Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@@H:33]([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[NH2:42][C:43]1[N:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52](O)=[C:51]([F:56])[CH:50]=2)=[CH:45][N:44]=1>O1CCCC1>[NH2:42][C:43]1[N:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([O:32][CH:33]([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:51]([F:56])[CH:50]=2)=[CH:45][N:44]=1
Reactant: Nc1ncc(-c2ccc(O)c(F)c2)cn1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(-c2cnc(N)nc2)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of triphenylphosphine (0.315 g, 1.2 mmol) in tetrahydrofuran (THF, 5.0 mL) was added diethyl azodicarboxylate (0.19 mL, 1.2 mmol) and tert-butyl (S)-2-hydroxypropanoate (292 mg, 2 mmol) followed by 4-(2-aminopyrimidin-5-yl)-2-fluorophenol (0.20 g, 1.0 mmol) at RT (RT) under nitrogen. The mixture was stirred overnight at RT, evaporated and the residue was purified by chromatography on silica gel to afford the desired product (0.24 g, 72%). LCMS: (M+H)=334.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:41]O)=[NH:40])[CH:37]=2)[N:32]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]3[N:40]=[C:5]([C:4]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH3:14])=[C:2]([Cl:1])[CH:3]=4)[O:7][N:41]=3)[CH:37]=2)[N:32]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]=1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Reactant: CCCOc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCOc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)OCC)no2)cc1Cl
Temperature: 80 °C

Procedure:
3-Chloro-4-(propyloxy)benzoic acid (D100) (150 mg, 0.70 mmol) stirring in DMF was treated with EDC (146 mg, 0.76 mmol) followed by HOBt (104 mg, 0.76 mmol). The resultant solution was stirred and ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (216 mg, 0.70 mmol) added. Heated mixture at 80° C. until reaction was complete. Work up obtained the title compound as 160 mg of pale cream solid. δH (400 MHz, d6-DMSO) 1.03 (3H, t), 1.10 (3H, t), 1.77-1.86 (2H, m), 2.90 (2H, t), 4.05 (2H, q), 4.18 (2H, t), 4.49 (2H, t), 7.40 (1H, d), 7.74 (1H, s), 7.81 (1H, d), 7.91 (1H, dd), 8.15 (1H, dd), 8.22-8.23 (2H, m). MS (ES) C24H2335Cl2N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]([CH2:18][C:19](OCC)=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1(C)C=CC=CC=1>[OH:20][C:19]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 25 °C

Procedure:
To a solution of m-anisidine (300 g, 2.44 mole) and ethyl benzoylacetate (234.2 g, 1.22 mole) in toluene (2.0 L) was added HCl (4.0 N in dioxane, 12.2 mL, 48.8 mmole). The resulting solution was refluxed for 6.5 hr using a Dean-Stark apparatus (about 56 ml of aqueous solution was collected). The mixture was cooled to rt, partitioned multiple times with aqueous HCl (10%, 3×500 mL), aqueous NaOH (1.0 N, 2×200 mL), water (3×200 mL), and the organic layer dried (MgSO4) and concentrated in vacuo to supply an oily residue (329.5 g). The crude product was heated in an oil bath (280° C.) for 80 min using a Dean-Stark apparatus (about 85 mL liquid was collected). The reaction mixture was cooled down to rt, the solid residue triturated with CH2Cl2 (400 mL), the resulting suspension filtered, and the filter cake washed with more CH2Cl2 (2×150 mL). The resulting solid was dried in vacuo (50° C.; 1 torr; 1 day) affording analytically pure 4-hydroxy-7-methoxy-2-phenylquinoline as a light brown solid (60.7 g, 20% overall). 1H NMR δ(DMSO): 3.86 (s, 3H), 6.26 (s, 1H), 6.94 (dd, J=9.0, 2.4 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.55-7.62 (m, 3H), 7.80-7.84 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 11.54 (s, 1H); 13C NMR (DMSO-d6) δ: 55.38, 99.69, 107.07, 113.18, 119.22, 126.52, 127.17, 128.97, 130.34, 134.17, 142.27, 149.53, 161.92, 176.48. LC-MS (retention time: 1.26, method D), MS m/z 252 (M++1).
Reaction SMILES: C([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][C:13]=1[F:23])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:28]([C:26]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][C:13]=2[F:23])=[C:9]([OH:8])[CH:27]=1)[CH3:29]
Reactant: CCc1ccc(Oc2ccc(NCCCO)cc2F)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCc1ccc(Oc2ccc(NCCCO)cc2F)c(O)c1
Temperature: 65 °C
Yield: 45.4 %

Procedure:
3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-ol (400 mg, 1.01 mmol) was taken in 15 ml of absolute ethanol, under nitrogen. To this was added Pd(OH)2, (20%, 50 mg) followed by ammonium formate (200 mg, 3.1 mmol). The reaction mixture was heated at 65° C. and monitored by TLC. After complete consumption of starting material (20 minutes), the heating was stopped and mixture cooled to rt. The reaction mixture was filtered through celite and the residue was washed with methanol. The combined filtrate was concentrated to obtain 300 mg of crude compound showing 70% by HPLC. The crude was purified by preparative HPLC (Column: C18 Symmetry (300×19 mm), 7μ, Mobile phase A: 20 mM ammonium acetate, Mobile phase B: Acetonitrile) to get 140 mg (45.3%) of title compound.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CO.CN(C)C=O>[NH2:13][C:9]1[N:8]=[C:7]([CH:5]([OH:6])[CH2:4][O:3][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:12]=[CH:11][N:10]=1
Reactant: CC1(C)OCC(c2ccnc(N)n2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a solution of 4-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-2-amine (2f) (7.18 g) in methanol (300 mL) was added p-toluenesulfonic acid monohydrate (10.49 g) and the solution was stirred at room temperature overnight. The mixture was filtered through sodium carbonate and concentrated under vacuum to give a brown solid that was dissolved in N,N-dimethylformamide (400 mL) to which was added imidazole (5.2 g) and tert-butyldimethylsilyl chloride (7.7 g) and the solution was stirred at room temperature overnight. The mixture was concentrated on silica under vacuum and purified by silica flash chromatography eluting with 50% to 75% ethyl acetate in heptane to give the title compound (850 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[N:3]=[CH:2]2
Reactant: COc1cccc2c(Cl)nc(C)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc2cnc(C)nc12
Reaction time: 3 h
Yield: 71.8 %

Procedure:
A mixture of 4-chloro-8-methoxy-2-methylquinazoline (5.12 g), 10% palladium on carbon (512 mg) and triethylamine (3.72 g) in ethyl acetate (51 ml) was stirred under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in methylene chloride, and the solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methylene chloride-methanol) to give 8-methoxy-2-methylquinazoline (3.07 g). mp: 131-132° C.
Reaction SMILES: [Br:1]CC1C=CC(S(C)(=O)=O)=C(F)C=1.[F:14][C:15]([F:28])([F:27])[S:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[Br:1][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([S:16]([C:15]([F:28])([F:27])[F:14])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Reactant: O=Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=S(=O)(c1ccc(CBr)cc1)C(F)(F)F

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde with 4-trifluoromethanesulfonyl-benzaldehyde.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:19]3[C:18]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[C:12](=[O:20])[C:11]=3[C:10]([NH:21][CH2:22][CH2:23][N:24]([CH2:26][CH2:27][CH2:28][N:29]([CH2:31][CH2:32][NH:33][C:34]3[C:46]4[C:45](=[O:47])[C:44]5[CH:43]=[N:42][CH:41]=[CH:40][C:39]=5[C:38]=4[C:37]4[CH:48]=[CH:49][C:50]([O:52]C)=[CH:51][C:36]=4[N:35]=3)[CH3:30])[CH3:25])=[N:9][C:8]=2[CH:54]=1>C(O)(=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[C:19]3[C:18]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[C:12](=[O:20])[C:11]=3[C:10]([NH:21][CH2:22][CH2:23][N:24]([CH2:26][CH2:27][CH2:28][N:29]([CH2:31][CH2:32][NH:33][C:34]3[C:46]4[C:45](=[O:47])[C:44]5[CH:43]=[N:42][CH:41]=[CH:40][C:39]=5[C:38]=4[C:37]4[CH:48]=[CH:49][C:50]([OH:52])=[CH:51][C:36]=4[N:35]=3)[CH3:30])[CH3:25])=[N:9][C:8]=2[CH:54]=1
Reactant: COc1ccc2c3c(c(NCCN(C)CCCN(C)CCNc4nc5cc(OC)ccc5c5c4C(=O)c4cnccc4-5)nc2c1)C(=O)c1cnccc1-3
Agent: Br
Solvent: CC(=O)O
Product: CN(CCCN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1cnccc1-2)CCNc1nc2cc(O)ccc2c2c1C(=O)c1cnccc1-2
Temperature: 120 °C

Procedure:
To a mixture of acetic acid (0.6 ml) and hydrobromic acid (48%, 0.6 ml) was added the compound of Example 3 (5.0 mg). The mixture was heated at 120° C. for nineteen hours. The mixture was cooled to room temperature and evaporated to dryness. The residue was purified by amino silica gel column chromatography developed by a mixture of dichloromethane-methanol=1:1 to give the desired compound. The desired product was obtained as a dark red powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: C=[N+](C)C
Reactant: Cc1ccc(-n2cnc(C)c2)c(C#N)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cnc(C)c2CN(C)C)c(C#N)c1
Yield: 64 %

Procedure:
In analogy to example 5b, 5-methyl-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 4 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as an oil that solidifies on standing (yield: 64%). MS: m/e=255.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[N:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:5]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(6-trifluoromethyl-pyridin-3-yl)-1H-pyrimidin-2-one (2.0 g, 7.84 mmol) and phosphoroxychloride (12 ml) according to the general procedure I. Obtained as an orange solid (1.33 g, 62%). MS (ISP) 274.1 [(M+H)+]; mp 123.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[CH2:21][S:20][C:19]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]2.C1(C)C=CC=CC=1.Br[C:50]1[N:54](COCC[Si](C)(C)C)[C:53]([C:63]2[CH:68]=[N:67][CH:66]=[CH:65][N:64]=2)=[N:52][CH:51]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:51]2[NH:52][C:53]([C:63]3[CH:68]=[N:67][CH:66]=[CH:65][N:64]=3)=[N:54][CH:50]=2)=[CH:4][C:3]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[CH2:21][S:20][C:19]([NH2:27])=[N:18]2
Reactant: C[Si](C)(C)CCOCn1c(Br)cnc1-c1cnccn1
Reactant: C[C@H]1OC[C@]2(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)SC[C@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@H]1OC[C@]2(c3cc(-c4cnc(-c5cnccn5)[nH]4)ccc3F)N=C(N)SC[C@H]12
Yield: 24.4 %

Procedure:
di-tert-Butyl {(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.1 g, 0.17 mmol) was dissolved in dry methanol (1 mL) and dry toluene (1 mL). To the solution was added 2-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrazine (mixture of isomers) (0.054 g, 0.15 mmol), palladium-triphenylphosphine (1:4) (0.020 g, 0.02 mmol) and Na2CO3 (0.33 mL, 1M solution in water) and the reaction was stirred at reflux in a sealed tube overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM and the layers separated. The aqueous layer was extracted with DCM (×2) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (0-15% MeOH in DCM). The product, (4aS,5R,7aS)-7a-{2-fluoro-5-[2-(pyrazin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl]phenyl}-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine was dissolved in EtOH (5 mL) and CHCl (2 mL) and the reaction was stirred at reflux overnight to remove the SEM protecting group. The reaction mixture was concentrated in vacuo and loaded onto a SCX ion exchange cartridge washing with MeOH followed by 2N NH3 in MeOH. The basic fraction was concentrated in vacuo. The residue was purified by column chromatography (gradient 0-15% MeOH in EtOAc) to afford the title compound (15 mg, yellow film). 1H NMR (400 MHz, MeOH-d4) δ ppm: 9.32 (s, 1 H), 8.65 (t, J=1.0 Hz, 1 H), 8.54 (d, J=2.5 Hz, 1 H), 7.73-8.01 (m, 2 H), 7.58 (br. s., 1 H), 7.17 (dd, J=12.1, 8.6 Hz, 1 H), 4.63 (d, J=9.1 Hz, 1 H), 4.30-4.40 (m, 1 H), 3.82 (dd, J=8.6, 2.3 Hz, 1 H), 3.16 (dd, J=13.5, 3.9 Hz, 1 H), 2.88 (dd, J=13.4, 4.0 Hz, 1 H), 2.61 (dt, J=8.3, 4.1 Hz, 1 H), 1.34 (d, J=6.1 Hz, 3 H).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([NH2:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].O.[C:16]1(C)[C:17](S(O)(=O)=O)=CC=C[CH:21]=1>CC(C)=O>[CH3:21][C:16]1([CH3:17])[NH:14][C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8]1
Reactant: NC(=O)c1ccccc1O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2ccccc2O1
Reaction time: 24 h

Procedure:
A 500-ml flask was charged with 250 ml of chloroform, 27.4 g (0.2 mol) of salicylamide, 23.2 g (0.4 mol) of acetone and 2.7 g of toluene sulfonic acid monohydrate. The flask was equipped with a Soxhlet extraction vessel containing 36.7 g of molecular sieves (Linde Type 3A, 1/16 inch) in the thimble. The reaction mixture was refluxed for 24 hours. Then fresh sieves were placed in the Soxhlet and 10 g of acetone was added to the reaction mixture. Reflux was continued for 24 hours.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16](=[O:33])[NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
45 mg of (6-{[(6-oxo-5,6-dihydro-phenanthridin-2-ylcarbamoyl)-methyl]-amino}-hexyl)-carbamic acid tert-butyl ester (0.097 mmol) were dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight, evaporated, taken up with diethyl ether, filtered and the collected solid was dried under vacuum to afford 30 mg (65% yield) of the title compound as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:33])[CH:3]=1>FC(F)(F)C(O)=O>[NH2:23][CH2:22][CH2:21][CH2:20][O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:31]=[CH:32][C:2]([Br:1])=[CH:3][C:4]=3[F:33])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN
Temperature: 85 °C
Yield: 99.7 %

Procedure:
4-(4-Bromo-2-fluorophenoxy)-7-(3-(N-tertbutoxycarbonylamino)propoxy)-6-methoxyquinazoline (5.46 g, 10.5 mmol) was taken up in trifluoroacetic acid (75 ml) and heated at 85° C. for 1.5 hours. The solution was allowed to cool and the excess trifluoroacetic acid removed by evaporation. The residue was then treated with aqueous ammonia (0.88) solution, extracted with dichloromethane (3×150 ml) and filtered through phase separating paper. The solvent was removed by evaporation to give 7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline (4.42 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]2([CH3:34])[CH2:31][O:30]C(C)(C)[O:28][CH2:27]2)[N:12]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C:26]([CH2:31][OH:30])([CH3:34])[CH2:27][OH:28])[N:12]=1
Reactant: CC1(Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)COC(C)(C)OC1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(CO)(CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2,2,5-trimethyl-1,3-dioxan-5-yl)oxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product from step ii) (0.46 g) in DCM (15 mL) was added iron (III) chloride hexahydrate (0.85 g) and the mixture was stirred and ambient temperature for 30 min. A saturated solution of sodium hydrogencarbonate was added and then extracted with DCM (×4). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using a MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white foam Yield: 100 mg
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH3:3].[CH:25](O)(C)C>>[CH3:3][CH:2]([O:4][C:5](=[O:24])[CH2:6][C:7]1[O:8][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH3:25]
Reactant: CC(C)O
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Na]
Product: CC(C)OC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 54 %

Procedure:
Sodium (80 mg, 3.5 mg atom) was dissolved in isopropanol (21 mL) and ethyl-4,5-diphenyl-2-oxazoleacetate (1.00 g, 3.2 mmol) added. The mixture was heated at reflux for about 1.5 hours, cooled and concentrated. The residue was diluted with water, acidified to pH=2 with 1N HCl solution and extracted with CH2Cl2. The combined extracts were dried over MgSO4, the solvent removed and the residue chromatographed or a column of silica gel. Elution with a mixture of hexanes and EtOAc (9:1) gave the title compound (0.57 g, 54%). IR (film) 1740 cm-1 ; 1H NMR (CDCl3) δ1.26 (6H, d, J=6Hz, CO2CH(CH3)2), 3.89 (2H, s, CH2CO2iPr), 5.08 (1H, septuplet, OCH(CH3)2), 7.25 to 7.40 (6H, m, aromatic H), 7.50 to 7.65 (4H, m, aromatic H); MS m/z 322 (MH+).
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][C:2]=12.[F:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:5]3[C:4](=[O:8])[N:3]4[CH2:9][CH2:10][CH2:11][C:2]4=[N:1][C:6]3=[O:7])[CH2:21][CH2:20]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=c1nc2n(c(=O)[nH]1)CCC2
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)nc3n(c2=O)CCC3)CC1

Procedure:
In the manner described in Example 1-2), 7,8-dihydro-2H,6H-pyrrolo[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in 1) above and 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as a caramel-like substance.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCN(S(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) was added methanesulfonyl chloride (10.6 μL, 0.137 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and concentrated via rotary evaporation. The resulting crude material was partitioned between EtOAc (2 mL) and water (1 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in EtOAc and MeOH, adsorbed on silica gel (0.75 g), and purified via medium pressure chromatography using a gradient eluant of 50% to 100% EtOAc in heptane on a 4 g silica gel column (Single Step™) to give the title compound (50.6 mg, 85%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12-1.19 (m, 6H), 2.53-2.61 (m, 4H), 2.74 (t, J=5.9 Hz, 2H), 2.97 (s, 3H), 3.00 (d, J=7.3 Hz, 4H), 3.44-3.48 (m, 1H), 3.59 (s, 2H), 4.02-4.10 (m, 1H), 4.16 (s, 2H), 5.41 (d, J=7.8 Hz, 1H), 7.08 (td, J=8.4, 2.2 Hz, 1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.54 (m, 1H); ESI-MS m/z [M+H]+ 480.9.