Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10](=[O:11])[C@@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:30]=[CH2:31])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(Br)c2)NC(=O)OC(C)(C)C)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: COCCOC
Product: C=Cc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Yield: 98 %

Procedure:
A suspension of (S)-tert-butyl 3-(3-bromophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (6.3 g, 13.6 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.3 g, 20.4 mmol), potassium carbonate (54 ml, 0.4 M) and tetrakis(triphenylphosphine)palladium(0) (0.79 g, 0.68 mmol) in 50 ml of DME, was heated at reflux overnight. The suspension was cooled and filtered through celite. The filtrate was washed with brine and filtered through celite. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (15-35% EtOAc/hexanes) to provide the desired product (5.47 g, 13.33 mmol), 94%. MS (m/z) 411 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH2:19]([OH:22])[C:20]#[CH:21]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]([C:21]#[C:20][CH2:19][OH:22])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=1
Reactant: C#CCO
Reactant: Clc1cc(Br)c2oc(-c3ccccc3Cl)nc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 6 h
Yield: 85.7 %

Procedure:
A solution of 17.15 g (50 mmol) of 7-bromo-5-chloro-2-(2-chlorophenyl)-benzoxazole and 4.40 ml (75 mmol) of propargylalcohol in 32 ml of toluene and 64 ml of triethylamine was heated under nitrogen to 80-5° C. with 175.4 mg (250 μM) of bis(triphenylphosphine)palladium (II) chloride and 8.6 mg (4.5 μM) of copper (1) iodide. After 6 hours, the solid was filtered off and washed with dichloromethane. The solution was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCl, sodium bicarbonate solution, and water. The ethyl acetate was removed in vacuo, the residue (15.46 g) was dissolved in dichloromethane and filtered through 60 g of silica gel to give the title compound (13.64 g, 85.8%), mp 165-9° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[N:23]3[C:19]([S:20][CH:21]=[CH:22]3)=[N:18][C:17]=2[Cl:24])(=[O:15])=[O:14])[CH:5]=1.[CH3:25][NH2:26]>C1COCC1>[Cl:24][C:17]1[N:18]=[C:19]2[N:23]([C:16]=1[S:13]([N:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH2:3][CH2:2][NH:26][CH3:25])=[CH:5]1)(=[O:14])=[O:15])[CH:22]=[CH:21][S:20]2
Reactant: O=S(=O)(c1c(Cl)nc2sccn12)n1cc(CCBr)c2ccccc21
Reactant: CN
Solvent: C1CCOC1
Product: CNCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Temperature: 50 °C

Procedure:
A solution of 3-(2-bromoethyl)-1-(6-chloroimidazo[2,1-b]thiazole-5-sulfonyl)indole (92 mg, 0.20 mmol) in THF is treated with methyl amine (2M in methanol, 0.4 mL, 2 eq.), heated at 50° C. for 24 h, cooled and concentrated in vacuo. The resultant residue is purified by HPLC1 to give the title product as a white solid, 18.5 mg, identified by HPLC2 and mass spectral analyses.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:20][CH2:19][CH:17]1[O:16][C:15](=[O:22])[N:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:3][CH2:4]3)=[CH:13][CH:12]=2)[CH2:18]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cc2)C(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC1CN(c2ccc([C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.5 g (1.639 mmol) of (RS)-3-[4-(trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one in 20 ml of methylene chloride and 5 ml of pyridine was treated dropwise with a solution of 0.95 ml (8.195 mmol) of benzoyl chloride in 10 ml of methylene chloride and stirred at room temperature for a further 3 hours. The reaction mixture was poured into ice-water, made acid with 3N hydrochloric acid and extracted with methylene chloride. The organic phase was washed with wate, dried over magnesium sulfate and the solvent was distilled off. The benzoate crystallized upon treatment with t-butyl methyl ether. There was obtained 0.52 g (77%) of benzoic acid (RS)-trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyl ester. M.p.: 104°-105°.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14][C@H:15]([OH:31])[C@@H:16]([NH:24]C(=O)C(F)(F)F)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14][C@H:15]([OH:31])[C@@H:16]([NH2:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-n2cnnc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-n2cnnc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1

Procedure:
0.756 g (1.38 mmol) of 1-[p-(1,2,4-triazol-4-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane (Example 14d) is initially introduced in 28 ml of methanol, and 6.9 ml (6.89 mmol) of a 1 M aqueous solution of potassium carbonate are then added. The reaction mixture is stirred under reflux for 3 h and then concentrated down to about 10 ml; it is then acidified with dilute hydrochloric acid and extracted with methylene chloride. The title compound crystallizes out on concentrating. HPLC20-100: tret=8.97. 1H NMR (CD3OD; 200 MHz) i.a.: 8.98/s (2H); 7.75-7.6/m (4H); 7.5-7.1/m (5H); 3.96/bs (2H); 1.32/s (9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.[CH2:30]([N:32]=[C:33]=S)[CH3:31]>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH3:20])[C:33]([NH:32][CH2:30][CH3:31])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COc1cc2c(NC(C)c3cnn(C)c3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: CCN=C=S
Solvent: CCO
Product: CCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1C(C)c1cnn(C)c1
Temperature: 60 °C
Yield: 40.3 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)quinoline-3,4-diamine (70 mg, 0.178 mmol, for a preparation see intermediate 22) was dissolved in ethanol (5 ml) and ethylisothiocyanate (31.1 mg, 0.357 mmol) was added. The solution was heated at 60° C. for 3 h, then cooled and evaporated in vacuo. The residue was dissolved in THF and heated to 60° C. for 4 h, then evaporated in vacuo and the residue dissolved in DMSO and purified by MDAP (formic method. The product-containing fractions were evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-8-methoxy-1-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-imidazo[4,5-c]quinolin-2-amine (32 mg, 0.072 mmol, 40.3% yield) as a beige solid. LCMS (formate) Rt 0.71 min, MH+ not found.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N:42]1[CH:46]=[CH:45][CH:44]=[CH:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][CH:44]=[CH:43]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCn1cccc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3cccc3)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (75 mg, 0.17 mmol) was dissolved in DMF (1 mL) at room temperature. K2CO3 (47 mg, 0.34 mmol) was added followed by 1-(3-bromopropyl)-pyrrole and the reaction was allowed to stir at 70° C. for 3 hrs. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate. Organic layers were washed with brine, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (1/1 ethyl acetate/hexanes) to afford the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH:18]2[C:37]([O:39]CC)=[O:38])=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:24])=[O:25])[CH2:19][CH:18]2[C:37]([OH:39])=[O:38])=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 1-(trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinecarboxylate (740 mg) in ethanol (15 ml) was added 1 N sodium hydroxide solution (10 ml), and the solution was stirred at room temperature for 15 hours. The reaction solution was concentrated, and the residue was dissolved in water, adjusted to pH 2 with 1 N hydrochloric acid, extracted with dichloromethane. The extract was dried and concentrated to give a colorless solid of the title compound (614 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][NH:13][CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3cc(CNC4CCNC4)ncn3)ccc21

Procedure:
(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg, 3.30 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is then extracted with EtOAc (3×) and the combined organic layers are washed with water, brine, dried with Na2SO4, filtered, and condensed. The residue is purified by FCC (0-10% 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 496.8 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1 H), 8.36 (d, J=8.84 Hz, 1 H), 8.06 (s, 1 H), 7.95 (d, J=3.54 Hz, 1 H), 7.88 (s, 1 H), 7.57 (t, J=7.83 Hz, 1 H), 7.44 (d, J=7.83 Hz, 1 H), 7.42 (d, J=2.27 Hz, 1 H), 7.03-7.13 (m, 2 H), 6.75 (d, J=3.79 Hz, 1 H), 3.80-3.85 (m, 2 H), 2.81-3.02 (m, 3 H), 2.52-2.75 (m, 2 H), 2.19-2.35 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38]>CC(O)C.Cl.C(Cl)Cl>[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH:38][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)C(F)(F)F)c4)nn4ccccc34)n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (150 mg, 0.36 mmol) (see Example 1, Step C) in i-PrOH (4 mL) were added 3-{[2-(dimethylamino)ethyl]oxy}aniline (80 mg, 0.45 mmol) and 12 N HCl (3 drops). The reaction was stirred overnight at 80° C. The crude reaction mixture was diluted with DCM and extracted with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and purified by column chromatography to generate the title compound in 84% yield. 1H NMR (400 MHz, d6-DMSO): δ 11.4 (bs, 1H), 9.58 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.50 (d, J=9.0 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.00 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.45-7.57 (m, 4H), 7.28 (d, J=9.4 Hz, 1H), 7.10-7.15 (m, 2H), 6.51-6.56 (m, 2H), 4.00 (t, J=5.7 Hz, 2H), 2.7 (bs, 2H), 2.35 (s, 6H). ES-LC/MS m/z=562 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].CS(O[CH2:19][CH:20]=[CH:21][C:22]([F:25])([F:24])[F:23])(=O)=O>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:19][CH:20]=[CH:21][C:22]([F:25])([F:24])[F:23])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: CS(=O)(=O)OCC=CC(F)(F)F
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC=CC(F)(F)F

Procedure:
The title compound (trans) was prepared as a pale yellow oil in 60.0% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 4,4,4-trifluoro-2-butenyl methanesulfonate (trans).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH3:15])=[O:14])=[O:5].[I:20]N1C(C)(C)C(=O)N(I)C1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[I:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH3:15])=[O:14])=[O:5]
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: Cc1ccccc1C(=O)Nc1ccccc1S(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(I)c1C(=O)Nc1ccccc1S(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 124 %

Procedure:
Into the same reactor as in Example 1 were charged 0.10 g of palladium acetate, 0.40 g of 2-methyl-2′-methylsulfinylbenzanilide, 0.33 g of 1,3-diiodo-5,5-dimethylhydantoin and 5 ml of N,N-dimethylacetamide. The mixture thus obtained was stirred at 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered with Celite, and the filtrate was poured into saturated aqueous solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with 0.1N-aqueous hydrochloric acid and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrate thus obtained was purified by silica gel dry column chromatography (hexane/ethyl acetate=1/2). Thus, 0.43 g (yield 72%) of 2-iodo-6-methyl-2′-methylsulfinylbenzanilide was obtained. Regioselectivity of iodination into the 2-position was 100%.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH3:15])[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]1.[OH-].[Na+]>C(O)C>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH3:15])[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1
Reactant: CCOC(=O)c1cn(CCF)c2c(F)c(C)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn(CCF)c2c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
3.13 g of ethyl 1-(2-fluoroethyl)-6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate are suspended in 50 ml of ethanol, and 50 ml of an aqueous 2% sodium hydroxide solution are added thereto. The suspension is stirred at room temperature for 3 hours. Then, the reaction mixture is evaporated under reduced pressure to remove solvent, and the residue is adjusted to about pH 1 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water and then dried. 2.85 g of 1-(2-fluoroethyl)-6,8-difluoro-7-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid are thereby obtained as crystalline powder. Yield: 100%
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:10]=3)=[CH:20][CH:21]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-chlorophenyl isocyanate (94 mg, 0.61 mmoles), the title compound was isolated as a white solid. Yield; 60 mg (30%); (M+H)=496.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][CH:6]([CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:19])([CH3:18])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[O:8].I([O-])(=O)(=O)=[O:27].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][CH:6]([CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:19])([CH3:18])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:17])=[O:27])=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCSC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCS(C)=O
Reaction time: 2.5 h

Procedure:
To a stirred solution of 2-(3,5-dichlorophenoxy)-N-(6-methyl-1-methylthio-hept-4-yn-6-yl) butyramide (0.21 g) in ethanol (2.5 ml) at ambient temperature was added dropwise a solution of sodium periodate (0.13 g) in water (2.5 ml). The mixture was stirred for 2.5 hours, stored for 18 hours then evaporated under reduced pressure. The residue was extracted with dichloromethane and the organic phase filtered then evaporated under reduced pressure to give the required product as a colourless oil, 0.18 g, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.56(3H, s); 1.58(3H, s); 1.92-2.00(4H, m); 2.34-2.42((2H, m); 2.62(3H, s); 2.76-2.84(1H, m); 2.90-2.96(1H, m); 4.34-4.38(1H, m); 6.26(1H, s); 6.82(2H, s); 7.02(1H, s).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:30]([O:32][CH3:33])=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:12]2=[O:34])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:30]([O:32][CH3:33])=[O:31])[C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12]2=[O:34])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COC(=O)C(c1ccc(OCc2ccccc2)cc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(c1ccc(O)cc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Yield: 71.1 %

Procedure:
3-(2-Phenylacetamido)-1-(α-methoxycarbonyl-4-benzyloxybenzyl)-2-azetidinone (70 mg) was dissolved in absolute ethanol (10 ml), and to the solution, there was added 10% palladium on carbon (30 mg). The mixture was subjected to catalytic reduction in a stream of hydrogen gas at ordinary temperature and ordinary atmospheric pressure. After a calculated volume of the hydrogen gas was absorbed into the mixture in the course of 3 hours, the catalyst was removed by filtration to give a filtrate, which was evaporated to dryness under reduced pressure. The resultant residue was treated with diethyl ether to give 3-(2-phenylacetamido)-1-(α-methoxycarbonyl-4-hydroxybenzyl)-2-azetidinone (40 mg), mp 171.5° to 175° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([CH3:24])[C@H:13]([CH2:14][F:15])[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd].[H][H]>[C:1]([O:5][C:6]([NH:8][C@:9]1([CH3:24])[C@H:13]([CH2:14][F:15])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CF)[C@@](C)(NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]1(C)CNC[C@H]1CF

Procedure:
To a solution of (3R,4R)-3-(tert-butoxycarbonylamino)-4-fluoromethyl-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidine (250 mg, 0.743 mmol) in ethanol (10 mL) was added 10% palladium-carbon catalyst (containing 52.8% water, 250 mg), and the suspension was stirred in an oil bath at 40° C. for 1.5 hours in hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 169 mg (98%) of the crude target compound as a colorless transparent syrup substance.