Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[C:29]([O:28][C:26](=[O:27])[NH:25][CH2:24][C:7]1[N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:9](=[O:19])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)O)cc12
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(CO)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 4-butoxy-3-{{(tert-butoxycarbonyl)-amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (synthesized according to the method similar to that in Example 76 (1)) (0.45 g, 3.5 mmol) and N-methylmorpholine (0.13 ml, 1.2 mmol) in tetrahydrofuran (10 ml) was added ethyl chloroformate (0.12 ml, 1.2 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the obtained mixture was added sodium tetrahydroborate (0.11 g, 3 mmol) and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(4-butoxy-6-hydroxymethyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.33 g, 76.7%) as crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][C:5]([NH:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[NH:10][C:9]1=[O:19])=[O:6].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([N:16]1[CH2:15][CH2:14][C:11]2([NH:10][C:9](=[O:19])[N:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH3:20])[CH3:1])[C:12]2=[O:13])[CH2:18][CH2:17]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCC(=O)NN1C(=O)NC2(CCNCC2)C1=O
Solvent: c1ccncc1
Product: CC(C)CCC(=O)NN1C(=O)NC2(CCN(S(C)(=O)=O)CC2)C1=O

Procedure:
A solution of 0.514 g of 2(R)-[1(S)-tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide in 10 ml of dry pyridine was cooled to 0° C. with stirring and 0.13 ml of methanesulphonyl chloride added. The mixture was allowed to return to room temperature and was stirred for 2 days. The solvent was evaporated and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography using 5% methanol in dichloromethane for the elution. There was obtained 0.322 g of 2(R)-[1(S)-tert-butoxycarbonyl)-4-phenylbutyl]-N-[8-(methanesulphonyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.C([O-])=O.[NH4+]>CO.[Pd].O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(O)c(N)c1
Reaction time: 0.04 h

Procedure:
To a 2000 ml three-necked flask containing 3-Nitro-4-hydroxy-benzoic acid methyl ester (43 g, 2188 mmol) in MeOH (860 ml; 20 vols) was added palladium on carbon in water (2 g in 10 ml of water). Ammonium formiate (68.76 g, 5 eq.) was added in a single portion under stirring. After 2 to 3 minutes a suspension was observed, and temperature raised from 20° C. to 30° C. Ice bath was used to cool reaction mixture to 20° C. and the reaction was stirred at 20° C. for 40 minutes until completion (no more yellow color). Reaction mixture was filtered on silica plug, rinsed with MeOH, and the filtrate was concentrated under vacuum to give a green oil which was taken up in ethyl acetate (400 ml). The organic phase was washed twice with water, dried over MgSO4, filtered and concentrated to give a cream solid m=31.35 g (86%).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[CH2:13]([C:15]1[CH:26]=[CH:25][C:18]2[C:19](=O)[O:20]C(=O)[NH:22][C:17]=2[CH:16]=1)[CH3:14].Cl.[OH-].[Na+]>CCCCCC.O1CCCC1.O>[NH2:22][C:17]1[CH:16]=[C:15]([CH2:13][CH3:14])[CH:26]=[CH:25][C:18]=1[C:19](=[O:20])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: CCc1ccc2c(=O)oc(=O)[nH]c2c1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)Cc2nnnn2C)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 13.4 ml) was added to a solution of 1,5-dimethyltetrazole (3.54 g) in dry tetrahydrofuran (83 ml) at 0° under nitrogen. The mixture was stirred for 0.5 hour and 7-ethyl-1H-3,1-benzoxazine-2,4-dione (2.3 g) was added. The mixture was allowed to warm to room temperature during 2 hours. Water (100 ml) was added. The mixture was acidified to pH 1 with hydrochloric acid (5N) and then neutralised with aqueous sodium hydroxide (5N). The mixture was extracted with dichloromethane (2×100 ml). The extract was dried and evaporated. The residue was purified by flash chromatography on Kieselgel 60 using dichloromethane:industrial methylated spirit 99:1 as the eluent. This gave the novel compound 1-(2-amino-4-ethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone in crude form as an oil.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.O.NN.[OH-].[K+].Cl>O(CCO)CCO.O>[CH:1]1([CH2:6][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ccc(-c2ccc(C(=O)C3CC=CC3)cc2)cc1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: Oc1ccc(-c2ccc(CC3CC=CC3)cc2)cc1
Temperature: 200 °C

Procedure:
A mixture of (3-cyclopenten-1-yl)(4'-methoxy-[1,1'-biphenyl]-4-yl)-methanone (30 g), hydrazine hydrate (36 ml) and potassium hydroxide (36 g) in 2,2'-oxybisethanol (250 ml) was heated gently, at reflux temperature for 45 min. The low boiling material was distilled off and the mixture was heated under reflux, at 200° C. for 2 h. The cooled reaction mixture was poured into water, acidified with dilute hydrochloric acid and the resulting light brown precipitate was filtered off. This solid was dissolved in methylene dichloride. The solution was washed twice with water and dried (MgSO4), and the solvent was removed. Trituration of the residue with light petroleum gave 4-(3-cyclopenten-1-ylmethyl)-4'-hydroxy-1,1'-biphenyl as a buff solid (25.5 g). A small sample, recrystallised from ether-light petroleum had m.p. 138°-140° C.
Reaction SMILES: CCN([CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)=[O:10])CC.[CH:18]1C=C[C:21]([CH2:24][O:25][C@H:26]([C:32]([OH:34])=[O:33])[C@H:27]([NH2:31])[C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:7]2[CH:6]=[C:21]([CH:20]=[CH:19][CH:18]=2)[CH2:24][O:25][C@H:26]([C:32]([OH:34])=[O:33])[C@@H:27]([C:28]([OH:30])=[O:29])[NH2:31])=[O:10])=[CH:16][CH:15]=1
Reactant: CCN(CC)CCNC(=O)c1ccc(I)cc1
Reactant: N[C@H](C(=O)O)[C@H](OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N[C@H](C(=O)O)[C@H](OCc1cccc(NC(=O)c2ccc(I)cc2)c1)C(=O)O
Reaction time: 24 h
Yield: 94.8 %

Procedure:
Protected I-BzA-TBOA (120 mg, 0.17 mmol) was dissolved in 1 ml of chloroform. After adding 1 ml of TFA, the obtained mixture was stirred for 24 hours. Then the solvent was distilled off and water was added to the residue followed by repeated freeze-drying. Thus, 78 mg (76%) of the title compound was obtained. Amorphous product; [α]D −37.7° (c 0.34, CHCl3); 1H NMR (CDCl3, 400 MHz); ™4.30 (d, 1 H, J=5.0 Hz), 4.45 (d, 1 H, J=11.0 Hz), 4.68 (d, 1 H, J=11.0 Hz), 7.14 (d, 1 H, J=7.5 Hz), 7.30 (t, 1 H, J=8.0 Hz), 7.59 (s, 1 H), 7.64 (d, 1 H, J=8.5 Hz), 7.67 (d, 2 H, J=7.5 Hz), 7.86 (d, 2 H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.[ClH:15].[C:16](=[NH:21])(OCC)[CH3:17].C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:15].[ClH:15].[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:16](=[NH:21])[CH3:17])[S:3][C:4]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(C)=N
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 25 °C
Reaction time: 240 h
Yield: 69 %

Procedure:
A suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)thiazole (205 mg), ethyl acetimidate hydrochloride (370 mg) and diisopropylethylamine (0.697 ml) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 10 days and evaporated under reduced pressure. To the residue was added hydrogen chloride in ethyl acetate (4N, 4 ml) and crystallized from methanol and ethyl acetate. The precipitate was collected by filtration and recrystallized from methanol and 2-propanol to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)acetamidine dihydrochloride (220 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl>>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCOCCl
Reactant: O=Cc1ccccc1O
Product: COCCOCOc1ccccc1C=O
Yield: 71.6 %

Procedure:
The hydroxyl group of 2-hydroxybenzaldehyde (3.0 g) was protected by use of 2-methoxyethoxymethyl chloride (3.1 g) in accordance with (production process 1), to thereby produce 2-methoxyethoxymethoxybenzaldehyde (3.7 g, yield: 70%). The thus-produced 2-methoxyethoxymethoxybenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.4 g, yield: 52%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3[C:29]2[N:34]=[C:33]([C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=2)=[N:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:29]2[N:34]=[C:33]([C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=2)=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Yield: 22.5 %

Procedure:
To a solution of 6-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylpicolinamide (100 mg, 0.189 mmol) in 1,4-dioxane (2 mL) was added aq.NaOH (7 M, 2 mL) and the reaction was heated at 90° C. for 1 h. The reaction was then quenched with water to get a precipitate. The precipitate was filtered and washed with water (2×100 mL) and dried. The crude product was crystallized from 20% EtOAc in petroleum ether (3×10 mL) to give 6-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)-N-methylpicolinamide (16 mg, 23%). MS (ESI, pos. ion) m/z: 377.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.67-8.69 (m, 2H), 8.48 (s, 1H), 8.00 (d, 2H, J=4.0 Hz), 7.80-7.82 (m, 1H), 7.69 (dd, 1H, J=8.4, 1.6 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=7.6 Hz), 3.71-3.78 (m, 1H), 2.93 (d, 3H, J=4.8 Hz), 1.23 (d, 6H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9].C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:29][C:24]1[CH:23]=[C:22]([C:5]2[N:4]=[N:3][C:2]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[C:7]([C:8]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[O:9])[CH:6]=2)[CH:27]=[C:26]([CH3:28])[CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(Cl)c3)nnc2Cl)cc1OC
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(Cl)c3)nnc2-c2ccccn2)cc1OC
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-6-(3-chloro-5-methylphenyl)-N-(3,4-dimethoxybenzyl)pyridazine-4-carboxamide (3-1, 0.01 g, 0.023 mmol, 1.0 equiv; made analogously to 1-3) in DMF (0.50 mL) at 25° C. was added 2-tributylstannylpyridine (0.017 g, 0.046 mmol, 2.0 equiv), cesium fluoride (0.007 g, 0.046 mmol, 2.0 equiv), copper (I) iodide (0.00044 g, 0.0023 mmol, 0.1 equiv), and tetrakis(triphenylphosphine) palladium(0) (0.0027 g, 0.0023 mmol, 0.1 equiv) and the reaction mixture was heated to 80° C. for 0.5 hours. The reaction was cooled and partitioned between EtOAc and water. The organic phase was dried over MgSO4 and concentrated. The reaction mixture was purified by normal phase column chromatography (0 to 100% EtOAc in hexanes) to give the product (3-2) as a tan solid. HRMS [M+H] C25H27ClN4O4 calc'd 475.1531. found 475.1549.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:4][CH:3]=1.C[Si]([N-:32][Si](C)(C)C)(C)C.[Li+]>>[NH2:32][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(Cl)nc4)c3s2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)nc4)c3s2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a stirred mixture of 4-(7-(6-chloropyridin-3-yloxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 130, Step B, 78 mg, 0.197 mmol), lithium bis(trimethylsilyl)amide (LHMDS, 0.433 mL, 0.433 mmol, 1M in hexanes), and Pd2(dba3) (9.02 mg, 0.00985 mmol), was added P,P-dicyclohexyl(3-(2-N, N-dimethylaminophenyl)-phenyl)phosphine (7.75 mg, 0.0197 mmol). The mixture was sparged with nitrogen for 2 minutes, and then heated to 80° C. for 18 hours. After cooling to room temperature, 2N aqueous HCl (0.5 mL) was added and stirring was continued for 1 hour at room temperature. The mixture was partitioned between dichloromethane (5 mL) and 1:1 saturated aqueous NaHCO3/water (5 mL). The phases were separated, and the aqueous phase was re-extracted with dichloromethane (2×2 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC plate (1 mm thickness, Rf=0.45) eluting with 15% MeOH/CHCl3. The product was obtained as a beige, waxy solid (11 mg, 12%). 1H NMR (400 MHz, 1:1 CDCl3/CD3OD) δ 8.44 (d, J=5 Hz, 1H), 7.84-7.95 (m, 6H), 7.41 (m, 1H), 6.71 (d, J=9 Hz, 1H), 6.63 (d, J=5 Hz, 1H), 2.97 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH3:16])=[CH:11][CH:10]=1>CCO>[CH3:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[OH:15]
Reactant: Cc1ccc(N)cc1O
Reactant: Brc1ccccn1
Solvent: CCO
Product: Cc1ccc(Nc2ccccn2)cc1O
Temperature: 90 °C
Yield: 43 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-bromopyridine (0.6 mL, 6.33 mmol) and 5-amino-o-cresol (390 mg, 3.16 mmol) in 10% aqueous EtOH (10 mL) was heated at 90° C. for 18 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 43% yield (271 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH:9]([CH3:27])[CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])=[O:12]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:17]([O:16][CH2:15][CH2:14][O:13][C:11](=[O:12])[CH2:10][CH:9]([CH3:8])[CH3:27])=[O:18])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CO)C(=O)O
Reactant: CC(C)CC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)CC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 58.8 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3-methylbutanoate (574 mg, 2.0 mmol) were reacted to provide 326 mg (59% yield) of the title compound (26) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.80 (m, 1H), 6.11 (m, 1H), 5.78 (br s, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.94 (m, 1H), 2.01-2.24 (m, 3H), 1.48 (2d, 3H), 0.99 (2d, 6H). MS (ESI) m/z 278.04 (M+H)+; 295.09 (M+NH4)+; 300.04 (M+Na)+; 276.10 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6](=[O:15])[CH2:7]C(OC(C)(C)C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6](=[O:15])[CH3:7]
Reactant: COC(=O)[C@H](CC(=O)CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 80 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-4-oxo-hexanedioic acid 6-t-butyl ester 1-methyl ester (3.04 g, 8.01 mmol), toluene (80 mL) and para-toluene sulfonic acid hydrate (115 mg, 0.61 mmol) and refluxed for 6.5 h and then overnight for 16 h at room temperature. The mixture was concentrated in vacuo and purified by flash column chromatography (silica gel 60, 230-400 mesh; 50% ethyl acetate/hexanes) which afforded (S)-2-benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester (1.79 g, 80%) as a pale yellow viscous oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:31]1[C:35]2[CH:36]=[CH:37][C:38](B(O)O)=[CH:39][C:34]=2[CH2:33][CH2:32]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH:28]2[CH2:29][CH2:30]2)[N:8]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC2CC2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(CC2CC2)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
A mixture of 4′-{[4-butyl-2-(cyclopropylmethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II) acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecular sieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.59 g, 76%) as a pale-yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:16]([C:25]([NH2:27])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][C:16]([C:25]([NH2:27])=[S:42])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=O)cc12
Solvent: Cc1ccccc1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Yield: 65 %

Procedure:
To a suspension of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.44 g, 1 mmol) in toluene (20 ml) was added Lawesson's reagent (0.24 g, 0.6 mmol), and the mixture was refluxed under heating for 1 h. The reaction mixture was purified by silica gel column chromatography to give tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.18 g, 39.1%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O>>[CH2:3]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)[CH2:4][CH:5]([CH3:8])[CH3:6]
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(-c2[nH]c(-c3ccc(NCCC(C)C)cc3)nc2C(=O)Nc2nccs2)cc1
Yield: 63.6 %

Procedure:
2-(4-Aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.8 g) obtained in Example 48, sodium borohydride (0.13 g), 2.5N sulfuric acid (0.4 ml) and isopentyl aldehyde (0.3 ml) were treated in the same manner as in Example 72 to give 2-(4-isopentylaminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (0.3 g), melting point 235-239° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Reactant: C1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.2 mmol, from Example Z) was reacted with pyrrolidine (3.0 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.44 g of 2-benzyloxy-5-methoxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.44 g, 1.08 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) afforded 0.2 g of the title compound, mp 177-179° C.;