Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CC)(CC)[C:4]1[O:5][CH:6]=[CH:7][N:8]=1)C.[CH2:13]([N:16]([CH2:30][CH2:31][CH3:32])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27](I)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:14][CH3:15]>CN(C)C=O>[CH2:30]([N:16]([CH2:13][CH2:14][CH3:15])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([C:4]2[O:5][CH:6]=[CH:7][N:8]=2)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:31][CH3:32]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: CC[Sn](CC)(CC)c1ncco1
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A stirred solution of 2-triethylstannyloxazole (Chem. Mater. 1994, 6, 1023) (1.5 g, 5.5 mmol) and methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.8 g, 4.6 mmol) in dimethylformamide (12 mL) was degassed under reduced pressure for 15 min and purged with argon. Palladium(0)tetrakis(triphenylphosphine) (158 mg, 0.14 mmol) was added and the reaction mixture was degassed under reduced pressure for 15 min and then purged with argon. The reaction mixture was heated at reflux for 2 d, cooled to room temperature, diluted with ethyl acetate, washed with water (3×50 mL), dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided methyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (423 mg): 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 3.97 (s, 3H), 3.49 (br s, 2H), 3.18 (br s, 2H), 1.72 (d, J=7 Hz, 2H), 1.55 (d, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH:30]=O)=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:8])=[O:7])=[CH:2]1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH2:30][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:8])=[O:7])=[CH:2]1
Reactant: C1CCNC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Yield: 70.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.0650 g, 0.114 mmol) was dissolved in acetonitrile (5.0 mL), and the solution was treated with pyrrolidine (0.191 mL, 2.29 mmol), acetic acid (0.131 mL, 2.29 mmol) and sodium triacetoxyborohydride (0.0730 g, 0.343 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15, 80/20) to obtain 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.0501 g, 70%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][CH:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:11][C:12]=2[C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH3:19])[C:14]=2[CH:20]=1)=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:18][C:16]1[N:15]([CH3:19])[C:14]2[CH:20]=[C:6]([C:4]([OH:5])=[O:3])[C:7]3[CH2:8][CH2:9][CH:10]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:11][C:12]=3[C:13]=2[N:17]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a suspension of 3.4 g (9.6 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid ethyl ester in 100 ml dioxane and 25 ml water were added 1.4 g (57.7 mmol) lithium hydroxide and the reaction refluxed for 6 h. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 2 M HCl solution. The precipitate was filtered off and crystallized with n-butanol to afford 3.0 g (96%) of the title compound as a beige solid of m.p. 323°-326° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH:6]([C:17]#[N:18])[C:5]=2[CH:4]=1.BrC1C=CC2C3C(=CC(Br)=CC=3)CC=2[C:21]=1[CH:34]=[O:35]>>[CH2:34]([O:35][C:17]([CH:6]1[C:5]2[CH:4]=[C:3]([Br:2])[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=2)=[NH:18])[CH3:21]
Reactant: N#CC1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: O=Cc1c(Br)ccc2c1Cc1cc(Br)ccc1-2
Agent: Cl
Product: CCOC(=N)C1c2cc(Br)ccc2-c2ccc(Br)cc21

Procedure:
Dry hydrogen chloride is passed into a solution of 2,7-dibromo-9H-fluorene-9-carbonitrile [obtainable e.g. from the corresponding 2,7-dibromo-9H-fluorene carboxaldehyde (J. Org. Chem., 1944, 9, 155) by oximation and dehydration] by a process analogous to that described in Example 1(a). After working up by a procedure similar to that described in Example 1(a) the product can be used crude or purified before use in Example 2(b) below.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15](CBr)=[CH:14][CH:13]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:3]([O:10][C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 92.7 %

Procedure:
To a solution of 1.07 g (26.8 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (80 ml) was added 4.02 g (21.5 mmol) of benzyl alcohol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. To the reaction mixture was then added 4.47 g (17.9 mmol) of 4-bromobenzyl bromide, and the mixture was allowed to react at room temperature for 19 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (1:2) yielded 4.61 g (16.6 mmol) of 4-bromophenyl benzyl ether.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:12][O:11][C:1](=[O:10])[CH2:2][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccccc1
Product: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Yield: 59 %

Procedure:
A solution of methyl cinnamate (4.93 g, 30.4 mmol) and teteramethylguanidine (3.99 g, 34.6 mmol) in nitromethane (30 ml) was stirred for 6 hours at 90° C. After removal of the solvent under reduced pressure, the residue was partitioned between water and ethyl acetate, and the organic layer was washed with water and brine and then dried over sodium sulfate. The organic solvents were removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=4/1) to afford 4-nitro-3-phenyl-butyric acid methyl ester (4.02 g, 59%)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)sc23)c1
Temperature: 80 °C

Procedure:
0.67 ml of 2 M aqueous sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 68.1 mg (0.45 mmol) of 3-methoxyphenylboronic acid in 2 ml of DMF. The reaction mixture is heated at 80° C. for 17 h, filtered through kieselguhr and evaporated to dryness. A purification by preparative HPLC is followed by column chromatography on silica gel (mobile phase: dichloromethane/methanol-/ammonia 90:9:1). The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1N hydrochloric acid and again concentrated. Drying under high vacuum results in 97.7 mg (48% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:28])=[C:6]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])[C:10]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:9]2)[CH:7]=1.[C:29](Br)(=[O:32])[CH2:30][CH3:31]>CN(C1C=CN=CC=1)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:11]2[C:10]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:9][N:8]([C:6]3[CH:7]=[C:2]([NH:1][C:29](=[O:32])[CH2:30][CH3:31])[CH:3]=[CH:4][C:5]=3[Cl:28])[C:12]=2[C:13]#[N:14])=[C:17]([F:23])[CH:18]=1
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Yield: 73 %

Procedure:
The acylation of 1-(5-amino-2-chlorophenyl)-4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1H-pyrazole-5-carbonitrile (from Step G) with propionyl bromide in the presence of DMAP followed the procedure of Example 1, Step J. Flash chromatography of the crude product on silica gel (gradient elution with 5:1 to 3:1 hexane-EtOAc) afforded a 73% yield of the title compound as a tacky oil; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 517, 519 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 1.22 (t, J=7.6 Hz, 3H), 1.32 (m, 2H), 1.54 (m, 2H, partially obscured by H2O peak), 2.38 (q, J=7.6 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 3.92 (s, 2H), 7.02 (dd, J≈8, 8.5 Hz, 1 H), 7.22-7.26 (m, 2H), 7.4-7.5 (m, 2H), 7.90 (d, J=2.2 Hz, 1H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:13]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH:13]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)#[CH:5]
Reactant: CN1CCC(OC(c2cccc(C#C[Si](C)(C)C)c2)c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[(3-trimethylsilylethynylphenyl)(1-methylpiperidin-4-yloxy)-methyl]-1H-benzimidazole (205 mg) in methanol (2 mL) is added potassium carbonate (81 mg). The reaction mixture is stirred at room temperature for 4 hours, then methanol is removed under reduced pressure. The residue is dissolved in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and solvent is removed under reduced pressure to give 2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32]([C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[O:33]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH2:11][C:12]([NH:40][S:37]([CH2:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]=2[C:32]([O:31][CH3:30])=[O:33])(=[O:38])=[O:39])=[O:14])[N:6]=1
Reactant: COc1cc(OC)nc(CC(=O)O)n1
Reactant: COC(=O)c1ccccc1CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1CS(=O)(=O)NC(=O)Cc1nc(OC)cc(OC)n1
Reaction time: 1 h

Procedure:
A solution of 1.9 g of (4,6-dimethoxypyrimidin-2-yl)acetic acid in 40 ml of absolute dichloromethane is added dropwise at 0° C. to 2° C. to a solution of 1.9 g of dicyclohexylcarbodiimide, 100 mg of 4-dimethylaminopyridine and 2.1 g of 2-methoxycarbonylbenzylsulfonamide in 40 ml of absolute dichloromethane. Stirring is continued for 1 hour at 0° C., and the mixture is allowed to come to room temperature and stirred for another 0.5 hour. The solids are filtered off, and the filtrate is concentrated in a rotary evaporator. 100 ml of 2 N sodium carbonate solution are added to the residue, the mixture is stirred for 0.5 hour at room temperature, and the solids are filtered off with suction. The sodium carbonate alkaline phase is extracted twice using diethyl ether, and a pH of 2-3 is established using concentrated hydrochloric acid. Stirring is continued for 15 minutes, the solids are filtered off with suction, the filter residue is washed once with water and twice with ether, and dried in vacuo. This gives 2.4 g of N-[2-(4,6-dimethoxypyrimidin-2-yl)acetyl]-2-methoxycarbonylbenzylsulfonamide of melting point 98°-101° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([NH:25][CH2:26][CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:28][CH2:27][CH2:26][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCNCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and benzylethylenediamine in DME. ES-MS m/e (%): 335 (M+H+, 100), 228 ([M+H-BnNH2]+, 45).
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH2:3][O:4][CH3:5].C(=O)=O.S(Cl)([Cl:17])(=O)=O>>[F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[CH2:3][O:4][CH2:5][Cl:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCC(F)(F)C(F)(F)F
Agent: O=C=O
Product: FC(F)(F)C(F)(F)COCCl
Temperature: 33 °C

Procedure:
Methyl 2,2,3,3,3-pentafluoropropyl ether (225g, 1.37 mole) in a flask fitted with a dry ice cooled condensor and moisture trap was stirred, heated to 33°C, irradiated with ultraviolet light, and sulfuryl chloride (174 g, 1.29 mole) was added dropwise. The reaction temperature dropped to about 0°C as SO2 returned from the condensor. The condensor was allowed to warm gradually to permit SO2 to escape and the reaction temperature to rise to about 33°C to complete the chlorination. The product was washed with ice cold water then with dilute sodium hydroxide solution to remove SO2 and dried to give 250 g of crude XXVII. This was fractionally distilled to give XXVII, b760 87.1-88.5; yield 159 g, purity 92% by GLC. The structure of XXVII was confirmed by proton NMR spectroscopy.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].C(NC(C)C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.COC1C=C(OC)C=C(OC)C=1P(C1C(OC)=CC(OC)=CC=1OC)C1C(OC)=CC(OC)=CC=1OC.[C:83]1([Sn](CCCC)(CCCC)CCCC)[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85][CH:84]=1>C1COCC1.CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:83]1([C:8]2[CH2:9][C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:24](=[O:25])[N:6]3[C:7]=2[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85][CH:84]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: [Pd]
Agent: COc1cc(OC)c(P(c2c(OC)cc(OC)cc2OC)c2c(OC)cc(OC)cc2OC)c(OC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C3=CCCCCC3)C[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 348 mg (1 mmol) of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl) -2-oxo-1-carbapenam-3-carboxylate in THF (5 ml) was added 0.154 ml (1.1 mmol) of diisopropylamine at -78° C., and the mixture was stirred for 10 minutes. To the mixture was added 0.189 ml (1.08 mmol) of trifluoroacetic anhydride at the same temperature. After 15 minutes, to the mixture was added 5 ml of N-methylpyrrolidinone followed by 20.7 mg of tris(dibenzylideneacetone)dipalladium-chloroform, 42.5 mg (0.08 mmol) of tris(2,4,6-trimethoxyphenyl)phosphine, a solution of 389 mg (1.01 mmol) of cyclohepten-1-yl(tri-n-butyl)tin in N-methylpyrrolidinone (1 ml) and a solution of 225 mg (1.66 mmol) of N-methylpyrrolidinone (2 ml). The -78° C. bath was removed and the reaction mixture quickly raised to ambient temperature using a lukewarm water bath, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ethyl ether and the organic layer was washed with water followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (elution with ethyl acetatehexane system) to give 148 mg (yield: 34.7%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[N:13]=1)=[N:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:23][O:22][C:14]1[N:13]=[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:38])[F:40])=[CH:33][N:32]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: COc1ccc(C(F)(F)F)c(-c2ccc3c(Cl)ccnc3n2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(F)(F)F)c(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)n1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a de-gassed mixture of 5-chloro-2-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (68 mg, 0.2 mmol), cesium carbonate (98 mg, 0.3 mmol), 2-amino-5-trifluoromethylpyridine (37 mg, 0.22 mmol) in dioxane (5 mL) under nitrogen, add Pd2 dba3 (12 mg) and xantphos (8 mg). Stir the mixture at 100° C. for 14 hours, cool, add water (20 mL) and extract with EtOAc. Dry the combined extracts over Na2SO4, concentrate under vacuum. Purify by chromatography eluting with DCM/MeOH/ammonium hydroxide mixture to give the title compound. 1H NMR δ (CDCl3) 9.01 (1H, brs), 8.59-8.62 (2H, m), 7.98-8.01 (2H, m), 7.91-7.84 (2H, m), 7.23-7.26 (2H, m), 6.90 (1H, d), 3.99 (3H, s). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:13][CH:14]2[N:19]([N:20]=O)[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH2:15]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1COCC1>[N:7]1([CH2:13][CH:14]2[N:19]([NH2:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH2:15]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=NN1c2ccccc2OCC1CN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1c2ccccc2OCC1CN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 56 g of lithium aluminum hydride in 500 ml of THF was added the (-)-3-(4 -morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine described above while cooling the reaction mixture to 0° C. with an external cooling bath. When addition was complete the cooling bath was removed, the reaction mixture was stirred for one hour at ambient temperature, cooled again to 0° C. and the excess hydride carefully quenched by the dropwise addition of 5 ml of water, followed by 8 ml of 10% aqueous sodium hydroxide, followed by an additional 5 ml of water. The mixture was stirred, filtered through filter aid, and the filtrate taken to dryness to afford 14.3 g of (-)-3-(4-morpholinylmethyl)-4-amino-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further characterization or purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1.Cl>CCOC(C)=O>[NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:3]=1[C:23]#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(N)c2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1c(N)cccc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 34d, 1.33 g, 4.0 mmol) in EtOAc (20 mL) was added dropwise aqueous HCl solution (12 N, 6.6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound (100%) as a brown solid, which is pure enough and used directly in the next step without further purification. MS 232 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1OS(C(F)(F)F)(=O)=O.[CH3:28][C:29]([CH3:34])=[CH:30]B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:28]=[C:29]([CH3:34])[CH3:30]
Reactant: CC(C)=CB(O)O
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OS(=O)(=O)C(F)(F)F)c1
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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=C(C)C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
To a stirred solution of 83.26C (0.500 g, 1.2 mmol) in DMF (6.1 mL) at 23° C. was added 2-methylprop-1-enylboronic acid (0.24 g, 2.4 mmol, commercially available from Synthonix), and potassium carbonate (0.51 g, 3.7 mmol). Tetrakis(triphenylphosphine)palladium (0.071 g, 0.061 mmol) was then added to the mixture. The mixture was heated to 90° C. and stirred for 15 hours. The reaction was then cooled to room temperature, diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 83.26D as a colorless oil (0.280 g, 73% yield).