCN1CCC=C(c2ccc([N+](=O)[O-])c(C)c2)C1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To MeOH (200 mL) was added 3-(3-methyl-4-nitrophenyl)-1-propylpyridinium iodide (9.4 g, 22.7 mmol). The solution was stirred at −10° C. for 10 min followed by the slow portionwise addition of solid NaBH4 (2.8 g, 68.1 mmol, Aldrich) over 5 min. The reaction was kept stirring at −10° C. for 1 h. The mixture was concentrated and diluted with Ethyl acetate (200 mL) before the addition of sat. NaHCO3 aq (150 mL). The organic phase was washed with brine, concentrated, and dried (Na2SO4). Purification via chromatography on SiO2 (0-10% MeOH/DCM) afforded 5-(3-methyl-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (t, J=7.3 Hz, 3 H), 1.48-1.57 (m, 2 H), 2.29 (td, J=5.7, 3.2 Hz, 2 H), 2.39-2.43 (m, 2 H), 2.51 (t, J=5.7 Hz, 2 H), 3.26 (d, J=1.8 Hz, 2 H), 3.94 (s, 3 H), 6.43 (ddd, J=3.8, 2.2, 2.0 Hz, 1 H), 7.10 (dd, J=8.5, 1.7 Hz, 1 H), 7.23 (d, J=1.8 Hz, 1 H), 7.83 (d, J=8.4 Hz, 1 H); ESIMS (M+H)+=261.