Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:37]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:38][C:39]([O-])=[O:40].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:39](=[O:40])[CH2:38][C:37]([O:43][CH2:44][CH3:45])=[O:42])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2C1C(=O)OCC
Yield: 74 %

Procedure:
A solution of ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.72 g), monoethyl malonate (0.94 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 g), triethylamine (1.78 g) in dichloromethane (20 ml) is stirred overnight at room temperature. The reaction mixture is washed with water and dried over sodium sulfate and then evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.57 g) as an oil.
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[O:13][CH:14]=2)=[CH:6][CH:7]=1.[CH2:27]([N:31]1[CH:35]=[CH:34][N:33]=[N:32]1)[CH2:28][C:29]#[CH:30].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu](I)I.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>[N:31]1([CH2:27][CH2:28][C:29]#[C:30][C:2]2[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]3[N:11]=[C:12]([CH:15]=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[O:13][CH:14]=3)=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=[N:32]1
Reactant: C#CCCn1ccnn1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(I)nn3)co2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(C#CCCn4ccnn4)nn3)co2)cc1
Reaction time: 3 h

Procedure:
3-Iodo-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine (0.114 g, 0.25 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (0.040 g, 0.30 mmol) and triethyl amine (NEt3) (0.125 ml) are dissolved in THF (1 ml) and copper iodide (CuI) (0.0048 g, 0.025 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min bis(triphenylphosphine)palladium(II) dichloride (0.088 g, 0.0125 mmol) is added and stirring is continued for 3 h at r.t. Ethyl acetate (30 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl) and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:3->ethyl acetate (100%)) yielding 3-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine as a colorless solid. Yield 93 mg (64%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:36])[CH2:12][CH:13]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:59][O:60][C:61](=[O:65])[CH2:62][CH2:63][NH2:64].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:59][O:60][C:61](=[O:65])[CH2:62][CH2:63][NH:64][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:14](=[O:15])[CH:13]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:29][CH:30]=2)[CH2:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[O:36])=[CH:17][CH:18]=1
Reactant: COC(=O)CCN
Reactant: CC(C)(C)c1ccc(C(=O)CC(C(=O)c2ccc(C(=O)O)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(C(=O)C(CC(=O)c2ccc(C(C)(C)C)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Yield: 104.8 %

Procedure:
4-[4-(4-tert-Butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoic acid (10.4 g, 20.86 mmol) was dissolved in DMF (150 mL) and added EDAC (5.60 g, 29.20) and HOBt (4.23 g, 31.29 mmol). After ½ h a solution of beta-alanine methyl ester hydrochloride (4.37 g, 31.29 mmol) and DIPEA (5.36 mL, 31.29 mmol) in DMF (20 mL) was added to the above mixture and the reaction mixture was stirred night over. The reaction was concentrated to approximately 100 mL and diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The water phase was extracted with additional ethyl acetate (75 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×150 mL), aqueous sodium chloride (50% saturation, 3×150 mL) and dried over magnesium sulphate. The dried organic phase was filtered and evaporated to dryness to afford 3-{4-[4-(4-tert-butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoylamino}propionic acid methyl ester (12.76 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1ccc(NC(=O)CCl)cc1
Solvent: CCCCCC
Product: COc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methoxy-phenyl)-acetamide [J. Heterocycl. Chem., 32, 1429. (1995)] and 4-benzyl-piperidine according to the method described in Example 143b. Melting Point: 81-83° C. (hexane)
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]([P:28](=[O:33])([OH:32])[O:29][CH2:30][CH3:31])#[C:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:34]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)#[CH:35]>[Au].ClC(Cl)C>[CH2:30]([O:29][P:28]1(=[O:32])[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:35]=[C:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[O:33]1)[CH3:31]
Reactant: C#CC1CCCCC1
Reactant: CCCCC#CP(=O)(O)OCC
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(C2CCCCC2)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]|SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen hex-1-ynylphosphonate (57.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, ethynylcyclohexane (64.9 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-cyclohexyl-1,2-oxaphosphorin 2-oxide (42.1 mg, 47%) which is a title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([O:24]C)=O)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:34][NH2:35]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:34][NH2:35])=[O:24])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: O
Solvent: CO
Product: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate (compound 215.5, 2.15 g, 4.99 mmol, 1.00 equiv) in methanol (20 mL), was added hydrazine hydrate (80%, 15 mL) batchwise. The reaction was stirred at 80° C. overnight. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:1) to furnish 1.13 g (53%) of the desired product as a pinkish solid.
Reaction SMILES: C([O:5]C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:55])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([S:27]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35]([C:39]([NH:41][C:42]([CH2:46]C)(CC)C)=[O:40])[CH2:34][CH2:33]4)(=[O:29])=[O:28])[C:18]2=[O:48])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>C(Cl)Cl>[OH2:5].[F:59][C:58]([F:61])([F:60])[C:56]([OH:62])=[O:57].[Cl:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:27]([C:30]1[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([N:41]([CH2:42][CH3:46])[CH2:56][CH3:58])=[O:40])[CH2:34][CH2:33]3)(=[O:28])=[O:29])[C:18](=[O:48])[C:17]2([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])[NH:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCC(C)(CC)NC(=O)N1CCc2cc(S(=O)(=O)N3C(=O)C(NCCC4CCN(C(=O)OC(C)(C)C)CC4)(c4ccccc4Cl)c4cc(Cl)ccc43)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)N3C(=O)C(NCCC4CCNCC4)(c4ccccc4Cl)c4cc(Cl)ccc43)ccc21
Product: O
Reaction time: 0.25 h

Procedure:
A solution of 1.17 g of the compound obtained in EXAMPLE 222 in 7.5 ml of DCM is cooled to +4° C., 15 ml of TFA are added and the reaction mixture is stirred for 3 hours 15 minutes at +4° C. It is concentrated under vacuum, the residue is taken up with DCM and the solvent is evaporated off under vacuum, this operation being repeated twice. The residue is taken up with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 0.6 g of the expected product after trituration in iso ether and then crystallization from a DCM/iso ether mixture. M.p.=133° C.
Reaction SMILES: [CH:1](N)([CH3:3])[CH3:2].[Li]CCCC.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11]C(C)C.[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[OH:29][C:28]([CH:1]([CH3:3])[CH3:2])([CH2:27][CH2:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11][C:10]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(C)C
Reactant: O=CCCCCc1ccccc1
Reactant: CC(C)N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CC(O)(CCCCc1ccccc1)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.4 mL (18.49 mmol, 1.5 eq) of isopropylamine in 50 mL of dry THF at -78° C. under argon is added 9.3 mL (14.8 mmol, 1.2 eq) of 1.6 M BuLi in hexanes solution. This is stirred at -78° C. for 1 hour at which time 1.8 mL (13.56 mmol, 1.1 eq) of methyl isovalerate is added dropwise. This mixture is stirred at -78° C. for 1.5 hours at which time 2 g (12.33 mmol) of 5-phenylpentanal in 10 mL of dry THF is added dropwise. This is stirred at -78° C. for 1 hour, then allowed to warm slowly to 0° C. over 3 hours. The reaction is quenched with saturated NH4Cl solution and then partitioned between ether and saturated NH4Cl solution. The organics are dried (Na2SO4) and concentrated in vacuo. The product is purified by flash silica gel chromatography to afford methyl 3-hydroxy-3-isopropyl-7-phenylheptanoate in the form of a yellow oil. (0.88 g, 26%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 0.95(t, 6H), 1.45(m, 3H), 1.6(m, 3H), 2.08(bs, 1H), 2.15(m, 1H), 2.35(t, 1H), 2.6(t, 2H), 3.68(s, 3H), 3.85(bm, 1H), 7.15(m, 3H), 7.25(m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3=[C:15]([OH:32])[C:16]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5[O:30][CH3:31])[C:20](=[O:21])[C:17]=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:37])[C@@H:3]1[OH:38].[C:39]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=O)[CH3:40].C1(C)C=CC=CC=1.CC(C)=O>C(Cl)Cl>[CH3:47][CH2:46][O:45][C:43](/[CH:42]=[C:39](/[NH:37][C@@H:4]1[C@H:3]([OH:38])[C@H:2]([CH3:1])[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:13](=[C:18]([OH:19])[C:17]4[C:20](=[O:21])[C:22]5[CH:23]=[CH:24][CH:25]=[C:26]([O:30][CH3:31])[C:27]=5[C:28](=[O:29])[C:16]=4[C:15]=3[OH:32])[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5]1)\[CH3:40])=[O:44]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)/C=C(\C)N[C@H]1C[C@H](O[C@H]2C[C@](O)(C(C)=O)Cc3c(O)c4c(c(O)c32)C(=O)c2c(OC)cccc2C4=O)O[C@@H](C)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.53 gram of daunorubicin in a free base is dissolved in 100 ml of methylene chloride. 1 ml of ethyl acetylacetate is added to the solution by constant stirring. The entire mixture is agitated for 12 hours at room temperature in a nitrogenic atmosphere. The reaction is checked by means of thin-layer chromatography on a silica gel in a toluene-acetone system in a ratio of 8:1. The solution is then evaporated until a small volume of composition remains and, the final product is pecipitated by the addition of a mixture of ethyl ether and hexane in a ratio of 1:1. The precipitated results from the mixture of acetone and ethyl ether. 0.4 g of N-(1-carboethoxy-propen-1-yl-2)-daunorubicin is obtained which corresponds to 60 percent of the theoretical yield. The composition decomposes at 151°-154° C., M.S.F.D. m/z 639 (M+, 80 percent of relative intensity); 640 (M+ +1, 100 percent of relative intensity); IR (KBr)ν=1590, 1610, 1650, 1670, 1715, 1720, cm-1 (chelate and free carbonyl groups).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
A mixture of 6-bromopicolinic acid (2.02 g, 10 mmol), phenyboronic acid (1.22 g, 10 mmol), cesium carbonate (5.00 g) and PdCl2[(t-Bu)2P(OH)]2 (70 mg, CombiPhos Catalysts, Inc. Princeton, N.J.) in DMF (20 mL) and water (3 mL) was purged with Ar-gas and heated at 110° C. for 24 h. The reaction was incomplete and did not progress further. To the reaction mixture were added EtOAc (200 mL) and 1 N aq. HCl (40 mL). The EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product (350 mg, 18%) as a white solid. 1H NMR (CDCl3) δ 10.45 (s, 1H), 8.18-7.96 (m, 5H), 7.51-7.53 (m, 3H).
Reaction SMILES: [CH3:1]/[C:2](/[O:8][Si](C)(C)C)=N\[Si](C)(C)C.O[C:14]1C=C[CH:21]=[C:20]2[C:15]=1[C:16](=[O:28])[C:17]([C:25]([Cl:27])=[O:26])=[C:18](O)[O:19]2.C(OCC)(=[O:31])C>>[OH:31][C:1]1[CH:14]=[C:15]2[C:20](=[CH:21][C:2]=1[OH:8])[O:19][CH:18]=[C:17]([C:25]([Cl:27])=[O:26])[C:16]2=[O:28]
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: O=C(Cl)c1c(O)oc2cccc(O)c2c1=O
Reactant: CCOC(C)=O
Product: O=C(Cl)c1coc2cc(O)c(O)cc2c1=O
Temperature: 0 °C

Procedure:
7β-[D-2-Amino-2-(4-hydroxyphenyl)acetamido]-7α-methoxy-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid trifluoroacetic acid salt (150 mg) was subjected to suspension into ethyl acetate (7.5 ml) and was added thereto with stirring at 0° C. N,O-bis(trimethylsilyl) acetamide (417 μl). To the resulting mixture was added with stirring at 0° C. dihydroxychromon-3-carbonyl chloride (58 mg) which was obtained in the preceding Item (a). There was added once more N,O-bis(trimethylsilyl)acetamide (417 μl), and the whole was stirred at 0° C. for three hours. After addition of ethyl acetate (150 ml) to the reaction solution, the mixture was washed successively with 30 ml each of 0.5 N hydrochloric acid, distilled water (twice) and a saturated saline. The organic layer recovered therefrom was dried over magnesium sulfate, and the solvent was distilled off. The residue thus obtained was dissolved in acetone (30 ml) and allowed to stand at room temperature overnight. After removal by filtration of a small quantity of an insoluble matter separated out, the solvent was distilled off. Ethyl ether was added to the residue to cause trituration of the latter. There was thus obtained through filtration the desired substance (105 mg).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[C:1]1([NH:11][C:12]([NH:35][CH2:34][C:33]2[C:28]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[N:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(Nc1nccc2ccccc12)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2nccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.6 %

Procedure:
Phenyl isoquinolin-1-ylcarbamate (80 mg, 0.30 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (87 mg, 0.32 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.08 mL, 0.61 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-(isoquinolin-1-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound 20) (46 mg, 34%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:31])[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30])=[O:21])[CH2:15][CH2:14]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([O:31][C:32](=[O:34])[CH3:33])[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=2[CH3:29])=[O:21])[CH2:17][CH2:18]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1)C1COc2ccccc2O1
Reaction time: 2 h

Procedure:
One g of 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is dissolved in 15 ml of pyridine and cooled in an ice bath to 0°-5° C. Acetic anhydride (0.6 g) is slowly added and the reaction mixture is stirred for 2 hr. After the addition of 100 ml of water, the reaction mixture is extracted twice with 100-ml portions of diethylether. After combining, the ether portion is washed twice with 100 ml of water and evaporated to dryness to produce 1-[2-(1,4-benzodioxan-2-yl)-2-acetoxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.FC(F)(F)S(O[CH2:15][C:16]([F:19])([F:18])[F:17])(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=c1ccc(Br)cn1CC(F)(F)F

Procedure:
5-bromo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one and 2,2,2-trifluoroethyl trifluoromethanesulfonate following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1>CO>[Cl:9][C:7]1[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=[C:3]([NH2:1])[N:8]=1
Reactant: N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CO
Product: Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammonia in methanol (7 N solution, 15 mL) was added dropwise to stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine 131 (5.0 g, 23.04 mmol) under argon, and the resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and then extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0-20% ethyl acetate-hexanes) to afford the product 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine 132. The regio-isomer 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine 133 can also be isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH2:25]=O.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:17]=[C:16]([CH2:18][N:19]([CH3:25])[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: C=O
Reactant: Cc1cc(CNCCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CN(C)CCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A solution of Example 227 (1.0 equiv) in MeOH (0.2 M solution) was treated with formaldehyde (5 equiv) and stirred at room temperature (r.t.) for 2 hours. Sodium Borohydride was added and stirred at r.t. overnight. The solvent was removed under vacuum and crude residue was purified by silica gel chromatography using the appropriate eluent (typically mixtures CHCl3/EtOH 7%/NH4OH 0.7%) to afford the title compound as a solid.