Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]2[CH2:49][CH2:48][N:47]3[CH2:51][CH2:52][CH2:53][C@@H:46]3[CH2:45]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[O:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:31])([CH3:32])[O:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2(C)C)cc1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (250 mg, 0.5 mol) in 1,4-Dioxane (10 mL) were added 4-methoxyphenylboronic acid (92 mg, 0.6 mol), Na2CO3 (127 mg, 1.5 mol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min followed by addition of Pd(PPh3)4 (58 mg, 0.05 mol) and then refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one-(40 mg, 18%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.41 (m, 1H), 8.02-7.98 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.68-7.52 (m, 2H), 7.25-7.21 (m, 4H), 7.02-6.98 (m, 4H), 5.40 (s, 2H), 5.25 (s, 2H), 3.79 (s, 3H). MS: M+H: m/z=452.2; M+Na: m/z=474.3. HPLC: 91%, (Condition-B).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25].O>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1
Solvent: O
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl-1-butynyl]benzenamine (Example 21) and acetyl chloride, containing 0.1 mol of water; mp 172°-173.4° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(Cl)cc21

Procedure:
Triethylamine (3 ml) was added to a stirred mixture of 7-chloro-3-hydroxy-1-methyl-4-quinolone (2.31g), methanesulphonyl chloride (1.3 ml) and dichloromethane (70 ml) and the resultant solution stirred for 90 minutes. The solvent was removed by distillation and the residue crystallised from industrial methylated spirit (30 ml) and the solid triturated with diethyl ether (50 ml) to give the novel compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 157°-158°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH:30](C)C)[N:9]=3)[CH2:2]1.Cl[C:35]([C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])=[O:36].CCN(CC)CC>C1COCC1>[CH3:38][C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[C:35]([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)=[O:36]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (32 μL, 0.22 mmol) and NEt3 (29 μL, 0.22 mmol) in THF (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-7%) affording the title compound as a white foam (97 mg, 75%)._LCMS (method A): RT 2.65 min [M+H]+ 575.3
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(N(C(C)C)C(C)C)C.Cl[CH2:42][C:43](Cl)=[O:44].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCCl>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[N:4]([C:43](=[O:44])[CH2:42][N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)[CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN1CCN(CC(=O)N2CC(C)(C)c3ccc(N4C(=O)N(Cc5ccnc6ccccc56)C(C)(C)C4=O)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 70 mg 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione in 2 ml 1,2-dichloroethane in a process vial 0.06 ml ethyl-diisopropyl-amine and 13.5 mg chloroacetylchloride were added at 0° C. After stirring for 1 hour at 0° C. 33.9 mg 1-methyl-piperazine were added. The resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoracetic acid). Lyophilization of the solution yielded a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[Cl:18].[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:14].[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:20]([CH3:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(OCCCCCBr)c(Cl)c1
Reactant: CNCc1ccccc1
Product: CN(CCCCCOc1c(Cl)cc([N+](=O)[O-])cc1Cl)Cc1ccccc1
Product: Cl

Procedure:
React 1-(5-bromopentyloxy)-2,6-dichloro-4-nitrobenzene with methyl(phenylmethyl)amine or benzyl(methyl)amine in a manner similar to Preparation 41 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:25])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].N12CCCN=C1CCCCC2>CN(C)C=O.O>[CH3:38][S:39]([NH:42][C:22](=[O:23])[CH2:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:25])(=[O:41])=[O:40]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
A solution of (R)-[3-(2-(tert-butoxycarbonylamino)propyl)-1H-indol-7-yloxy]acetic acid (0.30 g, 0.86 mmol) and carbonyldiimidazole (0.21 g, 1.3 mmol) in dimethylformamide (10 mL) is stirred at room temperature for 3 days. To the mixture are added methanesulfonamide (0.16 g, 1.7 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.26 mL, 1.7 mmol), and the mixture is stirred at 50° C. for 4 hours. After cooling, to the mixture is added water (0.1 mL), and the mixture is concentrated. The residue is purified by silica gel column chromatography (methanol/chloroform=1/10→1/3), and the resultant is dissolved in ethyl acetate, washed with a 0.05N hydrochloric acid (×2) and saturated brine, and further dried over magnesium sulfate and concentrated to give the desired tert-butyl (R)-{2-[7-(2-methanesulfonylamino-2-oxo-ethoxy)-1H-indol-3-yl]-1-methylethyl}carbamate (0.14 g, yield: 38%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2C(OC(C)(C)C)=O)[CH2:14][C@@H:15]([OH:44])[C@@H:16]([NH:24][C:25](=[O:43])[C@@H:26]([N:30]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[N:37]=[C:38]([CH3:41])[S:39][CH:40]=3)[C:31]2=[O:42])[CH:27]([CH3:29])[CH3:28])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:17]([C@H:16]([NH:24][C:25](=[O:43])[C@@H:26]([N:30]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[N:37]=[C:38]([CH3:41])[S:39][CH:40]=2)[C:31]1=[O:42])[CH:27]([CH3:29])[CH3:28])[C@H:15]([OH:44])[CH2:14][N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4](/[CH:3]=[N:2]/[OH:1])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:45][CH:46]1[CH2:50][CH2:49][CH2:48][NH:47]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN(CC3CCCN3C(=O)OC(C)(C)C)S(=O)(=O)c3ccc(C=NO)cc3)C(C)C)C2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN(CC3CCCN3)S(=O)(=O)c3ccc(/C=N/O)cc3)C(C)C)C2=O)cs1
Yield: 94.8 %

Procedure:
A solution of the product of Example 274E (12 mg) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 1 hour and concentrated. The residue was purified by HPLC reverse phase chromatography using water (0.1% trifluoroacetic acid):acetonitrile (95:5) to acetonitrile (100%) to give 10 mg (95%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:26])[N:3]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Br[C:34]1[C:35]([NH2:41])=[N:36][CH:37]=[C:38]([Br:40])[N:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1.O>[NH2:41][C:35]1[C:34]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:26])[N:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:16][CH:15]=2)=[N:39][C:38]([Br:40])=[CH:37][N:36]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)n(-c2ccccc2)n1C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(-c3nc(Br)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A suspension of the compound prepared in Example 2 (15 g), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (2.0 g), 3,5-dibromopyrazin-2-amine (9.5 g), and sodium carbonate (Na2CO3) (7.3 g) in 3:1 mixture of dioxane/water (350 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. for 5 hours, at which time LC/MS indicated the reaction was complete. The mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The product was absorbed onto silica gel (40 g) and purified by flash chromatography (silica gel, 400 g) using a gradient of 1 to 3% MeOH in DCM as the eluent. After purification, 1H NMR showed that pinicol was present as an impurity. The product was suspended in 10% aqueous potassium carbonate (300 mL), stirred for 30 minutes, filtered and washed with water (3×100 mL). The resulting solid was then evaporated from absolute ethanol (6×50 mL) to give the title compound (6.6 g) having the following physical data as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19](S(C)(=O)=O)=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH:9]=1.[CH3:26][NH2:27].O1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([NH:27][CH3:26])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH:9]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccccc4Cl)c3c2)o1
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3occ(-c4ccccc4Cl)c3c2)o1
Yield: 65 %

Procedure:
In the same manner as in Example 110 and using 2-[3-(2-chlorophenyl)-1-benzofuran-5-yl]-5-(methylsulfonyl)-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using 2M methylamine-tetrahydrofuran solution instead of 3-fluorobenzylalcohol, the title compound (yield 65%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10](=O)CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)[C:3]=1[OH:28].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:28]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2ocnc2c1
Yield: 368.1 %

Procedure:
A solution of 2-bromo-4-chloro-6-(3,5-di-t-butyl-4-hydroxy-phenylacetyl-amino)-phenol (35.67 g, 76.1 mM) and phosphorus oxychloride (41.8 ml, 457mM) in toluene was heated under reflux for 1 hour. Volatiles were removed in-vacuo and residual amounts of phosphorus oxychloride removed by azeotropic distillation with toluene (2×50 ml). The residue was taken up in acetone (50 ml) and ether (100 ml), and treated with water (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic solvents were removed in-vacuo and the precipitate collected to give 33.36 g (93.6%) of crude benzoxazole. The crude benzoxazole was dissolved in dichloromethane (100 ml), filtered, and the filtrate diluted with methanol (100 ml). The dichloromethane was removed by distillation and the resulting crystals collected, washed, and dried in-vacuo to give 28.86 g (80.9%) of the title compound (mp 133°-6° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=3)[N:9]=2)=[C:4]([S:23][CH2:24][CH3:25])[CH:3]=1.P(Cl)(Cl)([Cl:28])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:28][C:16]1[C:15]2[C:10](=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:23][CH2:24][CH3:25])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1cc(Cl)ccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1cc(Cl)ccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 1.46 g of 2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 0.39 ml of phosphorus oxychloride, 538 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 90° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.31 g of 4-chloro-2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 14).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24]Br)=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Mg+].[Br-]>CCOCC.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][CH3:28])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CBr)=CC1(C)C
Agent: [Cu]I
Agent: [Br-]
Solvent: CCOCC
Product: CCC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of N-tert-butyloxycarbonyl-4-bromomethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (structure 12, where R1 =phenyl) (20 mg, 0.047 mmol) and copper (I) iodide (4 mg, 0.02 mmol) in 1 mL of anhydrous ether at 0° C. was added MeMgBr (0.060 mL, 3M in ether). After 30 min of stirring at 0° C., the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil which was purified by SGC (silica gel, hexane/ethyl acetate, 9:1) giving N-tert-butyloxycarbonyl-4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (16 mg, 91%). 1H NMR (acetone-d6) 7.65 (d, J=8.7, 2H), 7.51 (dd, J=8.0, 1.7, 1H), 7.29 (m, 2H), 7.43 (m, 3H), 5.56 (s, 1H), 2.55 (q, J=8.9, 2H), 1.51 (s, 6H), 1.57 (s, 9H), 1.19 (t, J=8.9, 3H). To a solution of N-tert-butyloxycarbonyl-4-ethyl-1,2-dihydro-2,2-dimethyl-6-phenylquinoline (16 mg, 0.044 mmol) in 1 mL of dichloromethane at 0° C. was added 0.3 mL of trifluoroacetic acid. After 10 min of stirring, the reaction was quenched with saturated NaHCO3, and extracted with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to provide an oil that was purified by SGC (silica gel, hexane/ethyl acetate, 7:3) to provide 3 mg (25%) of Compound 112. Data for Compound 112: 1H NMR (acetone-d6) 7.55 (d, J=8.6, 2H), 7.37 (m, 3H), 7.23 (m, 2H), 6.59 (d, J=8.26, 1H), 5.38 (s,1H), 3.76 (s, 1H), 2.48 (q, J=7.4, 2H), 1.29 (s, 6H), 1.17 (t, J=7.4, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]#[N:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:28][NH:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:16][C:12]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=2)=[CH:15][S:14][N:13]=1)#[N:27]
Reactant: CNC
Reactant: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CBr)cc1)C(=O)NCC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CN(C)C)cc1)C(=O)NCC#N

Procedure:
N2-{4-[4-(bromoacetyl)phenyl]isothiazol-3-yl}-N1-(cyanomethyl)leucinamide (29 mg, 0.064 mmol) was dissolved in DMF (0.6 mL) and dimethylamine (0.13 mL of a 2 M solution in THF, 0.26 mmol) was added. The reaction mixture was stirred until disappearance of the starting material was observed by TLC (˜1 h). Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo and purified by flash chromatography with dichloromethane, methanol and ammonium hydroxide to yield N1-(cyanomethyl)-N2-{4-[4-(N,N-dimethylglycyl)phenyl]isothiazol-3-yl} leucinamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH2:24])=[CH:9][CH:8]=1)[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH:24][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(Br)cc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccc(Br)cc3c(=O)c12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
1-[[2-(Diethylamino)ethyl]amino]-4-(aminomethyl)-7-bromothioxanthen-9-one (1 g, 2.3 mmol) in 11.5 mL of dry pyridine under nitrogen was stirred in an ice bath for 15 min and 0.2 mL (2.6 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred at room temperature. The reaction mixture was poured into 200 mL of water, added 0.19 g of sodium hydroxide in ice/water, and extracted into chloroform. The organic layer was washed with water (2x) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated in vacuo and the residue was stirred in ether, filtered, and dried to afford 1.02g of N-[[1-[[2-(diethylamino)ethyl]amino]-7-bromo -9-oxothioxanthen-4-yl]methyl]-methanesulfonamide, m.p. 134°-139° C.