Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20].O>CN(C)C=O>[C:19]([CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1CC#N
Reaction time: 0.5 h

Procedure:
Ethyl indole-2-carboxylate (6.0 g) was dissolved in dimethylformamide (60 ml) and sodium hydride (60% in oil, 1.4 g) was added under ice-cooling. After stirring for 30 minutes, bromoacetonitrile (2.3 ml) was added and the mixture was stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 6.6 g of ethyl 1-cyanomethylindole-2-carboxylate.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(C1C=C(B(O)O)C=CC=1)(=O)C>>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: OB(O)c1ccncc1
Agent: CC(=O)c1cccc(B(O)O)c1
Product: O=C(NC1CC1)c1cn(-c2cccc(-c3ccncc3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of Step 5 of Example 1 but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and 4-pyridineboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a white solid.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[O:22][C:5]=2[CH:4]=1.C(N1CC=CC(O)C1)(OC(C)(C)C)=O.[Br:37]C1C=CC=C(Br)C=1O>>[Br:37][C:4]1[C:5]2[O:22][CH:10]3[CH:9]([C:6]=2[CH:7]=[CH:8][CH:3]=1)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3
Reactant: COc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Reactant: Oc1c(Br)cccc1Br
Agent: CC(C)(C)OC(=O)N1CC=CC(O)C1
Product: CC(C)(C)OC(=O)N1CCC2c3cccc(Br)c3OC2C1

Procedure:
Prepared as described for tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2,6-dibromo-phenol.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccc1
Yield: 25 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and cyclohexyl chloroformate. Yield: 25% of theory, C34H38N6O5 (610.7); Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=611; (M+2H)++=306.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[O:32][CH2:33][CH3:34])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: CCOC(=O)CBr
Agent: [Na]
Product: CCOC(=O)CONC(=O)Cc1ccc2c(C(=O)OCC)c(N)c(C(=O)OCC)c-2cc1
Yield: 24 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and ethyl bromoacetate the title compound is obtained in 24% yield as a wax.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[C:15]2[C:24]3[C:29]([CH2:30][C:14]1=2)=[CH:28][CH:27]=[CH:26][CH:25]=3.N1C2C(C=CC3C=2C=C2C=3C=CC=C2)=CC=1.[Cl:47][Si:48](Cl)([CH3:50])[CH3:49]>C1COCC1>[Cl:47][Si:48]([CH3:50])([CH3:49])[CH:30]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Agent: C1=Nc2c3c(ccc2=C1)=c1ccccc1=C3
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(n2C)C([Si](C)(C)Cl)c2ccccc2-1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
3.4 mL of a 2.5 M solution of n-BuLi in hexane (8.50 mmol) were added dropwise to a solution of 2.22 g of N-methyl-2-methoxy-5,6-dihydroindeno[2,1-b]indole, obtained as reported above, (Mw=249.32, purity 85.8%, 7.64 mmol; indenoindole: n-BuLi=1:1.1) in 50 mL of THF, previously cooled to −78° C. At the end of the addition, the brown solution was allowed to warm up to room temperature and stirred for 5 hours. Then it was cooled again to −78° C. and added dropwise to a solution of dichlorodimethylsilane (Mw=129.06, d=1.064, 0.92 mL, 7.64 mmol; indenoindole: Me2SiCl2=1:1) in 20 mL of THF, previously cooled to −78° C. At the end of the addition, the dark brown solution was allowed to warm up to room temperature and stirred overnight. The solvents were evaporated under reduced pressure to give the desired product, containing few by-products, in the form of a brown sticky solid; this product was used in the following step without further purification.
Reaction SMILES: [H-].[Li+].[CH2:3]=[O:4].CO.Cl[CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[CH2:13]([C:8]1([O:4][CH2:3]1)[C:9]([O:11][CH3:12])=[O:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCC(Cl)C(=O)OC
Reactant: C=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCCCCCCCCCC1(C(=O)OC)CO1
Reaction time: 1 h

Procedure:
Lithium hydride (0.32 g, 0.040 m), paraformaldehyde (0.16 g, 0.0053 m), and methanol (0.32 g, 0.010 m) were heated together in 25 ml DMF at 30°-40° C. After 1 hour, methyl α-chloropalmitate (3.05 g, 0.010 m) was added; the remaining paraformaldehyde (0.16 g, 0.0053 m) was added in two portions. The reaction was worked up after 51/2 hours of heating. The reaction mixture was extracted with hexane; the hexane was washed with water and dried over Na2SO4. The mixture was filtered and stripped to a crystalline residue. The residue was recrystallized from methanol to give 2.49 g (83.5%) yield of methyl tetradecylglycidate (m.p. 47°-48° C., glc purity>99%).
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.C(N(CC)CC)C>C1COCC1>[N:26]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH2:7][CH3:8])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccc(COCOC)cc2)cn1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(c1ccc(-c2ccc(COCOC)cc2)cn1)n1ccnc1
Temperature: 65 °C
Yield: 43.9 %

Procedure:
A mixture of 1-(5-(4-((methoxymethoxy)methyl)phenyl)pyridin-2-yl)propyl methanesulfonate (0.1 g, 0.27 mmol), 1H-imidazole (0.037 g, 0.54 mmol) and triethylamine (0.07 mL, 0.54 mmol) in THF (15 mL) was stirred and refluxed at 65° C. for 12 h, cooled to room temperature, poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under vacuo. The resulting residue was purified by preparative TLC using 5% methanol in dichloromethane and isolated as light green viscous liquid (0.04 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.06 (dd, 1H), 7.81 (s, 1H), 7.69 (d, 2H), 7.44 (d, 2H), 7.37 (d, 1H), 7.30 (s, 1H), 5.36 (q, 1H), 4.65 (s, 2H), 4.56 (s, 2H), 3.30 (s, 3H), 2.25 (m, 2H), 0.81 (t, 3H). LC-MS: m/z 338.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([CH2:18][C:19]1[NH:31][C:22]2=[CH:23][N:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=[C:21]2[CH:20]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15]C)([CH3:7])[CH3:6].B(Br)(Br)Br.CO>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]([OH:15])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:17])([CH2:18][C:19]2[NH:31][C:22]3=[CH:23][N:24]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:26]=[C:21]3[CH:20]=2)[C:2]([F:32])([F:1])[F:33])[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cc(S(C)(=O)=O)ncc2[nH]1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(Cc1cc2cc(S(C)(=O)=O)ncc2[nH]1)C(F)(F)F)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol (179 mg, 0.37 mmol) was dissolved in 10 mL of dichloromethane. 3.7 mL of a 1 M solution of boron tribromide (3.7 mmol) in dichloromethane were added. The resulting solution was stirred at normal room temperature overnight. After dropwise addition of MeOH (1 mL) at 0° C., the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate (NaHCO3) solution. The organic phase was separated and the aqueous layer was extracted with four 10 mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed. Flash chromatography of the residue yielded 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-3-(5-methanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1,1-dimethylbutyl]phenol as a white solid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[Cl:39][C:40]1[CH:41]=[C:42]([C:48]2([C:64]([F:67])([F:66])[F:65])[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]4([F:63])[CH2:62][NH:61][CH2:60]4)=[CH:55][CH:54]=3)[CH2:49]2)[CH:43]=[C:44]([Cl:47])[C:45]=1[F:46]>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[C:42]([C:48]2([C:64]([F:65])([F:66])[F:67])[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]4([F:63])[CH2:62][N:61]([C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH2:60]4)=[CH:55][CH:54]=3)[CH2:49]2)[CH:43]=[C:44]([Cl:47])[C:45]=1[F:46]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc(C4(F)CNC4)cc3)=NO2)cc1Cl
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of butyric acid (50 mg) in DMF (5 mL) was added HATU (200 mg) then triethyl amine (150 μL). The resulting solution was stirred at ambient temperature for 15 minutes then 5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole hydrochloride (Preparation 16 100 mg) was added in one portion. Reaction stirred at ambient temperature for 16 hours. Solvent was removed in vacuo and the residue partitioned between water (10 mL) and CH2Cl2 (10 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 86 mg (80%). 1H NMR (CDCl3) δ 7.75 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.68-4.33 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.19 (m, 2H), 1.73 (m, 2H), 1.01 (m, 3H). LC/MS retention time=3.688 minutes, MS calculated for (C23H19Cl2F5N2O2), 520.07; found 521.0 M+H.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)[CH3:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OCC)nc1)C(=O)OCC
Temperature: 130 °C
Yield: 93.7 %

Procedure:
A mixture of 2-ethoxy-5-aminopyridine (2.89 g, 20.9 mmol) and diethyl ethoxymethylenemalonate (4.23 mL, 20.9 mmol) was heated at 130° C. for 4.5 hours. While warm, the mixture was evacuated. After cooling, the product was triturated with 2:1 hexanes:ether and collected to afford 6.04 g of diethyl (2-ethoxy-5-pyridylaminomethylene)malonate as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccncc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (41 mg), were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C., for 3 hr. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 65 mg (yield 66%) of the title compound.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:6]2[N:5]=1)=O.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[OH:19])[N:6]4[N:5]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5O)n4n3)cc2)CC1
Yield: 51.7 %

Procedure:
Into a microwave vial, 2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.165 g, 0.604 mmol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.254 g, 1.33 mmol), 1-Methoxy-2-propanol (1.20 mL) and N,N-Diisopropylethylamine (0.231 mL, 1.33 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenol as a yellow solid (125 mg, 51%). LCMS (E/I+) 401.10 (M+H). NMR 1H (DMSO-d6)-9.73 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1H), 7.92 (d, 1H, J=7.74 Hz), 7.61 (d, 2H, J=8.23 Hz), 7.25 (t, 1H, J=7.26 Hz), 6.93-7.08 (m, 3H), 6.88 (d, 1H, J=4.35 Hz), 6.81 (d, 2H, J=8.23 Hz), 3.03 (bs, 4H), 2.44 (bs, 3H), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40].CO>C1COCC1>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:38](=[O:41])[CH:39]=[CH2:40])[CH:10]=1)[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccccc1Nc1cc(N(Cc2cccnc2)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of 1-[6-(2-amino-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-pyridin-3-ylmethyl-urea (53 g, 0.1 mmol) in THF (10 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 0.5 mL, 0.1 mmol) at −10° C., and the mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-TLC to obtain the title compound (9 mg, yield: 15%). 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 6H), 5.01 (s, 2H), 5.69 (d, 1H), 5.75 (s, 1H), 6.10 (dd, 1H), 6.34 (d, 1H), 6.47 (s, 1H), 7.00 (d, 1H), 7.09-7.24 (m, 2H), 7.28 (t, 1H), 7.32 (s, 1H), 7.47 (d, 1H), 7.69-7.71 (m, 2H), 8.31-8.34 (m, 2H), 8.40-8.42 (m, 1H), 12.60 (s, 1H); MS (ESI): 594 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][OH:27]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[O:27][CH2:26][CH2:25][CH2:24][O:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc(Br)cc2ccoc12
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(C2OCCCO2)c2occc2c1

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (400 mg), 4-methylphenylsulphonic acid (0.38 g) and 1,3-propanediol (10 ml) in toluene (15 ml) was heated at reflux for 19 h, with azeotropic removal of water by Dean-Stark Apparatus. The reaction mixture was cooled, diluted with water (80 ml) and extracted with toluene (30 ml). The organic phase was dried, filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluted with hexane:ethyl acetate (7:1→3:1) gave the title compound as a yellow solid (427 mg).
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([C:7]([O-:9])=[O:8])[C:4]([O-:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:10]([C:3]([CH2:1][CH3:2])([C:7]([O:9][CH2:2][CH2:1][CH2:3][CH2:10][CH3:11])=[O:8])[C:4]([O:6][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:5])[CH3:11]
Reactant: CCCCCBr
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOC(=O)C(CC)(CC)C(=O)OCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.4 %

Procedure:
To a stirring solution of diethylmalonate (8.0 g, 50 mmol) in THF (100 mL, 0.5 M) was added sodium hydride (1.2 g, 50 mmol). The solution began bubbling and an exothermic reaction occurred. The reaction eventually turned clear and then pentyl bromide (6.2 mL, 50 mmol) was added. The reaction was refluxed for 20 hours and then cooled to room temperature. Another equivalent of NaH (1.2 g, 50 mmol) was added to the cloudy white mixture which was then stirred for 4 hours at room temperature. Another equivalent of pentyl bromide (6.2 mL, 50 mmol) was added and the reaction was refluxed for 20 hours. The reaction was cooled to room temperature and filtered to remove the precipitated sodium bromide. The mother liquor was collected and concentrated in vacuo to a yellow oil. The crude product was then distilled under vacuum (140° C.) to afford 9.34 g (62%) of pure product.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([O:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[O:30]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O1CCOCC1.O.[NH4+].[Cl-]>[OH:30][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([O:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1cc(-c2cccc(OS(=O)(=O)c3ccccc3)c2)c2ncccc2c1
Agent: [Ce+4]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1cc(-c2cccc(OS(=O)(=O)c3ccccc3)c2)c2ncccc2c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To solution of KBrO3 (1.1 eq) in 5 mL of dioxane/water (3/2; 0.14M) was added the quinoline of EXAMPLE 25 (1.0 eq) and CAN (0.1 eq). The mixture was stirred at 75° C. for 16 h, poured in saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:21][N:22]=[C:23]=[S:24]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:23]([NH:22][CH3:21])=[S:24])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN=C=S
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Solvent: Cc1ccccc1
Product: CNC(=S)Nc1nc2nc(C)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
A mixture of 25.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 18.0 g of methyl isothiocyanate in 125 ml of toluene is heated at reflux for 28 hours. Cooling gives a precipitate of crude product which is collected by filtration and washed with ether. Further purification may be effected by recrystallization from isopropanol to give N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-yl]-N'-methylthiourea, mp 207.5°-208.5° C. (dec.).