Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH:13]([CH2:35][OH:36])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:36][CH2:35][CH:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[N:18]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OCc4ccccc4)CC3CO)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CCNCC3CO)nc(-c3ccccc3O)nc2c1

Procedure:
To 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (200 mg, 0.41 mmol) in 1.7 mL of methanol was added 39 mg of Pd/C (10% weight Pd on carbon). The reaction mixture was subjected to hydrogenation using a H2 balloon for 3 h. The reaction mixture was filtered through Celite and the solvent was removed to give 2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. This amine was treated with (R)-2-hydroxy-4-methyl-pentanoic acid (60 mg, 0.45 mmol), BOP (200 mg, 0.45 mmol) and 115 μL of triethylamine in 1.6 mL of DMF at room temperature for 12 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and 20 mL of water, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was subjected to purification using 60-100% EtOAc-hexanes to give (R)-2-hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one. LC/MS: m/z 465 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:19](=[O:21])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of 2-tert-butylaniline (5.0 g, 33.5 mmol) and triethylamine (11.2 g, 110.6 mmol) in THF (350 mL) was added acetyl chloride (2.89 g, 36.9 mmol). After being stirred at room temperature for 3 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting white solid was triturated with hexane/ethyl acetate to give the title compound (6.13 g) as a white crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14].O.O.Cl[Sn]Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1Cc2cccc(N)c2C1=O
Temperature: 80 °C
Yield: 96.2 %

Procedure:
At room temperature, a solution of N-Methyl-7-nitro-2,3-dihydroisoindole-1-one (561.0 mg, 2.92 mmol) in EtOAc (8.4 mL) is treated with SnCl2.2H2O (2.68 g), stirred at 80° C. under reflux for 5 h, and treated with 30 mL of 5N NaOH at 0° C. After the both layers are separated, the aqueous layer is extracted with EtOAc (2×8 mL), the combined extracts are washed with brine (5 mL), dried (MgSO4), and evaporated to give 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (455.9 g, 2.81 mmol) in 96%. Yellow solid. Rf (CH2Cl2/EtOAC 1:1) 0.53. 1H-NMR (400 MHz, CDCl3) 3.12 (s), 4.28 (s), 5.20 (br. s), 6.56 (d, J=8.0), 6.68 (d, J=8.0), 7.21 (dd, J=8.0, 8.0).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:16]1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc2ccccc2[nH]1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(1H-Indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.165 g) in dichloromethane (10 mL) was treated with trifluoroacetic acid (2 mL) and stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure to afford (1H-Indol-2-yl)-piperazin-1-yl-methanone trifluoroacetate salt. (1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=8.07 Hz, 1H), 7.44 (dd, J=8.3, 0.8 Hz, 1H), 7.24 (m, 1H), 7.08 (m, 1H), 6.91 (s, 1H), 4.12 (t, J=5.0 Hz, 4H), 3.35 (t, J=5.3 Hz, 4H)). This intermediate was dissolved in acetone (5 mL), treated with potassium carbonate (0.22 g), iodohexane (0.106 g) and heated at 50° C. for 10 h. Evaporation of the solvent under reduced pressure afforded crude product which was purified via preparative thin layer chromatography eluting with 10% methanol/dichloromethane to give the title compound (0.06 g). 1H NMR (400 MHz, CD3OD): δ 7.60 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.21(ddd, J=8.1, 7.1, 1.1 Hz, 1H), 7.16-7.04 (m, 1H), 6.81 (s, 1H), 3.89 (br s, 4H), 2.56 (t, J=5.0 Hz, 4H), 2.43-2.40 (m, 2H), 1.58-1.52 (m, 2H), 1.34 (br s, 6H), 0.94-0.90 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])C=C.[CH3:26][C:27]1C=CC=C[C:32]=1C>>[CH2:32]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:9][CH:10]=[N:11]2)[CH:27]=[CH2:26]
Reactant: C=CCOc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OC
Reactant: Cc1ccccc1C
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine (0.46 g, 1.13 mmol) (from Example 19, Step C, supra) in o-xylene (75 mL) was heated at 150° C. for 4 hours. At the end of this period, TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solution was concentrated to a small volume and filtered. The solid was collected and dried in vacuo to give the desired 5-allyl-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.35 g, 76%).
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:32])[C@@H:20]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2)C1
Reaction time: 0.03 h
Yield: 68.7 %

Procedure:
Add aqueous 37% formaldehyde (45 mL, 0.55 mmol) to a solution of 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene (200 mg, 0.5 mmol) in dichloroethane (30 mL). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (159 mg, 0.75 mmol). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry (MgSO4), filter and concentrate. Purify the residue via chromatography eluting with methylene chloride/methanol (90:10) to provide the title compound as a yellow solid (143 mg, 67%): mp 87–91° C.: 1H NMR (CDCl3): δ1.78 (m, 1H), 1.96 (m, 1H), 2.22 (m, 1H), 2.32 (s, 3H), 2.35 (s, 3H), 2.38 (ddd, 1H), 2.58 (ddd, 1H), 2.75 (ddd, 1H), 2.86 (ddd, 1H), 2.94 (dd, 1H), 3.16 (ddd, 1H), 3.90 (m, 1H), 4.05 (m, 1H), 4.94 (s, 1H), 6.30 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.98 (t, 1H), 7.04 (d, 1H), 7.17–7.32 (m, 5H); MS (APCI) m/z (rel intensity) 417 (100).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1.C(O)=O>O>[CH:23]([N:20]1[CH2:19][CH2:18][N:17]([C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:2]=[O:1])[CH2:22][CH2:21]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCN(c2cc(OC(F)(F)F)cc(C3OCCO3)c2)CC1
Solvent: O=CO
Solvent: O
Product: CC(C)N1CCN(c2cc(C=O)cc(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Yield: 69.6 %

Procedure:
Water (1.3 mL) was added to a suspension of 1-(3-(1,3-dioxolan-2-yl)-5-(trifluoromethoxy)phenyl)-4-isopropylpiperazine (22, 996 mg, 2.76 mmol) and formic acid (6.71 g, 145 mmol). The mixture was heated to 60° C. for 20 h. The reaction mixture was concentrated to a brown oil in vacuo. The oil was dissolved in EtOAc (100 mL) and the solution was washed with saturated aq. NaHCO3 solution (100 mL) and brine (100 mL). After drying over Na2SO4, the suspension was filtered and the filtrate concentrated to an orange oil. The residue was purified by silica gel chromatography eluting with 0-80% EtOAc in hexanes to afford the title compound (608 mg, 70%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.92 (s, 1H), 6.93 (s, 1H), 7.31 (s, 1H), 7.13 (s, 1H), 6.92 (s, 1H), 3.30-3.28 (m, 4H), 2.73 (sept, 1H), 2.70-2.64 (m, 4H), 1.10 (d, J=6.5 Hz, 6H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:33]=[CH:32][C:14]2[S:15][CH2:16][CH2:17][N:18]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1)=[O:10].C([O-])(=O)C.[NH4+]>CN(C=O)C>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([S:19]([N:18]2[CH2:17][CH2:16][S:15][C:14]3[CH:32]=[CH:33][C:11]([C:9]4[O:10][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=5[N:8]=4)=[CH:12][C:13]2=3)(=[O:21])=[O:20])=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccccc1O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCS2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCSc2ccc(-c3nc4ccccc4o3)cc21
Yield: 5.7 %

Procedure:
N-(2-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (25 mg, 51 μmol) was dissolved in 1 mL of DMF. Ammonium acetate (39 mg, 506 μmol) was added and the reaction was subjected to microwave irradiation (150° C., 25 min). LCMS analysis of the reaction mixture showed consumption of starting material. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography with gradient elution of hexanes with 10-60% EtOAc to provide 2-(4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)benzo[d]oxazole (1.4 mg, 2.9 μmol, 6% yield) as a yellow oil. LCMS (+ESI) m/z=477.4 [M+H]+; 1H-NMR (CDCl3) δ 7.7-7.9 (m, 6H), 7.40 (d, 2H), 7.30 (d, 1H), 7.05 (dd, 1H), 6.80 (d, 1H), 3.50 (t, 2H), 3.05 (t, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 55 (216 mg, 0.46 mmol) is treated with acid chloride 6 (137 mg, 0.55 mmol) using Method D to give the title compound.
Reaction SMILES: IC.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([OH:17])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([O:17][CH3:27])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Iodomethane (554 mg) was added to a suspension of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionoic acid (1.1 g) and potassium carbonate (539 mg) in N,N-dimethylformamide (7 mL). The mixture was stirred for 2 hours at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate (1.2 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=O)[NH:19]4)[CH:17]=3)[C:5]2=[N:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[CH:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=[S:39])[NH:19]4)[CH:17]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)NC(=O)COCC1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)NC(=S)COCC1(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 129 %

Procedure:
To a solution of (5R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (intermediate A22A) (62 mg, 146 μmmol) in dioxane (2.2 ml) at 23° C. was added 2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (38.3 mg, 94.6 μmmol) and the mixture was stirred at 80° C. for 3 h. The reaction mixture was poured onto sat. NaHCO3-solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a yellow solid, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the (R)-5-[5-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thione (54 mg, 84%) as a white solid. MS (ISP): m/z=443.0 [(M+H)+].
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:16]([Cl:20])=[CH:17][C:18](Cl)=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[Cl:21])[C:6]1=[O:22])[CH:2]=[CH2:3].[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C(#N)C>[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:18]2[CH:17]=[C:16]([Cl:20])[C:13]3[C:14](=[O:15])[N:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6](=[O:22])[C:7]4[C:12]=3[C:11]=2[C:10]([Cl:21])=[CH:9][CH:8]=4)[CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(Cl)cc(Cl)c(c23)C1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCON1C(=O)c2ccc(Cl)c3c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc(Cl)c(c23)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
A suspension of 2-allyloxy-4,6,7-trichlorobenzo[de]isoquinoline-1,3-dione (0.44 g, 1.2 mmol, from Example I4), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (0.3 g, 1.5 mmol), triethylamine (0.2 g, 2.0 mmol), and 20 mL of acetonitrile was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the residue partitioned between water and dichloromethane. The organic layer was dried and evaporated in vacuo. The residue was chromatographed on silica gel (ICN 230-400 mesh) eluting with dichloromethane/ethyl acetate (80:20) to give 0.35 g of the title compound, mp 123-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24](=[S:26])[NH2:25])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:28]1[C:33](=O)[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[S:26][C:28]5[CH2:29][NH:30][CH2:31][CH2:32][C:33]=5[N:25]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1nc2c(s1)CNCC2
Temperature: 60 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a solution of 2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethanethioamide (0.300 g, 0.733 mmol) in DMF (5 mL) was added 1,1-dimethylethyl 3-bromo-4-oxopiperidine-1-carboxylate (0.310 g, 1.11 mmol). The solution was stirred at 60° C. for 72 h. An additional 0.100 g (0.360 mmol) of 1,1-dimethylethyl 3-bromo-4-oxopiperidine-1-carboxylate was added to the reaction mixture, which was then heated at 60° C. for an additional 24 h. The solvent was removed in vacuo and the crude reaction mixture was purified via column chromatography (SiO2, 50% hexanes/ethyl acetate). This intermediate was then subjected to 10% TFA in CH2Cl2 at room temperature. After removal of the solvent, the crude amine salt was taken up in fresh MeOH and treated with Bio-Rad AG 1-X8 resin hydroxide form until pH 8. Filtration and concentration in vacuo provided 0.247 g (69%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].P(Cl)(Cl)([Cl:32])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2[Cl:32])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 1 hour at room temperature there is obtained isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]4-fluorobenzoate, 1H-NMR (CDCl3, 60 MHz): 7.90 ppm (d,1H), 7.48 ppm (d,1H), 6.96 ppm (s,1H), 5.30 ppm (m,1H), 1.40 ppm (d,6H);
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1/[CH:17]=[CH:18]/[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20].O>CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH:17]1[CH2:4][CH:18]1[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20]
Reactant: CON(C)C(=O)/C=C/c1cc(F)ccc1Br
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 122 mg, 3.05 mmol, Aldrich) was added to a suspension of trimethylsulfoxonium iodide (671 mg, 3.05 mmol, Aldrich) in DMSO (6 mL). The mixture was stirred at 25° C. for 30 min, and (E)-3-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylacrylamide was added as a solution in DMSO (3 mL). The mixture was stirred at 25° C. for 12 h, then transferred to a separatory funnel with H2O (40 mL), and the title compound was extracted using 75% ether/hexane (3×40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by flash column chromatography (33% EtOAc/hexane) afforded the title compound as a colorless oil. MS m/z: 302 and 304 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23]>>[NH2:1][C@H:2]([C:11]([NH:16][C@H:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 2 h
Yield: 75 %

Procedure:
In a batch procedure (300 l), Mal-Tyr-OEt (0.25M) and Arg-OEt (0.25M) are reacted with α-chymotrypsin (0.025 mg/ml) at pH 9.5 and 25° C. After 2 hours, filtration of the precipitate and washing with water result in 26.0 kg of Mal-Tyr-Arg-OEt (75% of theoretical yield) with an HPLC purity greater than 97%.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:29]1
Reactant: OC1CCCNC1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCCC(O)C4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 3-hydroxypiperidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.40 (2H, m), 1.75 (1H, m), 1.80 (1H, m), 2.92 (1H, dd, J=12.64, 8.79 Hz), 3.51 (1H, m), 4.10 (1H, m), 4.33 (1H, dd, J=12.63, 3.84 Hz), 4.91 (1H, d, J=4.40 Hz), 7.15 (1H, tt, J=7.42, 1.09 Hz), 7.20 (1H, d, J=9.34 Hz), 7.42 (2H, dd, J=8.52, 7.42 Hz), 7.80 (1H, d, J=9.34 Hz), 8.21 (2H, dd, J=8.79, 1.38 Hz), 8.53 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-chlorophenol was dissolved in dichloromethane. Triethylamine (1 eq) and acetic anhydride (2 eq) were added. The mixture was stirred at room temperature for 5 hours. Solvent was eliminated by vacuum evaporation. The evaporation residue was taken up in dichloromethane, dried on magnesium sulfate and the solvent was eliminated by vacuum evaporation. Purification was made by chromatography on silica gel (elution: cyclohexane/ethyl acetate 95:5).