Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[CH2:7][C@@H:6]1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C[C@H]1C[C@@H]1C(=O)O

Procedure:
Tert-butyl (1S,2R)-2-(2-methoxy-2-oxoethyl)cyclopropanecarboxylate was dissolved in a mixture of trifluoroacetic acid:methylene chloride (7:3) and stirred at room temperature until the t-butyl ester was removed. The solvent was removed under reduced pressure to give product. 1H NMR (CDCl3) δ 3.70 (s, 3H), 2.35 (d, J=7.5 Hz, 2H), 1.85-1.70 (m, 1H), 1.52-1.49 (m, 1H), 1.39-1.30 (m, 1H), 0.93-0.87 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)=[C:12]=[O:13]>>[CH:19]1[C:20]2[C:15](=[C:14]([NH:11][C:12](=[O:13])[O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: N#Cc1ccc(CO)cc1
Product: N#Cc1ccc(COC(=O)Nc2cccc3cnccc23)cc1
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Cyanobenzyl alcohol (150 mg, 1.13 mmol) diethyl ether (10 mL) was treated with the product from Example 61A as an ethereal solution. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound as an off-white solid (150 mg, 44%). 1H HMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.32 (d, J=1.0 Hz, 1H), 8.52 (d, J=6.1 Hz, 1H), 7.88-7.99 (m, 5H), 7.65-7.70 (m, 3H), 5.31 (s, 2H); MS (ESI+) m/z 304 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[CH2:31][S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=1)C.[OH-].[Li+].O>CO>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[C:16]([CH2:31][S:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:17]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)c2ccc(Cl)cc2)cc1CSc1ccccc1
Temperature: 60 °C

Procedure:
To {3-[4-(4-chloro-benzoylamino)-2-phenylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.9 mmol) was added lithium hydroxide (0.3), H2O (5 mL), and MeOH (20 mL). The reaction was stirred at 60° C., and then worked up and purified by preparative HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1[CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.O1CCCC1.Cl>C(O)C>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: O=CNc1nc(CSc2ccncc2)c(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(CSc2ccncc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.9 %

Procedure:
A solution of 5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole (4.9 g) in a mixture of ethanol (25 ml), tetrahydrofuran (20 ml) and concentrated hydrochloric acid (7 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8 using aqueous sodium bicarbonate under ice-cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-chloro-4-(4-pyridylthiomethyl)thiazole (0.26 g, yield: 56.6%). IR (Nujol): 3350, 3250, 1685, 1530 cm-1
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32].O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 200 mg, 0.80 mmol) in DMSO (4 mL) was added K2CO3 (333 mg, 2.41 mmol) followed by 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) and the reaction stirred at room temperature for 18 h. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4) filtered and the solvent removed under reduced pressure to give the title compound (245 mg, 72%) as a solid.
Reaction SMILES: [CH:1]([C:4]1[NH:9][C:8](=O)[C:7]([C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br-:13].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C1(C)C=CC=CC=1>[Br:13][C:8]1[N:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[C:11]#[N:12]
Reactant: [Br-]
Reactant: CC(C)c1ccc(C#N)c(=O)[nH]1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc(C#N)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of the product of Example 8B (4.35 g, 0.0269 mol), tertrabutylammonium bromide (10.4 g, 0.0323 mol) and phosphorous pentoxide (8.01 g, 1.05 mol) in toluene (80 mL) was heated under reflux for 5 hours. The reaction mixture was then cooled to room temperature, water (80 mL) was added, and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with toluene (20 mL) and the organic layer separated. The aqueous layer was washed with toluene (50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as a yellow oil (5.64 g, 93%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
The compound (820 mg, 2.6 mmol) prepared in Example 1 was dissolved in dichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol) and triethylamine (0.81 ml, 3.1 mmol) were added thereto, and the mixture was stirred for 30 min at 0° C. After completion of the reaction, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (600 mg, Yield 60%).
Reaction SMILES: [OH-].[K+:2].[S:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[N:4]1>O.C(O)C>[S:3]1[C:7]([C:8]([O-:10])=[O:9])=[CH:6][N:5]=[N:4]1.[K+:2]
Reactant: CCOC(=O)c1cnns1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1cnns1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of potassium hydroxide (3.30 g.) in water (7 ml.) was added to a solution of ethyl 1,2,3-thiadiazole-5-carboxylate (8.00 g.) in ethanol (25 ml.). The mixture was stirred at 23° C. for 2 hours, and then was worked up to yield potassium 1,2,3-thiadiazole-5-carboxylate. A suspension of this salt (3.00 g.) in toluene (25 ml.) was treated at 0° C. with oxalyl chloride (1.6 ml.), stirred at 0° C. for 1 hour, and then was worked up to yield 1,2,3-thiadiazole-5-carbonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=2[F:32])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>CS(C)=O>[CH3:36][C:33]([C:21]1[C:22]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=2[F:32])=[CH:23][C:18]([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)=[CH:19][CH:20]=1)([CH3:34])[CH3:35]
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C(C)(C)C)c1
Reactant: CCOC(=O)[C@H](C)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CS(C)=O
Product: COc1ccc(F)c(-c2cc(COc3ccc(C[C@@H](C)C(=O)O)cc3)ccc2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A reaction mixture of (R)-ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate (40.0 mg, 192 μmol), 5-(chloromethyl)-2-(1,1-dimethylethyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl A (58.9 mg, 192 μmol) and cesium carbonate (125.1 mg, 384 μmol) in DMSO (1.0 mL) was stirred at room temperature for 16 hours. Lithium hydroxide (0.3 mL, 3.33 M in water) and DMSO (1.0 mL) were added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (reverse phase) to give the title compound 26. 1H NMR (400 MHz, CD3CN) δ ppm 1.11 (d, J=6.65 Hz, 3H) 1.23 (s, 9H) 2.62-2.71 (m, 2H) 2.89 (s, 1H) 3.79 (s, 3H) 5.04 (s, 2H) 6.84-6.98 (m, 4H) 7.07-7.15 (m, 4H) 7.44 (dd, J=8.22, 1.96 Hz, 1H) 7.64 (d, J=8.22 Hz, 1H). MS ESI (neg.) m/e: 449.2 (M−H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:35]5[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3OC)nc21
Product: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCC(O)CC4)cc3OC)nc21
Yield: 91 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 206 was used in place of the compound obtained in Example 48, and 4-hydroxypiperidine was used in place of N-methylpiperazine. In this manner, 155 mg (91%) of the captioned compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][C:6]1[CH:5]=[C:4]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: Brc1ccccc1
Product: Cc1cc(C)cc(Oc2ccccc2)c1
Yield: 98 %

Procedure:
Following General Procedure A (90° C., 30 hours), 3,5-dimethyl phenol (183 mg, 1.5 mmol) is coupled with bromo-benzene (106 μL, 1.0 mmol) to give 98% 1,3-dimethyl-5-phenoxybenzene.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].[SH:10][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17](=[O:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:19]([CH2:18][C:17]([NH:16][C@H:12]1[C@@H:11]([S:10][CH2:2][C:3]([CH:5]2[CH2:9][CH2:8][CH2:7][O:6]2)=[O:4])[NH:14][C:13]1=[O:15])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1S
Reactant: O=C(CCl)C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)C1CCCO1
Yield: 59 %

Procedure:
(RS)-2-Chloroacetyltetrahydrofuran (2.46 g, 16.5 mmol), (3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-one (4.157 g, 16.5 mmol) and potassium carbonate (2.227 g, 16.5 mmol) in DMF (10 ml) were stirred for 2 h, diluted with ethyl acetate, washed twice with water and with brine, dried concentrated and flash chromatographed eluting with 40,30,20,10 and 0% hexane in ethyl acetate to give the title compound as a foam (3.547 g, 59%); νmax (CH2Cl2) 3405, 1785, 1693, 1520, 1496 and 1240 cm-1 ; δ(CDCl3, 250 MHz) 1.9-2.3 (4H, m), 3.42 and 3.62, 3.46 and 3.56 (together 2H, 2 ABq, J15.8 Hz, 15.4 Hz), 3.85-4.0 (2H, m), 4.4-4.5 (1H, m), 4.58 (2H, s), 5.01, 5.04 (together 1H, 2d, J4.7 Hz), 5.59 (1H, dd, J 8.8, 4.5 Hz) 6.62, 6.68 (together 1H, 2s), 6.9-7.4 (5H, m) and 7.45, 7.47 (together 1H, 2d, J8.8 Hz). [Mass spectrum: M+ (364)].
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25](=[O:31])[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25](=[O:31])[N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-{3-(2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 52) (309 mg, 0.71 mmol) was treated with trifluoroacetic acid (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a pale yellow oil (200 mg).
Reaction SMILES: [Cl-].[NH4+:2].[OH-].[NH4+].[CH3:5][O:6][C:7]([C:9]1[NH:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:8].[H-].[Na+].NCl>C(OCC)C.CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[N:10]([NH2:2])[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:8]
Reactant: COC(=O)c1cc(C#N)c[nH]1
Reactant: [NH4+]
Agent: NCl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cn1N
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Solid ammonium chloride (5.8 g, 109.4 mmol) was suspended in diethyl ether (300 mL) and the suspension was cooled to −5° C. To this were added 29.56% aqueous ammonium hydroxide solution (16 mL) and 6.15% aqueous bleach solution (“Chlorox”, 240 mL) over a period of 15 min. The mixture was stirred for 30 min at −5° C. and then the layers were separated. The organic layer was washed with brine, filtered over sodium sulfate and stored over solid calcium chloride at −5° C. 4-Cyano-1H-pyrrole-2-carboxylic acid methyl ester (Example 15a, 1.09 g, 7.265 mmol) was dissolved in N,N-dimethylformamide (30 mL) and a 60% dispersion of sodium hydride in mineral oil (0.378 g, 9.445 mmol) was added. After stirring for 1 h at 25° C., the above ˜0.36 M solution of monochloramine in ether (26 mL, 9.445 mmol) was added and stirred for 2 h at 25° C. The reaction was quenched with saturated aqueous sodium thiosulfate solution followed by water. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-amino-4-cyano-1H-pyrrole-2-carboxylic acid methyl ester, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 3.88 (3H, s), 5.67 (2H, bs), 7.07 (1H, d, J=1.7 Hz), 7.37 (1H, d, J=1.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>CC#N>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2nc(Cl)cn2c1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Clc1ccc2nc(Cl)c(I)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a suspension of 2,6-dichloro-imidazo[1,2-a]pyridine, compound 12 (4.0 g, 0.02 mol) in dry CH3CN (50 mL) was added N-iodosuccinimide (NIS, 5.3 g, 0.024 mol) and the mixture stirred at room temperature for 1 h. The reaction mixture was heated at reflux for 10 min and then cooled to room temperature. Chloroform (200 mL) was added to the reaction mixture and the organic phase washed successively with 10% NaOH (100 mL), sodium thiosulfate (100 mL) and water (2×100 mL) then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting solid was suspended in MeOH and filtered to give 5.0 g (80%) of compound 19 as white crystalline solid.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:75])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[O:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:74])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:75])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[O:67][C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)=[O:59])=[CH:55][CH:56]=3)=[CH:47][CH:48]=2)[C:43]1=[O:74])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Oc4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 68 %

Procedure:
The compound of example 48 was prepared analogous to compound of example 8 by hydrolysis of compound of example 47.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([C:4]2[CH:3]=[C:2]([CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[O:6])=[CH:8][CH:9]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(C(=O)c2cccc(Br)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(C(=O)c2ccc(OC)cc2)c1

Procedure:
A mixture of 3-bromo-4'-methoxybenzophenone (Allen, Schumann, Day and Van Campen, J. Amer. Chem. Soc., 1958, 80, 591) (14.6 g), ethyl acrylate (25.3 g), palladium (II) acetate (100 mg), triphenylphosphine (225 mg) and triethylamine (2.65 g) in acetonitrile (20 mL) was heated in a stainless steel autoclave under a nitrogen atmosphere at 155° for 5 hours. After cooling, water was added and the precipitated solid was recrystallized from methanol to yielded ethyl 3-(4-methoxy benzoyl)cinnamate, m.p. 71°-71.5° (5.6 g).
Reaction SMILES: [NH3:1].[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13]([C:15]1[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29](OC)=[O:30])[CH2:23][CH2:22]3)[CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:9]2>CO>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([NH2:1])=[O:30])[CH2:23][CH2:22]3)[N:20]=1)[CH2:9]2
Reactant: COC(=O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Reactant: N
Solvent: CO
Product: NC(=O)CCN1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
7N ammonia in methanol (2 ml) was added into methyl 3-(4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazin-1-yl)propanoate (94 mg, 0.22 mmol), and then the resulting mixture was stirred at room temperature for 48 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 54 mg of colorless oil (60%). MS (ESI): 412 [M+H]
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added N-methyl piperazine (0.146 mL, 1.317 mmol) followed by diisopropyl ethylamine (0.229 mL, 1.317 mmol) and tetrabutyl ammonium iodide (162.15 mg, 0.439 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea (21 mg, 8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.32 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.40 (m, 2H), 7.25 (s, 1H), 6.98 (m, 1H), 6.48 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 2.82-2.25 (m, 10H), 2.15 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 576 (M+H)+.