Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=C=O.[CH2:29]([N:31]1[C:43]2[CH:42]=[CH:41][C:40]([NH2:44])=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30]>>[CH2:29]([N:31]1[C:43]2[CH:42]=[CH:41][C:40]([NH:44][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:7])=[O:18])=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)Nc3cccc(C)c3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methylbenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 89% purity by LC/MS. MS(ESI+): m/z=484.4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:22]#[N:23])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[NH:12][C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31].[C:33](OCC)(=O)C>CN(C=O)C>[CH2:30]([N:12]1[C:11]([N:8]2[C:9]3[CH:10]=[C:2]([CH3:33])[CH:3]=[C:4]([C:22]#[N:23])[C:5]=3[CH:6]=[CH:7]2)=[C:16]([CH:17]([CH3:19])[CH3:18])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:31]
Reactant: CCOC(C)=O
Reactant: CCI
Reactant: CC(C)c1c(-n2ccc3c(C#N)cc(Cl)cc32)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-n2ccc3c(C#N)cc(C)cc32)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
6-Chloro-1-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (35 mg, 0.113 mmol, 1.0 eq.) was dissolved in 0.5 mL DMF. Potassium carbonate (16 mg, 1 eq.) was added and the reaction mixture was stirred at room temperature for 10 minutes. EtI (9.1 μL, 1 eq.) was added. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated and purified (silica gel, 0-80% EtOAC/hexane) to give a white powder (14 mg, 37%). LC-MS shows 335.0 (M−1). 1H NMR (300 MHz, CDCl3): δ 9.37 (br, 1 H), 8.05 (s, 1H), 7.08 (m, 2H), 6.80 (d, 1H), 3.58 (m, 1H), 3.17 (m, 1H), 2.62 (s, 3H), 1.88 (m, 1H), 1.17 (dd, 6H), 1.02 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>CN(C=O)C>[CH2:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:20][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[CH3:12]
Reactant: CCN(CCCl)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
A mixture of compound 3a (500 mg, 2.7 mmol), K2CO3 (750 mg, 5.4 mmol), and KI (90 mg, 0.54 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (600 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. The reaction was quenched and the solvent evaporated and purified by silica gel column chromatography to provide compound 3 (400 mg, 1.55 mmol, 57% yield) as a brown oil. 1H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 7.14 (m, 2H), 6.75-6.64 (m, 6H), 6.57 (m, 1H), 3.98 (t, J=5.8 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H), 3.41 (q, J=7 Hz, 2H), 1.09 (t, J=7 Hz, 3H). HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.1494, found: 258.1436.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](C2C=CC(F)=CC=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[CH:10][C:9]([C:10]2[C:9]3[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[N:34][N:33]=[N:32]5)[CH:26]=4)=[N:7][C:8]=3[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2cccc(-c3ccc(F)cc3)c2N1

Procedure:
Prepared from {4′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K56) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (54 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:20]=[N:19][C:18]=1[O:29]C)=O)(C)(C)C.C[Si](C)(C)Cl.Cl.CN(C)C=O>C(#N)C.O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:29])[NH:19][N:20]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:22]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
25 mg of 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester, 7.4 mg trimethylchlorosilane and 11.3 mg KI dissolved in 1 ml of acetonitril are stirred for 2 h at 60° C. Subsequently 0.5 ml of a 4N solution of hydrochloric acid in dioxane is added and stirred for 2 h at room temperature. The solution is diluted into DMF (dimethylformamide)/water and directly purified by HPLC (high performance liquid chromatography) on a RP18 (reversed phase 18) column giving 4.5 mg 4-(1H-Indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[Al](Cl)(C)C.[CH3:12][S:13]([C:16]1[CH:43]=[CH:42][C:19]([O:20][C:21]2[C:26]3[CH:27]=[C:28]([CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[O:29][C:25]=3[CH:24]=[C:23]([C:37](OCC)=[O:38])[CH:22]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>ClCCCl>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:37]([C:23]2[CH:22]=[C:21]([O:20][C:19]3[CH:42]=[CH:43][C:16]([S:13]([CH3:12])(=[O:14])=[O:15])=[CH:17][CH:18]=3)[C:26]3[CH:27]=[C:28]([CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[O:29][C:25]=3[CH:24]=2)=[O:38])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CN3CCCC3=O)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(CN4CCCC4=O)oc3c2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
To a solution of 3-amino-1-methyl pyrazole (106 mg, 1.09 mmol) in DCE (10 mL) at 0° C. was added Al(CH3)2Cl (1.09 mL, 1M in hexanes) drop-wise. After removal of the ice-bath, the mixture was stirred for min at room temperature. Ethyl 4-(4-(methylsulfonyl)phenoxy)-2-((2-oxopyrrolidin-1-yl)methyl)benzofuran-6-carboxylate (50 mg, 0.11 mmol) was added and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (22 mg, 47%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.97-2.13 (m, 2 H) 2.44 (t, J=8.01 Hz, 2 H) 3.08 (s, 3 H) 3.46 (t, J=6.97 Hz, 2 H) 3.81 (s, 3 H) 4.60 (s, 2 H) 6.54 (s, 1 H) 6.79 (d, J=2.26 Hz, 1 H) 7.09-7.17 (m, 2 H) 7.29 (d, J=2.26 Hz, 1 H) 7.44 (s, 1 H) 7.81-7.98 (m, 3 H) 8.54 (s, 1 H). LCMS m/z 509.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH2:3]1.[Cl:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH2:3]2)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CC(N)C2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 63.3 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(3-aminoazetidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (218b) (144 mg, 0.60 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (104 mg, 0.60 mmol), WSC hydrochloride (343 mg, 1.79 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol) and N-methylmorpholine (0.13 mL, 1.19 mmol), to obtain 151 mg of the title compound as a white solid (64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[C:11]([F:16])([F:15])[CH:12]([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: FC(F)C(F)(F)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Temperature: 70 °C

Procedure:
To a solution of 3-bromo-5-fluorophenol (104 mmol crude) and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and saturated NaCl (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: RT=1.91 min, [M+H] No Ionizable peak (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, 1H, d, J=8.35 Hz; 5.88 ppm, 1H, tt; J=52.95 Hz and 2.64 Hz.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:10]=2[C:9](=[O:19])[N:8]([OH:20])[C:7]1=[O:21].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[C:4]([CH2:5][N:6]2[C:11]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:10]=3[C:9](=[O:19])[N:8]([OH:20])[C:7]2=[O:21])[CH:3]=1
Reactant: O=c1c2sc3ccccc3c2n(Cc2cccc(Br)c2)c(=O)n1O
Reactant: OB(O)c1ccccc1
Product: O=c1c2sc3ccccc3c2n(Cc2cccc(-c3ccccc3)c2)c(=O)n1O

Procedure:
1-(3-Bromo-benzyl)-3-hydroxy-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was treated with phenylboronic acid according to general procedure C. The title compound was obtained as a yellow solid following purification by preparative HPLC. 1H NMR (d6-DMSO, 300 MHz) δ 5.79 (s, 2H); 7.26-7.69 (m, 10H); 8.00 (d, J=9 Hz, 1H); 8.13 (d, J=8 Hz, 2H); Ret. time=3.19 min., m/z=399.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][C:15]=2[OH:25])=[C:4]([CH3:26])[N:3]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[OH:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the product of example 77 (100 mg) in THF (5 mL), LiOH (35.1 mg) in water (5 mL) was added and stirred for 16 h at rt. The solvent was evaporated, the residue redissolved in water and AcOH was added. The precipitate was filtered and dried to give the subtitle compound as a white solid, 50 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(I)cc4)nc23)CC1
Yield: 19.5 %

Procedure:
Beginning with 0.090 gm (0.39 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.157 gm (0.59 mMol) 4-iodobenzoyl chloride, 0.035 gm (19%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH:20](O)([CH3:22])[CH3:21]>>[CH:20]([O:4][C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][N:1]1[S:16]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17])=[O:5])([CH3:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(O)C1CCCN1
Reactant: CC(C)O
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared from DL-proline, isopropanol, and 4-fluorobezenesulfonyl chloride according to the procedure of Intermediate 48 as a clear oil; 1H NMR (CDCl3) δ 1.21-1.28 (m, 6H), 1.80-1.85 (m, 1H), 1.95-2.10 (m, 3H), 3.31-3.49 (m, 2H), 4.26-4.36 (m, 1H), 4.95-5.08 (m, 1H), 7.15-7.23 (m, 2H), 7.89-8.08 (m, 2H); MS (ES) m/z 315.8 (MH+); HRMS for C14H18FNO4S: 338.0830 (M+Na)
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[C:1]1(/[CH:7]=[CH:8]/[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a stirred solution of 2-phenylacetaldehyde (5.0 g, 32.3 mmol) and malonic acid (4.0 g, 38.8 mmol) in pyridine (25.0 mL) was added a catalytic amount of piperidine (0.64 mL, 6.46 mmol) then heated to reflux. After 3 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was slowly added 2N HCl. The white precipitate was filtered off and dried under vacuum to produce the title compound (3.5 g, 55˜80%)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Br:18]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:18][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCCCC(=O)c1ccc(Cl)s1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 118.8 %

Procedure:
Ethyl 6-(5-chloro-2-thienyl)-6-oxohexanoate (50.0 g) was dissolved in methylene chloride (150 ml), to which was added dropwise bromine (24.5 g) with stirring at room temperature. The mixture was stirred at room temperature for 1 hour, a 10% aqueous solution of sodium sulfite was then carefully added until disappearance of the red color of bromine, which was extracted with diethyl ether (200 ml×2). The organic layer was washed with a10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(5-chloro-2-thienyl)-6-oxohexanoate as an oil (64.4 g, >99%).
Reaction SMILES: Cl.[NH2:2][C:3]([CH2:10][CH3:11])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5].[F:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([F:23])[CH:22]=1)[C:16](=[O:19])[CH2:17]Br.C([O-])(O)=O.[Na+].Cl>CN(C=O)C>[F:12][C:13]1[CH:14]=[C:15]([C:16](=[O:19])[CH2:17][NH:2][C:3]([CH2:10][CH3:11])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)(NCC(=O)c1cc(F)cc(F)c1)C(=O)OC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-amino-2-ethylbutanoate hydrochloride from Step A (2.10 g, 11.6 mmol), 3,5-difluorophenacyl bromide (2.99 g, 12.7 mmol), and NaHCO3 (2.43 g, 28.9 mmol) in DMF (20 mL) was stirred at 45° C. for 1 h, and at ambient temperature for 2 h. 1 N aqueous HCl (50 mL) was added and the mixture was extracted with EtOAc (75 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 10 by addition of saturated aqueous Na2CO3 (150 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were treated with CF3CO2H (1.5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=300 (M+1).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.IC1SC2C=CC([O:43][C:44]([F:47])([F:46])[F:45])=CC=2N=1>>[NH:25]1[CH2:26][CH2:27][CH:22]([N:20]2[CH:21]=[C:17]([C:15]3[CH:16]=[C:11]([C:8]4[S:9][C:10]5[CH:2]=[CH:3][C:4]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:5][C:6]=5[N:7]=4)[C:12]([NH2:28])=[N:13][CH:14]=3)[CH:18]=[N:19]2)[CH2:23][CH2:24]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: FC(F)(F)Oc1ccc2sc(I)nc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(OC(F)(F)F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-5-trifluoromethoxy-1,3-benzothiazole and conducting the Suzuki coupling at 50° C. for 2 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.84 (d, J=1.6 Hz, 1H), 8.43 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.15 (m, 1H), 8.09 (s, 1H), 7.55 (m, 1H), 4.68 (m, 1H), 3.61-3.68 (m, 2H), 3.28-3.30 (m, 2H), 2.35-2.42 (m, 4H). MS(ES+): m/z=461.15 [MH+]. HPLC: tR=1.84 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:28][O:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:29])[NH:6]2.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:28][C@@H:26]([OH:27])[CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:29])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H](O)CN1CCN(C(C)=O)CC1
Yield: 66.1 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 51, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmethoxy]quinazoline (200 mg, 0.506 mmol), (prepared as described for the starting material in Example 48), was reacted with 1-acetylpiperazine (195 mg, 1.51 mmol) to give 7-{(2R)-3-[4-acetylpiperazin-1-yl]-2-hydroxypropoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (175 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NC(=O)Nc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 40.3 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.10 mmol) obtained in Example 1, (3), and 2-chlorophenyl isocyanate (30 μL, 0.25 mmol), the title compound (19 mg, yield 40%) was obtained in the same manner as that of Example 20.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].[C:23](O)(=[O:30])[CH:24]([CH2:26][C:27]([OH:29])=[O:28])[SH:25]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]2[N:18]([CH2:19][CH2:20][CH2:21][OH:22])[C:23](=[O:30])[CH:24]([CH2:26][C:27]([OH:29])=[O:28])[S:25]2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCO
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C(O)CC(S)C(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C2SC(CC(=O)O)C(=O)N2CCCO)cc(C(C)(C)C)c1O
Yield: 24.8 %

Procedure:
In benzene (200 ml) were suspended 3,5-di-tert-butyl-4-hydroxybenzaldehyde (23.4 g) and 3-aminopropanol (9.01 g) under a nitrogen atmosphere. After fitting a Dean-Stark trap to the reactor, the suspension was refluxed for 2 hours. After allowing the mixture to cool, thiomalic acid (19.52 g) was added thereto, then the mixture was refluxed for an additional period of 3 hours. Benzene was removed by evaporation, and the resulting white solid was recrystallized from aqueous methanol to afford 10.5 g (25%) of the title compound as colorless crystals. mp 227-228° C. NMR (d6 -DMSO) (200 MHz) d: 1.37 (18H, s), 1.2-1.8 (2H, m), 2.3-2.8 (1H, m), 3.0-3.6 (5H, m), 4.0-4.2 (1H, m), 4.37 (1H, brs), 5.73 (1H, s), 7.10 (2H, s), 7.13 (1H, s)