Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[OH-].[Li+].Cl>CO.O>[C:18]1([S:15]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C=Cc1ccc2c(S(=O)(=O)c3ccccc3)c[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=Cc1ccc2c(S(=O)(=O)c3ccccc3)c[nH]c2c1
Yield: 58.2 %

Procedure:
To a solution of 23 (0.36 g, 1.05 mmol) in MeOH (10 mL) and water (2 ml), lithium hydroxide (0.05 g, 2.11 mmol) was added. The reaction mixture was refluxed for 6 h and was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water. 3N HCl was added up to acidic pH and the mixture was extracted with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a brown residue, which was recrystallized by EtOH to afford 24 (0.2 g). 1H NMR (500 MHz, CD3OD): δ 6.46 (d, J=15.8 Hz, 1H), 7.62-7.69 (m, 4H), 7.81 (s, 1H), 7.81 (d, J=16.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.12 (d, J=7.3 Hz, 2H), 8.21 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36][NH2:37])[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:36]([C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:31]=5)[N:37]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc4c(c3)OC(F)(F)O4)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and (3-methane sulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=473.2 (M+H)+
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4](O)=[O:5].[C:8]([O:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1)([CH3:11])([CH3:10])[CH3:9].C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C.ClCCl>[C:8]([O:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:4](=[O:5])[CH:3]([CH3:7])[CH2:2][SH:1])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(CS)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To the cold (5°) solution of 1.2 g. (10 mMol.) of 3-mercapto-2-methylpropanoic acid and 1.7 g. (10 mMol.) of L-proline tert. butyl ester in 25 ml. dichloromethane 2.26 g. of dicyclohexylcarbodiimide in 5 ml. dichloromethane is added in portions. After 2 hours at room temperature, 5 drops of acetic acid are added, the mixture is filtered and the filtrate evaporated to an oily residue. This residue is taken up in 20 ml. of petroleum ether-ethyl acetate (3:1) and applied to a 150 ml. silica gel column prepared in petroleum ether. The fraction eluted with petroleum ether-ethyl acetate (1:1) contains the product, 1-(3-mercapto-2-methylpropanoyl)-L-proline tert.butyl ester. This fraction (0.6 g.) is dried over P2O5 in vacuo for 12 hours. Rf 0.6 (Silica gel, Benzene/Acetic acid 3:1), Rf 0.8 (Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Reaction SMILES: C1(CO[C:9](=O)[NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=3)[NH:15][CH:14]=2)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>C1COCC1>[CH3:9][NH:10][CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=2)[NH:15][CH:14]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNCCc1c[nH]c2ccc(CNS(C)(=O)=O)cc12
Yield: 107 %

Procedure:
A solution of phenylmethyl[2-[5-[[(methylsulphonyl)amino]methyl]-1H-indol-3-yl]ethyl]carbamate (0.02 g) in dry THF (1 ml) was added to a stirred suspension of lithium aluminium hydride (0.1 g) in THF (2 ml) and the mixture was refluxed under nitrogen for 3 h. The mixture was cooled and excess reagent was decomposed by the addition of 10% water in THF. Salt and ethyl acetate (20 ml) were added and the organic layer was dried (Na2SO4) and evaporated in vacuo to leave the title compound as a brown oil (0.015 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=3[N:32]([CH3:34])[CH3:33])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=2)[N:3]=1.[NH2:39][CH2:40][CH2:41][CH2:42][OH:43]>>[CH3:33][N:32]([CH3:34])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=3)[N:3]=[C:2]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])[N:11]=2)[CH2:14][CH2:15]1
Reactant: COc1cc2nc(Cl)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC
Reactant: NCCCO
Product: COc1cc2nc(NCCCO)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC

Procedure:
Following General Procedure D, Compound 75 (0.25 g, 0.10 mmol) and 3-amino-1-propanol (0.12 mL, 1.61 mmol) were converted into compound 207 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:15]1([C:20]2[CH:39]=[CH:38][C:23]([CH2:24][NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:10]=1)[C:7]([N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:39][CH:38]=1)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:9]
Reactant: FC(F)(F)c1cccc(CCNCc2ccc(C3CCCC3)cc2)c1
Reactant: CC(C)Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 50 mg of 5-chloro-2-isopropylamino-benzoic acid (0.23 mmol) and 81 mg (0.23 mmol) of (4-cyclopentyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 4 ml of DMF were added 75 mg of TBTU (0.23 mmol) and 0.2 ml (1.17 mmol) of N,N-di-isopropylethyl amine. After stirring the reaction mixture over night at RT it was diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with 10%-aqueous KHCO3 solution, 0.1M HCl solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The remaining oil was purified by column chromatography (silica gel; heptane 100% to heptane/EtOAc 4:1) to give 90 mg (71%) of a colorless oil. MS (ISP) 543.5 (M+H)+.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]3[CH:42]=[CH:41][C:40]([N:43]([C:53]4[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][CH2:61][CH3:62])=[CH:55][CH:54]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([S+:50]([CH3:52])[CH3:51])[CH:45]=4)=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)[C:20]2[CH:21]=[C:22]([S+:26]([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].[O-]S(C(F)(F)F)(=O)=O.[F:71][Sb-:72]([F:77])([F:76])([F:75])([F:74])[F:73].[Na+]>CC(C)=O>[F:71][Sb-:72]([F:77])([F:76])([F:75])([F:74])[F:73].[CH2:9]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]([C:53]4[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][CH2:61][CH3:62])=[CH:55][CH:54]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([S+:50]([CH3:52])[CH3:51])[CH:45]=4)=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)[C:20]2[CH:21]=[C:22]([S+:26]([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[CH:17][CH:18]=1)[CH2:10][CH2:11][CH3:12].[F:71][Sb-:72]([F:77])([F:76])([F:75])([F:74])[F:73]
Reactant: CCCCc1ccc(N(c2ccc(/C=C/c3ccc(N(c4ccc(CCCC)cc4)c4cccc([S+](C)C)c4)cc3)cc2)c2cccc([S+](C)C)c2)cc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCc1ccc(N(c2ccc(C=Cc3ccc(N(c4ccc(CCCC)cc4)c4cccc([S+](C)C)c4)cc3)cc2)c2cccc([S+](C)C)c2)cc1

Procedure:
Trans-[3-((4-butylphenyl){4-[2-(4- {(4-butylphenyl)[3-(dimethylsulfonio)phenyl]amino}phenyl)vinyl]phenyl}amino)phenyl](dimethyl)sulfonium triflate (19) (0.87 g, 0.83 mmol) was dissolved in acetone (20 ml). To this solution was added 20 ml of an aqueous solution of sodium hexafluoroantimonate (0.88 g, 3.40 mmol). The resultant mixture was stirred two days in the dark at room temperature; with slow evaporation of acetone, a yellow solid was formed and collected by filtration. The yellow solid was washed four times with water and three times with ether. A NMR-pure product was obtained without further purification and isolated in 93.8% (0.95 g) yield. 1H NMR (CD3COCD3, 500 MHz) δ ppm: 7.1-7.4 (m, 24 Ar—H, 2 ═CH), 3.06 (s, 6H, CH3,) 2.72 (t, J=7.7 Hz, CH2, 4H), 1.71 (m, CH2, 4H), 1.46 (m, CH2, 4H), 1.04 (t, J=7.3 Hz, CH3, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[OH-].[K+]>C(O)C.O>[Cl:26][C:4]1[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[NH:10][CH:9]=2)[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2nccnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1cc(-c2c[nH]c3nccnc23)cc(Cl)n1
Temperature: 50 °C

Procedure:
A suspension of EXAMPLE 14A (0.300 g, 0.740 mmol) in ethanol (6 mL) was treated with a solution of potassium hydroxide (0.166 g, 2.96 mmol) in water (1.5 mL). The mixture was heated at 50° C. for 1.5 h. After cooling, the mixture was concentrated and 20% brine, sodium bicarbonate, and ethyl acetate were added. The suspension in both layers was filtered, washed with water, and dried to give the title compound. The organic layer in the filtrate was separated, dried, and concentrated. The residue was treated with ethyl acetate and diethyl ether, filtered, washed with diethyl ether, and dried to give additional title compound for a combined yield of 0.140 g (71%).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:46][C:47]([F:57])([F:56])[C:48]1[CH:55]=[CH:54][C:51]([CH2:52]O)=[CH:50][CH:49]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:52][C:51]3[CH:50]=[CH:49][C:48]([C:47]([F:46])([F:56])[F:57])=[CH:55][CH:54]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C(=O)OCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 393 (1.87 g, 5.09 mmol) and methylene chloride (20 ml) was added trifluoroacetic acid (20 ml) followed by stirring for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in DMF (20 ml). To the solution, a mixture of 1,1′-carbonyldiimidazole (1.76 g, 10.9 mmol), 4-(trifluoromethyl)benzyl alcohol (1.92 g, 10.9 mmol) and DMF (20 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=3/1), recrystallized from isopropyl alcohol. The resulting solids were filtered off and then dried under reduced pressure to afford 4-trifluoromethylbenzyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (1.48 g, yield 53%) as a light yellow powder.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:13])[CH2:8]2
Reactant: NCCCCO
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCCCCO

Procedure:
5-(4-Hydroxy-butylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 4-amino-1-butanol. Mass spectrum (ES) MH+=409.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][N:54]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:53]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.4 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (60.8 mg) in N,N-dimethylformamide (1.0 ml) was added (3R)-(+)-3-dimethylaminopyrrolidine (41.7 mg), followed by stirring at room temperature for 7 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:2, and the precipitated solid was collected by filtration. This was dried under aeration to provide the titled compound as white powder (18.3 mg). This was purified again by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:2, and the precipitated solid was collected by filtration. This was dried under aeration to provide the titled compound as white powder (12.3 mg, 23.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:17]=[C:16](Cl)[N:15]=2)[CH:8]=1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>C(O)C>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:17]=[C:16]([N:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:15]=2)[CH:8]=1)=[O:5]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)c1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)c1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 140 °C
Yield: 48.3 %

Procedure:
To a microwave tube with a solution of 2,6-dichloro-N-(2-(2-chloro-6-isopropylpyrimidin-4-ylamino)pyridin-4-yl)benzamide (0.050 g, 0.11 mmol) in ethanol (2 mL) was added diisopropylethylamine (1.5 mL) and 1-(methylsulfonyl)piperazine (0.18 g, 1.1 mmol). The resulting mixture was heated to 140° C. under microwave irradiation for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (30 mg, 46% yield). 1H NMR ((500 MHz, DMSO-d6): δ 11.05 (s, 1H), 9.77 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.54 (m, 1H), 6.87 (m, 1H), 6.48 (s, 1H), 3.95-3.91 (m, 4H), 3.17-3.14 (m, 4H), 2.85 (s, 3H), 2.67 (m, 1H), 1.17 (d, J=7.0 Hz, 6H). LCMS (ESI) m/z: 564.0 [M+H+].
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.O(C(C)C(Cl)=O)C1C=CC=CC=1>>[O:1]([CH:8]([CH3:12])[C:9]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: CC(Oc1ccccc1)C(=O)Cl
Product: CC(Oc1ccccc1)C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 88.2 %

Procedure:
2-Phenoxypropionic acid (32 mg, 0.193 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-phenoxypropionic acid chloride mentioned above, the title compound (39 mg, yield 88%) was obtained in the same manner as that of Example 1.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:7]=1.[Cl:23]C1C(NC(=O)C)=C(C)C=CC=1.NC1C=CC(C)=C(NC(=O)C)C=1>>[Cl:23][C:7]1[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[C:5]([CH3:22])[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reactant: CC(=O)Nc1c(C)cccc1Cl
Agent: CC(=O)Nc1cc(N)ccc1C
Product: Cc1cccc(Cl)c1Nc1ncc(-c2ccc(C#N)cc2)o1
Yield: 89 %

Procedure:
The same procedure outlined above in the preparation 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(6-chloro-2-methyl-phenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=89%.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].O>O1CCCC1>[CH3:1][NH:2][S:12]([C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylamine (2 M in tetrahydrofuran) (24 mL, 47.5 mmol) was added to an ambient temperature solution of p-nitrobenzenesulfonyl chloride (3.5 g, 15.8 mmol) in tetrahydrofuran (30 mL). After stirring at ambient temperature for 30 min, the reaction mixture was poured into water and extracted with ethyl aceate. The organic phase was dried (magnesium sulfate) and concentrated to afford N-methyl-4-nitrobenzenesulfonamide which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:13])[CH:6]=[CH:5]2.CCN(CC)CC.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH:13][C:21](=[O:23])[CH3:22])[CH:6]=[CH:5]2
Reactant: CC(=O)Cl
Reactant: NCc1ccc2cc(Br)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2cc(Br)ccc2n1

Procedure:
To a slurry of 4b (401 mg, 1.7 mmol) in CH2Cl2 at room temperature was added NEt3 (0.47 mL, 3.4 mmol), followed by acetyl chloride (0.18 mL, 2.6 mmol). Once the reaction was complete by LCMS analysis, the mixture was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes, followed by 10% MeOH in EtOAc) to give the desired product, 4c.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:38]=[C:37]([CH3:49])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:38]=[C:37]([CH3:49])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (276 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (470 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[N:16]([CH2:17][CH2:18][CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:13]2=O)=[CH:5][CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:15](=[O:20])[N:16]2[CH2:17][CH2:18][CH3:19])=[CH:7][CH:8]=1
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CCCc1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 103 %

Procedure:
A solution of 5-[3-(4-methoxy-phenyl)-propyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione (1.26 g, 3.19 mmol) in THF (20 ml) was treated dropwise with 1 M solution of borane-THF complex in THF (16 mL, 16 mmol) and then stirred at room temperature under N2 for 22 h. The reaction was quenched with methanol (20 mL) and stirred at room temperature for 2 hr. The solvent was removed in vacuo to give 1.25 g (100%) crude 4-[3-(4-methoxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one that was carried on without purification. MS (ES+) Calc'd for C24H33N2O2 (M+1) 381. Found m/z 381 (100%). 1H NMR.