Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:16][CH2:17][CH2:18]Cl.C([O-])([O-])=O.[K+].[K+].[OH-].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[Cl:16][CH2:17][CH2:18][O:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: ClCCCl
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: FC(F)(F)c1ccc2c(OCCCl)ccnc2c1
Temperature: 75 °C
Reaction time: 5 h
Yield: 23.7 %

Procedure:
7-Trifluoromethyl-4-quinolinol (500 mg, 2.3 mmol) and 1,2-dichloroethane (11.6 g, 11.7 mmol) were charged in a 50 ml round-bottomed flask equipped with a magnetic stirrer. TBABr (370 mg, 1.2 mmol), K2CO3 (950 mg, 6.9 mmol), KOH (760 mg, 11.5 mmol) and water (6 mL) were added and the reaction mixture was stirred for 5 h at 70-80° C. The reaction mixture was poured in 50 mL of H2O and extracted with CH2Cl2 (150 mL). The organic layer was washed with water (30 mL), brine (2×10 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:EtOAc=5:5) to give after evaporation 4-(2-chloroethoxy)-7-(trifluoromethyl)quinoline 31 (150 mg, 25% yield) as a beige solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][NH2:9])[CH3:7])[CH3:5].[O:10]1[CH2:15][CH2:14][O:13][C:12]([C:16](=[N:25][O:26][CH3:27])[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=O)=[N:11]1>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:6](=[N:8][N:9]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[C:16]([C:12]1[O:13][CH2:14][CH2:15][O:10][N:11]=1)=[N:25][O:26][CH3:27])[CH3:7])[CH3:5]
Reactant: CON=C(C)C(C)=NN
Reactant: CON=C(C1=NOCCO1)c1ccccc1C=O
Solvent: CCO
Product: CON=C(C)C(C)=NN=Cc1ccccc1C(=NOC)C1=NOCCO1
Temperature: 20 °C
Yield: 64.2 %

Procedure:
0.5 g (0.0039 mol) of 3-hydrazono-butan-2-one O-methyl oxime is boiled under reflux in 5 ml of ethanol with 0.96 g (0.0039 mol) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde for 2 hours. The reaction mixture is allowed to cool slowly to 20° C. and the crystals are filtered off to give 0.9 g (64.7% of theory) of 3-({2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzylidene}-hydrazono)-butan-2-one O-methyl oxime.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:24]([CH3:26])[S:25][C:19]=2[N:18]=[C:17]1[CH3:33]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[C:24]([CH3:26])[S:25][C:19]=4[N:18]=[C:17]3[CH3:33])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1sc2nc(C)n(N)c(=O)c2c1-c1ccccc1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1sc2nc(C)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c2c1-c1ccccc1

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2,6-dimethyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87-1.08 (m, 6 H) 1.08 (s, 3 H) 1.19 (d, 3 H) 1.46-1.69 (m, 1 H) 1.75-2.06 (m, 7 H) 2.10-2.25 (m, 1 H) 2.27-2.44 (m, 2 H) 7.43-7.51 (m, 3 H) 7.54 (d, J=7.8 Hz, 1 H) 7.75-7.84 (m, 1 H) 8.08 (dd, J=7.9, 1.19 Hz, 1 H); MS (ESI+) m/z 448 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[C:9]([C:11]3[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=3[C:19](=O)[C:4]=2[CH:3]=1)=[O:10].Cl>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[C:9]([C:11]3[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=3[CH2:19][C:4]=2[CH:3]=1)=[O:10]
Reactant: Cc1cc(O)c2c(c1)C(=O)c1cc(O)cc(O)c1C2=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(O)c2c(c1)Cc1cc(O)cc(O)c1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of 20 grams of emodin, 1000 mL of acetic acid, 82.8 grams of stannous chloride was heated to reflux. Hydrochloric acid (60 mL) was added slowly in minutes and continued reflux for 1 hour. Remaining 167 mL of HCl was added slowly at reflux and continued for an additional 1 hour. Orange color mixture was cooled to room temperature and left over night. Product was isolated by filtration and washed with water. Finally the product (emodin anthrone) was dried in vacuo at 60° C. to a constant weight to afford 18.1 grams (Yield: 95%) of an orange powder.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[NH:13].Br[CH2:19][CH2:20][O:21][C:22]([C:24]1[CH:46]=[CH:45][C:27]([O:28][CH:29]2[CH2:34][CH2:33][N:32](C(OCC3C=CC=CC=3)=O)[CH2:31][CH2:30]2)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.C(O)C.[C].[Pd]>[NH:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]2[CH:45]=[CH:46][C:24]([C:22]([O:21][CH2:20][CH2:19][O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[NH:14])[NH2:13])[CH:10]=3)=[O:23])=[CH:25][CH:26]=2)[CH2:34][CH2:33]1
Reactant: O=C(OCCBr)c1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: N=C(N)c1cccc(O)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Product: N=C(N)c1cccc(OCCOC(=O)c2ccc(OC3CCNCC3)cc2)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Hydroxybenzamidine trifluoroacetate (298 mg, 1.19 mmol) obtained in Step 1 of Example 2, benzyl 4-{4-[(2-bromoethoxy)carbonyl]phenoxy}piperidine-1-carboxylate (500 mg, 1.08 mmol), and cesium carbonate (717 mg, 2.20 mmol) were suspended in dehydrated DMF, and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was ice-cooled, and 1N hydrochloric acid (4.5 ml) was added to the mixture and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, and the mixture was washed with 0.1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained crude product (about 700 mg) was dissolved in ethanol (15 ml). 10% Palladium-carbon (105 mg) was added thereto, and the mixture was stirred for 5.5 hours under hydrogen atmosphere. After filtration through celite, the solvent was evaporated to give the title compound as a crude product. This compound in a crude state was used for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:5][CH:4]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.Cl>O.C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:24])[C:13]2=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccn(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: COc1ccc2ccn(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2c1

Procedure:
A mixture of 0.2 g 1B, 0.25 g potassium carbonate and 15 ml acetonitrile is treated with 0.2 g methyl iodide at room temperature. After stirring over night the mixture is poured into water, acidified with aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([OH:19])[CH2:11][CH2:10]1.CN1CCOCC1.N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([O:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCOc2ccccc21
Agent: c1c[nH]cn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-chloro-dimethyl-silane (10.54 g, 70 mmol) was added to a CH2Cl2 (200 mL) solution of 4-chromanol (10.00 g, 66.6 mmol), N-methylmorpholine (10.98 mL, 100 mmol) and imidazole (0.20 g, 3 mmol) at 0° C. The mixture was stirred for 3 days at RT. The reaction was diluted with CH2Cl2 (200 mL), washed with dilute HCl and H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@@H:9]([CH3:47])[C:10]([NH:12][C@@H:13]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:14]([N:16]1[C@H:25]([C:26](=[O:38])[NH:27][C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:39]([O:41]C)=[O:40])=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@@H:9]([CH3:47])[C:10]([NH:12][C@@H:13]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:14]([N:16]1[C@H:25]([C:26](=[O:38])[NH:27][C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:39]([OH:41])=[O:40])=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of (S)-methyl 2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1.34 g, 2.02 mmol) in THF (13.5 mL) and MeOH (6.7 mL) was added NaOH(aq.) (3N, 3.4 mL, 10.1 mmol). After 3 h, the reaction mixture was poured into a sep funnel containing EtOAc and 1N HCl. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (1.25 g, 1.93 mmol, 95%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 649.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:18]([O-])=O.[Na+]>Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[(4-fluorophenyl)sulfonyl]phenylamine (IV, Step II, 3.10 g, 12.3 mmol) in concentrated hydrochloric acid (30 mL) at 0° is treated with sodium nitrite (934 mg, 13.5 mmol) in H2O (15 mL). After 30 min, the mixture is treated with stannous chloride (5.57 g, 24.7 mmol) in concentrated hydrochloric acid (15 mL). The mixture is stirred at 0° for 1 hr, and then at 20-25° for 1 hr. The precipitate is collected and slurried in H2O. The mixture is made basic (sodium hydroxide, 50%) and the solid isolated. The material is partitioned between methylene chloride and saline. The organic layer is dried, filtered, and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.85-7.95, 7.74, 7.13, 6.85, 5.64 and 3.65 δ.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.O[C:28]1[C:32]([CH:33]=[O:34])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:33]([C:32]1[C:28]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=4)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=3[CH3:14])=[CH:25][CH:26]=2)=[N:29][N:30]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=1)=[O:34]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CO)cc3)c(C)o2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3)c(C)o2)c1
Reaction time: 15 h
Yield: 44.6 %

Procedure:
To a mixture of methyl 3-(4-{[4-(hydroxymethyl)phenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate (1.34 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), tributylphosphine (0.77 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.96 g) was added at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as crystals (0.62 g, yield 47%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[C:6](=O)[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:12]=[N:11][C:5]2=[C:6]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:7]=[N:8][CH:9]=[C:4]2[CH:3]=1
Reactant: C1COCCN1
Reactant: O=c1[nH]ncc2cc(Br)cnc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Brc1cnc2c(N3CCOCC3)nncc2c1
Temperature: 95 °C

Procedure:
A mixture of 3-bromopyrido[2,3-d]pyridazin-8(7H)-one (0.206 g, 0.91 mmol) and phosphorus oxychloride (5.00 ml, 55 mmol) was heated at 95° C. After 2 h the reaction was cooled to 25° C. and diluted with 30 mL of CHCl3. The solution was cooled to 0° C. and the solid was filtered and washed with CHCl3. The filtrate was concentrated to dryness and azeotroped with toluene (2×). The residue was dissolved in CH3CN and heated with morpholine (0.079 ml, 0.91 mmol) at 190° C. for 15 min in the microwave. The crude material was purified by flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:24) to give the title compound as an orange amorphous solid. MS m/z: 295.0 [M+1].
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C@H:9]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC[C@H](N)C(=O)NCc1ccc(I)cc1
Yield: 99.3 %

Procedure:
A solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(4-iodobenzylamino)-5-oxopentanoate (2.129 g, 4.47 mmol) in DCM (15 mL) and TFA (10 mL) was stirred at room temperature for 4 h. After the solvent was evaporated, the reaction mixture was diluted with DCM, washed with sat. K2CO3 aqueous solution and concentrated in vacuo to afford (S)-methyl 4-amino-5-(4-iodobenzylamino)-5-oxopentanoate (1.67 g). A solution of (S)-methyl 4-amino-5-(4-iodobenzylamino)-5-oxopentanoate (1.67 g), Boc-Glu(OMe)—OH.DCHA (1.97 g, 4.44 mmol), EDCI (1.02 g, 5.33 mmol), HOBt (0.599 g, 4.44 mmol) in DCM (100 mL) containing DIPEA (2.26 mL) was stirred at room temperature under nitrogen for 20 h. The reaction mixture was diluted with DCM, washed with 1N HCl aqueous solution, sat. NaHCO3 aqueous solution and brine. The organic phase was separated and evaporated under reduced pressure to give a crude product, which was purified by flash chromatography with hexane/ethyl acetate as eluent to give (S)-methyl 4-(tert-butoxycarbonylamino)-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate (2.137 g, 77% over 2 steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.4 Hz, 2H), 5.44 (brs, 1H), 4.48-4.30 (m, 3H), 4.06-4.02 (m, 1H), 3.69 (s, 6H), 2.54-2.37 (m, 4H), 2.20-1.93 (m, 3H), 1.37 (s, 9H); MS (ESI), 620 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[CH:18][N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Br)[N:23]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[CH:18][N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:23]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-amino ethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.086 mmol), 2-amino-6-bromopurine (0.033 g, 0.16 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H16FN8OS (M+H)+: m/z=423.1. Found: 423.0. 1H NMR (DMSO-d6, 400 MHz) δ 7.98 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.52 (1H, d, J=4.8 Hz), 7.46 (1H, m), 7.20 (2H, m), 6.84 (1H, br s), 5.41 (1H, br s), 5.07 (1H, m), 1.26 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −114 ppm.
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[C:14]2[C:8]([CH:9]=[C:10]([O:16][CH3:17])[O:11][C:12]2=[O:13])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].[Cl:18]N1C(=O)CCC1=O>CN(C=O)C>[NH:1]([C:5]1[CH:15]=[C:14]2[C:8]([C:9]([Cl:18])=[C:10]([O:16][CH3:17])[O:11][C:12]2=[O:13])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc2ccc(NC(=N)N)cc2c(=O)o1
Solvent: CN(C)C=O
Product: COc1oc(=O)c2cc(NC(=N)N)ccc2c1Cl
Yield: 37.4 %

Procedure:
0.27 g of 7-guanidino-3-methoxyisocoumarin (1 mmole) was chlorinated with 0.15 g of N-chlorosuccinimide (1.1 mmole) in 5 ml DMF at r. t. overnight. The reaction mixture was evaporated to dryness, and purified by silica gel column chromatography which is eluted with methylene chloride and methanol (5:1) to give 0.1 g of 7-guanidino-3-methoxy-4-chloroisocoumarin (yield 34%). One spot on TLC, Rf=0.75 (Butanol:acetic acid:pyridine:water=4:1:1:2); NMR spectrum is similar to 7-guanidino-3-methoxyisocoumarin except no peak at 6.1 ppm; mass spectrum (FAB+), m/e=268 (M+ -Cl). Anal. Calc. for C11H11N3O3Cl2. 1/2 H2O: C, 42.17; H, 3.83; N, 13.41; Cl, 22.68. Found: C, 42.65; H, 3.72; N, 13,28; Cl, 22.32.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:24][N:25]([CH3:27])[CH3:26])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Yield: 91.7 %

Procedure:
A suspension of 6.17 g of ethyl 3-(2-chloro-6,7-difluoro-3-quinolyl)-3-oxopropionate in 7.15 g of N,N-dimethylformamide dimethyl acetal and 60 cm3 of ethyl acetate is heated at a temperature close to 75° C. for 1 hour 15 minutes. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue is taken up in 50 cm3 of diisopropyl ether, drained and washed with 3 times 25 cm3 of the same solvent. 6.65 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are obtained in the form of an orange solid melting at 140° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:11])[C:4]([CH:6]1[CH2:9][C:8](=[O:10])[CH2:7]1)=[O:5].CO.[BH4-].[Na+].Cl>>[OH:10][CH:8]1[CH2:9][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:11])=[O:5])[CH2:7]1
Reactant: CON(C)C(=O)C1CC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CON(C)C(=O)C1CC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.6 %

Procedure:
N-Methoxy-N-methyl-3-oxocyclobutanecarboxamide (1 g, 0.006 mol) was dissolved in methanol (8 mL, 0.2 mol). To the mixture, sodium borohydride (0.2 g, 0.006 mol) was added. The reaction was stirred at rt for 1 h. To the reaction mixture was added 1N aq. HCl to adjust the pH to 2. The mixture was concentrated, then extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude product (1.4 g) as light yellow oil. LCMS calculated for C7H14NO3(M+H)+: 160.0. Found: 160.3.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14](F)=[CH:13][N:12]=[C:11]([C:16]([NH:18][C:19]4[N:20]=[C:21]([C:24]5[N:28]([CH:29]6[CH2:31][CH2:30]6)[CH:27]=[N:26][N:25]=5)[S:22][CH:23]=4)=[O:17])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:13][N:12]=[C:11]([C:16]([NH:18][C:19]4[N:20]=[C:21]([C:24]5[N:28]([CH:29]6[CH2:31][CH2:30]6)[CH:27]=[N:26][N:25]=5)[S:22][CH:23]=4)=[O:17])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1csc(-c2nncn2C2CC2)n1)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1csc(-c2nncn2C2CC2)n1)c1cc(-n2cnc(C3CC3)c2)c(N2CCOCC2)cn1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a mixture of intermediate D (450 mg, 1.03 mmol) and K2CO3 (430 mg, 3.09 mmol) in DMF (3 mL) was added morpholine (270 μl, 3.09 mmol) and the reaction was heated to 80° C. overnight. The reaction was concentrated and purified by RP-HPLC to afford 390 mg (75% y) of 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-5-morpholinopicolinamide. All final compounds were isolated as the HCl salt from the preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CS(C)=O.CCOC(C)=O>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:13][C:6]=1[C:7]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)=[O:12]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 2): A mixture of 6-hydroxy-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione (360 mg, 2 mmol) and 4-aminomethyl-1-diphenylmethylpiperidine (420 mg, 1.5 mmol) in DMSO (5 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with AcOEt and washed twice with brine. The organic layer was dried over MgSO4 and evaporated, and then the residue was purified by column chromatography on silica gel to give 2-amino-5-hydroxy-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 520 mg (63%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])=[N:4][N:3]=1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Cc1nnc(N)o1
Product: Cc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 261-263° C. and MS: m/e=307.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl[1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acid chloride.