Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]#[N:21])([C:14](OCC)=[O:15])[C:10](=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[Pt]=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:14](=[O:15])[NH:21][CH2:20][CH2:19]2)[CH:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Agent: O=[Pt]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCC12CCN(Cc1ccccc1)CC2O
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a flask charged with ethyl 1-benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate (900 mg, 3.0 mmol) and a stir bar was added platinum oxide (100 mg, 0.44 mmol), MeOH (20 mL) and acetic acid (20 mL). The mixture was allowed to stir vigorously under an atmosphere of hydrogen for 24 hours. LC indicated complete reaction at that point. The catalyst was removed by filtration through a pad of CELITE®, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (100 mL), and K2CO3 was added (2.1 g, 15 mmol). The mixture was heated to 90° C. for 4 hours. The reaction was cooled, and DCM was added (200 mL) to precipitate the solids. The solids were then removed by filtration, and the crude reaction was adsorbed onto silica gel, and flushed out with DCM and 10% MeOH (mixed with 10% NH4OH) to give the title compound. LCMS: m/z 261 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:22][CH3:23])[C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=2[NH:11][C:10](=[O:24])[CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCCl>[CH2:29]([O:28][C:26]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([O:22][CH3:23])[C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=2[NH:11][C:10](=[O:24])[CH2:9]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(Cc1ccccc1)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCCl
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of (4-benzyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (900 mg, 3.0 mmol) in 1,2-dichloroethane (150 mL) was added benzyl chloroformate (900 mg, 3.0 mmol). The mixture was warmed to reflux for four hours whereupon LCMS indicated completion of reaction. The mixture was cooled to ambient temperature, washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (EtOAc-hexanes) gave 7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (390 mg, 40%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.67 (s, 1H), 7.30 (m, 6H), 5.09 (s, 2H), 4.67 (s, 2H), 3.90 (s, 2H), 3.77 (s, 3H); MS (m/e) 372 (M+1); mp 191° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36](B(O)O)[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CO>[C:1]([O:5][C:6](=[O:33])[N:7]([CH3:8])[CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:36]2[CH:35]=[N:34][C:43]3[C:38]([CH:37]=2)=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:15]([C:20]#[C:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccc3ccccc3c2)n1)N(C)C(=O)OC(C)(C)C
Reactant: OB(O)c1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C(=O)Nc1ccc(-c2cnc3ccccc3c2)c(C#Cc2ccc3ccccc3c2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-naphthalen-2-ylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate C2c (150 mg, 0.30 mmol), quinolin-3-ylboronic acid (61 mg, 0.35 mmol), Dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.06 mmol), Na2CO3 (63 mg, 0.59 mmol), dioxane (1 ml), MeOH (0.2 ml) and water (0.1 ml) is stirred under argon atmosphere for 2 h at 85° C. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by RP HPLC. Yield: 91 mg (55%).
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8].[CH3:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:19].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[O:28]=[C:27]([NH:10][NH:9][C:7]([C:6]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([F:14])([F:15])[F:2])[CH:5]=1)=[O:8])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([O:17][CH3:16])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a solution of 3-(trifluoromethyl)benzohydrazide hydrochloride (2.3 g) in N,N-dimethylformamide (20 mL) were added the compound (1.8 g) obtained in Example 206a, N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (3.50 g), 1-hydroxybenzotriazole (1.25 g) and triethylamine (4.68 g). The reaction mixture was stirred at room temperature overnight, poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.0 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11](OC(Cl)(Cl)Cl)=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cl)cc1F
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a stirred solution of 20.0 grams (0.13 mole) of 4-chloro-2-fluoroaniline in 250 ml of toluene was added dropwise a solution of 17.2 ml (0.13 mole) of trichloromethyl chloroformate in 40 ml of toluene. Upon completion of addition the reaction mixture was heated to reflux where it stirred for 16 hours. The solvent was separated from the reaction mixture by distillation to yield 21.8 grams of 4-chloro-2-fluorophenyl isocyanate as an oil. The reaction was repeated several times.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:36]=[O:37]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH:36]=[O:37])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
In an argon atmosphere, tris(4-bromophenyl)amine (964 mg, 2.00 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to −78° C. n-Butyl lithium (a 1.6 mol/L hexane solution, 1.5 mL, 2.4 mmol) and dimethylformamide (0.19 mL, 2.4 mmol) was dripped thereto at a system temperature of −60° C. or less, followed by stirring for 10 minutes. To the reaction liquid was added water and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=8/1) to give 4-[bis(4-bromophenyl)amino]benzaldehyde (377 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C@@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:11])[CH:6]=[CH:5][N:4]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:18]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:11][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccnc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-(2-methoxy-4-pyridinyl)alaninate (1.47 g, 6.56 mmol), N-α-t-boc-glycine (1.26 g, 7.22 mmol, Aldrich, St. Louis, Mo.), HATU (2.99 g, 7.87 mmol, Aldrich, St. Louis, Mo.) and N,N-diisopropylethylamine (3.42 mL, 19.68 mmol, Aldrich, St. Louis, Mo.) in DMF (6 mL). The reaction mixture was stirred room temperature for 18 h, diluted with water (50 mL), and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give ethyl N-(tert-butoxycarbonyl)glycyl-3-(2-methoxy-4-pyridinyl)alaninate (2.31 g) as a colorless oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][C@H:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C@H:5]([C:31](O)=[O:32])[CH2:4]1)=[O:2].[NH2:34][OH:35]>>[CH:1]([N:3]1[CH2:7][C@H:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[C@H:5]([C:31]([NH:34][OH:35])=[O:32])[CH2:4]1)=[O:2]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 52 %

Procedure:
According to the procedure of Example 17, Step 5, the reaction of 175 mg of cis-1-formyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid with hydroxylamine provided 76 mg (52% yield) of cis-1-formyl-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxamide. MS: 485.2 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[N:14]1([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[N:14]1([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[CH:2][C:1]([C:4]3[CH:13]=[CH:12][C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=3)=[O:3])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccc(N2CCCC2)cc1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(N2CCCC2)cc1)c1ccc2c(c1)CCCC2

Procedure:
A solution of 2.6 g of 1 (15 mmol), 2.6 g of p-pyrrolidinylbenzaldehyde (15 mmol), and 0.66 g of sodium hydroxide in 100 ml of ethanol was stirred under nitrogen at 50° for 24 hr. The reaction mixture was cooled in an ice bath, and the precipitated yellow solid 3-[4-(1-pyrrolidinyl)phenyl]-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-one was collected by filtration and washed with cold ethanol. Yield: 3.2 g (64%); m.p. 167° to 169°. λmax (CHCl3): 420 nm (ε=36,800); 330 nm (4,300); 276 nm (16,400). Calcd for C23H25NO: C, 83.34; H, 7.60; N, 4.23. Found: C, 82.68, 82.67; H, 7.57, 7.55; N, 4.03, 4.15.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26]([O:28]C)=[O:27])[CH2:11]2)=[CH:6][CH:5]=1.CC(C)([O-])C.[K+]>>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]3)=[O:17])[CH2:13][CH:12]([C:26]([OH:28])=[O:27])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1

Procedure:
According to General Method 4A, 2.7 g (6.1 mmol) of methyl 5-[4-(difluoromethoxy)phenyl]-1-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]piperidine-3-carboxylate were reacted with 6.9 g (61.3 mmol) of potassium tert-butoxide. Yield: 2.1 g (77% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[CH:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH:14]=[O:15])=[CH:17]1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (10 ml) was added 3-formylindole (623 mg) and potassium carbonate (593 mg), the mixture was heated at 90° C. for 1.5 hrs. The reaction was cooled to room temperature and diluted with water (200 ml) and extracted with ether (200 ml). The organic fraction was separated and evaporated to dryness to give the title compound as a pale yellow crystaline material, m.p. 167-169° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CCOC(C)=O>[OH:49][CH:46]1[CH2:45][CH2:44][N:43]([C:40]2[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:38][CH:39]=2)[CH2:48][CH2:47]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCC(O)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was 1-(4-amino-phenyl)-piperidin-4-ol (prepared below, 48.3 mg, 0.251 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and Hexanes (40 mL). The precipitate that formed was then filtered and washed with 0° C. iPrOH (5 mL) to afford the title compound in 24% yield (0.034 g, 0.06 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:19]([C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)#[N:20]
Reactant: Brc1cccc(-c2nc(-c3ccccn3)co2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-c2nc(-c3ccccn3)co2)c1
Temperature: 80 °C
Yield: 32 %

Procedure:
A mixture of 2-[3-bromophenyl]-4-[pyridin-2-yl]-1,3-oxazole (23 mg, 0.076 mmol) and zinc cyanide (112 mg, 0.96 mmol) in N,N-dimethylformamide (2 mL) was treated with Pd(PPh3)4 (74 mg, 0.064 mmol) and heated overnight at 80° C. Standard work up and chromatography afforded 6 mg (32%) of 2-[3-cyanophenyl]-4-[pyridin-2-yl]-1,3-oxazole as a white solid. 1H-NMR (CDCl3), δ (ppm): 8.61 (d, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 8.36 (m, 1H), 8.00 (d, 1H), 7.80 (m, 2H), 7.61 (t, 1H), 7.23 (m, 1H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>O1CCCC1.Cl>[C:1]([NH:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of benzoic acid hydrazide (5.70 g, 0.042 mol) in tetrahydrofuran (75 mL) was added acetophenone (5.5 g, 0.046 mol) followed by concentrated HCl (3 drops). The reaction was allowed to stir for 12 h at 25° C. during which time the product precipitated as a colorless crystalline solid. The product was filtered, washed with tetrahydrofuran (1×30 mL), diethyl ether (3×60 mL) and pentane (2×60 mL), and the crystalline solids were dried in vacuo (6.65 g, 64%). 1H NMR (CD2Cl2): δ2.35 (s, 3H, CH3), 7.30-8.0 (m, 10H, Ph), 9.0 (br, 1H, NH). All other substrates were prepared in a similar fashion.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(SC)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
The methyl 2-hydroxy-4-(methylthio)benzoate (4.00 g, 20.2 mmol) was dissolved in THF (300 mL). The solution was cooled to 0° C. and the N-Boc-4-hydroxypiperidine (4.07 g, 20.2 mmol) and triphenylphosphine (6.35 g, 24.2 mmol) were added, followed by diethyl azodicarboxylate (4.0 mL, 25.4 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and left overnight. The reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (about 500 g silica, 15% EtOAc/hexanes tthrough 20% EtOAc/hexanes) to give the desired product (7.185 g, 18.83 mmol, 93%).
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[CH2:43]([O:45][N:46]=[C:47]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)[C:48](Cl)=[O:49])[CH3:44].O>C(OCC)(=O)C.O1CCCC1>[CH2:43]([O:45][N:46]=[C:47]([C:51]1[N:55]=[C:54]([NH2:56])[S:53][N:52]=1)[C:48]([NH:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:49])[CH3:44]
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
A mixture of benzhydryl 7-amino-3-[2-(2-pyridyl)-vinyl]-3-cephem-4-carboxylate (trans isomer) (25 g) and N-(trimethylsilyl)acetamide (4.2 g) in ethyl acetate (20 ml) and tetrahydrofuran (10 ml) was stirred at ambient temperature for 20 minutes to give a clear solution. To the solution was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetylchloride (syn isomer) (1.4 g) at -15°~-20° C. and stirred at the same temperature for 30 minutes. Water (20 ml) was added to the resulting solution, and the separated organic layer was washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Li]CCCC.C1CCCCC1.[CH:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[C:28]([Cl:33])[CH:29]=[C:30](Cl)[N:31]=2)=[CH:24][CH:25]=1>C1COCC1.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:33][C:28]1[N:27]=[C:26]([C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[N:31]=[C:30]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:29]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloroaniline (127.6 mg, 1 mmol) in dry THF (2 mL) was cooled in a dry-ice/acetone bath and treated dropwise with a solution of nBuLi in cyclohexane (0.5 mL, 2M, 1 mmol). The mixture was treated with additional dry THF (2 mL) and was allowed to warm slightly (˜15 minutes) till the material went into solution. The material was then transferred by cannula into a solution of fenclorim (XXII) (225 mg, 1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol) in dry THF (2 mL). Rinsed with dry THF (2 mL) and stirred at room temperature for 30 minutes. The reaction was partitioned between saturated sodium bicarbonate and ethyl acetate. Added brine to help clear an emulsion. Separated layers and the aqueous layer was extracted twice with ethyl acetate. The combined organics was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield a film. The film was taken up in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate/hexanes followed by 20% ethyl acetate/hexanes. The appropriate fractions were concentrated to yield 6-chloro-N-(4-chlorophenyl)-2-phenylpyrimidin-4-amine (XXIII) as a film (161.87 mg). ESI/MS 315.9, 317.9 (M+H), 314.0, 316.0 (M−H).