Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[N:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])=[O:5])C.[OH-].[Na+]>CO>[C:13]([C:9]1[C:10]([O:11][CH3:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:17])[N:8]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1c(OC)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(C)(C)C)nn(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-tert-Butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (52.8 mg, 0.220 mmol, prepared as described in the previous step) was dissolved in MeOH (1 mL) then 2 M NaOH (143 μL, 0.286 mmol) was added. The resulting mixture was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was dissolved in H2O (10 mL) and acidified to pH ˜2 using 3 M HCl. The aqueous layer was extracted with EtOAc (3×5 mL) and the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 11.65 (br. s., 1H), 4.08 (s, 3H), 3.89 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C(=O)C.Cl>CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CC(=O)n1ncc2c(Br)cccc21
Agent: Cl
Solvent: CO
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of the 1-(4-bromo-indazol-1-yl)-ethanone A (3.09 g, 12.9 mmol) in MeOH (50 mL) was added 6N aqueous HCl (30 mL) and the mixture was stirred at room temperature for 7 h. The MeOH was evaporated and the mixture partitioned between EtOAc (2×50 mL) and water (50 mL). The combined organic layers were washed with brine (50 mL), separated and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to give 4-bromo-1H-indazole B (2.36 g, 93%).
Reaction SMILES: Cl.C([O:4][C:5](=[O:25])[C@H:6]([OH:24])[CH2:7][C@H:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)C>>[NH2:23][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:7][C@@H:6]([OH:24])[C:5]([OH:25])=[O:4]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Product: N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
1 M aqueous HCl (2.0 mmol) was added to (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (150.0 mg, 431 μmol) and the mixture was stirred at 100° C. for 2 hours. The mixture was concentrated under vacuum for 3 hours and the residue was purified by reverse phase to yield the title compound (117 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3nc4cc(C(F)(F)F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(-c3nc4cc(C(F)(F)F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(1-methyl-5-trifluoromethyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[O:25]C(C)=O>O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:10](=[O:25])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Product: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)C(=O)C1
Reaction time: 0.5 h

Procedure:
4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13 g) in AcOEt (300 ml) was added at RT under an argon atmosphere to a vigorously stirred solution of RuCl3×H2O (1.71 g) and NaIO4 (44.078 g) in water (300 ml). This mixture was vigorously stirred 30 minutes at RT. Then water and AcOEt were added and the layers were separated. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated to give the crude product as brown oil (8.78 g) which was used in next reaction step without further purification. MS (ESI): 352.17 (M+Na)+ and 230.13 [(M-C5H8O2)H+]
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].[CH:8]([NH2:11])([CH3:10])[CH3:9]>>[CH:8]([NH:11][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])([CH3:10])[CH3:9]
Reactant: CC(C)N
Reactant: C=C(C)C(=O)OC
Product: C=C(C)C(=O)NC(C)C
Yield: 32 %

Procedure:
200 g of methyl methacrylate and 142 g of isopropylamine were heated at 190° C. for 21/2 hours in a 0.5-liter stirred autoclave (pmax =15 atmospheres). N-isopropyl-methacrylic acid amide was formed in this way in a 32% yield.
Reaction SMILES: I.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([S:19][CH3:20])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[C:32]1([O:31][C:29]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=[C:10]2[S:19][CH3:20])=[O:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Agent: CN(C)c1ccncc1
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-(methylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydroiodide (42) (1.00 mg, 2.52 mmol), triethylamine (0.528 mL, 0.379 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (20 mL) is added phenyl chloroformate (0.379 mL, 3.02 mmol), and the mixture is stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water, brine, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 0.58 g of the product 548. 1H NMR (CDCl3) δ 7.25-6.95 (m, 11H), 6.95-6.80 (m, 2H), 6.80-6.70 (m, 2H), 5.80-5.65 (m, 2H), 2.62 (s, 3H). MS: m/z 389 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:51])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:51])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([N:46]3[CH2:47][CH2:48][CH2:49][CH2:50]3)[CH:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (419 mg, 84%).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18](=[O:26])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:17])[CH2:9][CH2:8]2)(=O)C.C[O-].[Na+].Cl.CCOC(C)=O>CO.O>[CH2:20]([NH:19][C:18]([C:10]1([CH3:17])[CH2:9][CH2:8][C:7]2[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=2[CH3:27])[O:11]1)=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCNC(=O)C1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 8 h
Yield: 108 %

Procedure:
Crude 2-(hexylcarbamoyl)-2,5,7,8-tetramethylchroman-6-yl acetate (187 mg, 0.25 mmol) in 1.25 mL MeOH was treated with 33.7 mg (0.625 mmol) NaOMe and let stir overnight. The stirred brown solution then was diluted with water (10 mL), neutralized with 2.5 M HCl (1.5 mL) and 10 mL EtOAc added. The layers were separated and the organics dried over Na2SO4 and concentrated. Flash chromatography yielded 90 mg of N-hexyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([CH:12]([CH2:22][CH2:23][CH2:24][CH:25]([OH:38])[CH2:26]OC1C=CC(C(C)(C)C)=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])[CH3:10]>>[C:9]([CH:12]([CH2:22][CH2:23][CH2:24][CH:25]([OH:38])[CH2:26][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])[CH3:10]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Reactant: Oc1ccccc1F
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccccc1F

Procedure:
The synthesis of this compound is carried out by the procedure of Example 10 except that an equivalent amount of 2-fluorophenol is substituted for the 4-tertbutylphenol of Example 10. The title compound is obtained as a viscous oil after purification by silica gel column chromatography.
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].C(OC(=O)C)(=O)C>I>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:8]1[C:3]2[O:20][C:18](=[O:19])[CH2:17][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(CC(=O)O)cccc1Oc1ccccc1C
Agent: I
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
2-[2-Methoxy-3-(o-tolyloxy)phenyl]acetic acid (34.0 g) was added to a mixture of acetic anhydride (50 ml) and 50% aqueous solution of hydrogen iodide (100 ml), and the mixture was refluxed under heating for an hour. The reaction mixture was poured into ice-water (1 l) and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water (twice) successively, dried over magnesium sulfate and then evaporated. The oily residue (34.0 g) was dissolved in acetic anhydride (50 ml), stirred at 100° C. for 1.5 hours and then evaporated. The crystalline residue (29.0 g) was recrystallized from methanol and diisopropyl ether successively to give colorless crystals of 7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (22.0 g). mp 110°-111° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCOc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1
Yield: 71.4 %

Procedure:
A microwave tube was charged with 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (146 mg, 0.52 mmol), 3-ethoxybenzeneboronic acid (94 mg, 0.57 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (34 mg, 0.041 mmol), and K2CO3 (179 mg, 1.30 mmol). Dioxane (4 ml) and water (1 ml) were added, and the tube was microwaved at 150° C. for 30 min. The reaction mixture was partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark brown solid. The crude product was purified by preparative thin layer chromatography (70% EtOAc/Hexane) as eluant to provide 120 mg (72%) of 1-[2-(3-ethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow solid. MP 195-196° C., M+H=324.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[P:23]([O:32][CH2:33][CH:34]=[CH2:35])([O:28][CH2:29][CH:30]=[CH2:31])[O:24][CH2:25][CH:26]=[CH2:27]>O=O.O>[P:23]([O:28][CH2:29][CH:30]=[CH2:31])([O:32][CH2:33][CH:34]=[CH2:35])([O:24][CH2:25][CH:26]=[CH2:27])=[O:2]
Reactant: C=CCOP(OCC=C)OCC=C
Reactant: O=C([O-])[O-]
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: O=O
Solvent: O
Product: C=CCOP(=O)(OCC=C)OCC=C
Yield: 96 %

Procedure:
To 10 ml. of an aqueous solution containing 0.5 g. of sodium carbonate and 0.25 g. of sodium bicarbonate there is added a solution of 1.0 g. of potassium dichromate in 50 ml. of water, then 60 ml. of triallyl phosphite. The resulting mixture is stirred at 25°-30°C while passing in oxygen for eight hours. The aqueous layer is removed, leaving a 96% yield of substantially pure triallyl phosphate.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]1[C:14]2[CH:23]=[CH:22][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:15]=2[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1.[C:34]1([OH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:19][N:17]1[CH:18]=[C:13]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[O:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:14]2[CH:23]=[CH:22][NH:21][C:15]=2[C:16]1=[O:20]
Reactant: CCOC(=O)c1ccc(F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of Example 9a (1.43 g, 3.05 mmol), phenol (0.0344 g, 3.66 mmol) and cesium carbonate (0.995, 3.05 mmol), in DMSO (15 mL) was heated at 110° C. for 12 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 30-80% ethyl acetate/hexane) to afford 0.85 g (72%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.31 (t, J=7.02 Hz, 3H), 3.55 (s, 3H), 4.32 (q, J=7.22 Hz, 2H), 6.23 (t, J=2.29 Hz, 1H), 6.97 (d, J=8.54 Hz, 1H), 7.06 (d, J=8.24 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.36-7.51 (m, 3H), 7.94 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.02 (s, 1H). MS (ESI+) m/z 389.2 (M+H)+.
Reaction SMILES: CO.[CH:3]1([O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:45])=[CH:12][C:13](=[O:44])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH2:33][C:34]4[CH:43]=[CH:42][C:37]5[O:38][CH2:39][CH2:40][O:41][C:36]=5[CH:35]=4)C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4]1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[CH:3]1([O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:45])=[CH:12][C:13](=[O:44])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH:22]([NH:25][CH2:33][C:34]4[CH:43]=[CH:42][C:37]5[O:38][CH2:39][CH2:40][O:41][C:36]=5[CH:35]=4)[CH2:23][CH2:24]3)=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC3CC3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC3CC3)ccc12
Reaction time: 1.5 h

Procedure:
To 1 mL of methanol solution containing 85 mg of tert-butyl (1-(2-(7-cyclopropoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1.5 hours. 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and further stirred for 30 min. Ethyl acetate was added, and the resulting solid was filtered to give 60 mg of 7-cyclopropoxy-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[S:11][C:12]([CH:14]([OH:17])[CH2:15][CH3:16])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C.C(OCC)C>[Cl:20][C:19]1[C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]([OH:17])[CH2:15][CH3:16])[S:11][C:10]=2[C:18]=1[Cl:21]
Reactant: CCOC(=O)COc1cc2cc(C(O)CC)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCC(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To 9.5 g of ethyl[[6,7-dichloro-2-(1-hydroxypropyl)benzo[b]thien-5-yl]oxy]acetate in 210 ml of ethanol is added 180 ml of 6N sodium hydroxide solution and the mixture is stirred at 100° for 30 mins. The cooled mixture is concentrated in vacuo to give a white slurry which is diluted with 400 ml of ice water and 300 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate and evaporated to dryness. Recrystallization of the residue from ethyl ether and hexane gives 7.5 g of [[6,7-dichloro-2-(1-hydroxypropyl)benzo[b]thien-5-yl]oxy]acetic acid, mp 156°-158°.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1c(F)cccc1Nc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1c(F)cccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
A mixture of (3-fluoro-2-nitrophenyl)phenylamine (1.06 g, 4.56 mmol) and 10% Pd/C (100 mg) in EtOAc (20 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 7 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% EtOAc in cyclohexane) affording 3-Fluoro-N1-phenylbenzene-1,2-diamine (440 mg, 48%). LCMS: RT 3.46 min [M+H]+ 203.1.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].C([NH:35][CH2:36][C:37](O)=[O:38])(OC(C)(C)C)=O>>[NH2:35][CH2:36][C:37]([NH:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4])=[O:38]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Product: NCC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1

Procedure:
(2R)-2-Amino-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one (free-base) was acylated with Boc-glycine and deprotected according to Step 2 of Example 1 to furnish (2R)-2-(2-Aminoacetamido)-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one. Rt 2.23. MS (ESI+) [M+H]+ 419.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[NH2:26][C:27]1[CH:32]=[C:31]([C:2]2[C:3]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[N:6][CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(N)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-aminophenylboronic acid, hemihydrosulfate in a manner analogous to Example 269. MS (M+H)+ 457.
Reaction SMILES: [CH3:1][SH-:2][C:3](=[S:9])[N:4]([CH2:7][CH3:8])[CH2:5][CH3:6].CCN(C([S-])=S)CC.I([O-])(=O)(=O)=[O:19].[Na+].O>CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:6][CH2:5][N:4]([C:3]([S:2]([CH3:1])=[O:19])=[S:9])[CH2:7][CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCN(CC)C(=S)[SH-]C
Agent: CCN(CC)C(=S)[S-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=S)S(C)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DDTC-Me SO) was prepared from S-Methyl-N, N-diethyldithiocarbamate (DDTC-Me). The synthesis of DDTC-ME was carried out as described by M. D. Faiman et al., Alcoholism, 7, 307 (1983), Sodium metaperiodate (200 mg) (Sigma Chemical Co.) was dissolved in 25 ml of 50:50 MeOH:H2O at 0° C. DDTC-Me (200 mg) was separately dissolved in 2 ml of methanol, and was then cooled to 0° C. before addition to a constantly stirring solution of sodium metaperiodate in MeOH:H2O. The reaction mixture was stirred for 24 hr at 0° C. and then was diluted to 100 ml with cold 0.1 M potassium phosphate buffer (ph 7.4). The resulting colorless solution was then extracted with methylene chloride. The organic layer was treated with activated charcoal, and the charcoal was removed by filtration through a Celite bed. The solvent was removed under reduced pressure to obtain the crude product which was then purified by preparative HPLC (C-18, 5 micron, 150 mm×10 mm column, Alltech) using 30:70 acetonitrile:H2O (acetonitrile, Fisher Scientific, HPLC grade) at a flow rate of 2.5 ml/min. The fractions containing the DDTC-Me SO were pooled and diluted with four times the original volume with water. The diluted pooled fractions were extracted with methylene chloride. The solvent was dried with sodium sulfate and removed under reduced pressure to yield 50 mg of product a colorless oil: 1H NMR (300 MHz, CDCl3) 3.25-3.42 (m, 4H), 2.72 (s, 3H), 1.23 (t, 3H), 1.17 (t, 3H); mass spectroscopy: CIMS (NH3) M/Z, 180 (M+1); IR (neat): 2954, 1668, 1436, 1400, 1317, 1136, 1113, 747 cm-1.