Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[C:4]=1[CH3:15].[CH3:16][NH:17][CH2:18][CH2:19][C:20]#[N:21].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[C:20]([CH2:19][CH2:18][N:17]([CH3:16])[S:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[C:5]=1[CH3:14])(=[O:12])=[O:11])#[N:21]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CNCCC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)CCC#N)c(C)c1C
Reaction time: 16 h

Procedure:
4-Methoxy-2,3,6-trimethylbenzenesulfonyl chloride (5.00 g, 20 mmol) was added at room temperature to a solution of 3-methylaminopropionitrile (1.50 g, 18.3 mmol) and triethylamine (5.50 g, 55 mmol) in THF (30 ml), and stirring was carried out for 16 h. Ethyl acetate (50 ml) was then added to the reaction mixture, and washing with sodium hydrogen carbonate solution (3×50 ml) was carried out. The organic phase was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21]CC)=[O:20])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>N1C=CC=CC=1.C(Cl)Cl>[C:3]([NH:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([OH:21])=[O:20])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)Nc1ccccc1C(=O)O)c1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
NaOH (aq, 2 M, 0.7 mL) was added to a stirred solution of ester 23a (53.1 mg, 0.14 mmol) in pyridine (0.7 mL) at room temperature. After 3 h, the reaction was diluted with DCM and washed with HCl (3×, 1 M in brine), NaHCO3 (aq, sat), brine and dried over Na2SO4 before being purified by preparative HPLC to give acid 23b in 70% yield (35 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.C(Cl)Cl.CC(O)=O.CC([O-])=O.[K+].Br[C:32]1[S:33][C:34]2[C:40]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)=[C:39]([C@H:48]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:49]([O:51]CC)=[O:50])[C:38]([CH3:59])=[CH:37][C:35]=2[N:36]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.O1CCOCC1>[C:55]([O:54][C@@H:48]([C:39]1[C:38]([CH3:59])=[CH:37][C:35]2[N:36]=[C:32]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[N:6]=[C:5]4[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[S:33][C:34]=2[C:40]=1[C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:49]([OH:51])=[O:50])([CH3:58])([CH3:56])[CH3:57]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CN1CCN(c2nn(C)c3ccc(Br)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3ccc4c(c3)c(N3CCN(C)CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole (64.0 mg, 0.208 mmol), bis-pinacolatodiboron (58 mg, 0.23 mmol), PdCl2(dppf).DCM (17 mg, 21 μmol), glacial AcOH (13 μL, 0.23 mmol), KOAc (67 mg, 0.69 mmol), and dioxane (1.6 mL). The reaction was heated to 100° C. for 2 h. To this reaction was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (103 mg, 0.208 mmol), KHCO3 (23 mg, 0.23 mmol), 2 M aq K2CO3 (400 μL), and Pd(PPh3)4 (24 mg, 21 μmol). The reaction was heated for another 1 h at 100° C. Finally, EtOH (absolute, 800 μL) and 10 M aq NaOH (500 μL) were added. The reaction was heated to 100° C. for another 1 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C33H36ClN5O3S: 618.2, 620.2 (M+H+); Found: 618.4, 620.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J=9.1 Hz, 1H), 7.62-7.47 (m, 4H), 5.24 (s, 1H), 4.31-4.01 (m, 2H), 3.94 (s, 3H), 3.74-3.54 (m, 2H), 3.54-3.35 (m, 2H), 3.32-3.16 (m, 2H), 3.00 (s, 3H), 2.61 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH2:21][CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>FC(F)(F)C(O)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH2:13][C:15]([F:18])([F:17])[F:16])[CH2:21][CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)NCCO3
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CC(F)(F)F)CCO3
Yield: 198.1 %

Procedure:
Compound 132 was prepared according to General Method 3 (EXAMPLE 1) from 3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (20.0 mg, 0.064 mmol) and sodium borohydride (excess of 20 mg) in 3 mL trifluoroacetic acid to afford 25 mg (ca. 100%) of 3,4-dihydro-8-isopropoxy-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a red oil. No further purification was performed and the material was directly transformed according to General Method 4 (EXAMPLE 1) from 3,4-dihydro-8-isopropoxy-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (25 mg) in 0.32 mL conc. HCl and 0.64 mL glacial acetic acid heated at 70° C. for 90 minutes to afford 11 mg (49%) of Compound 132 after purification by flash chromatography (9:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (400 MHz, acetone-d6) δ 11.05 (br s, 1H), 7.31 (d, J=9.0, 1H), 7.04 (d, J=8.8, 1H), 6.92 (s, 1H), 4.32 (t, J=4.3, 2H), 4.14 (q, J=9.5, 2H), 3.61 (t, J=4.4, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14]>ClCCl.CO>[NH2:19][C:17]1[CH:16]=[CH:15][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][OH:14])=[C:3]([O:2][CH3:1])[CH:18]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC[C@H]1CO
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 3.1.b. from {(S)-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]pyrrolidin-2-yl}methanol. Yield: 0.15 g (83.4% of theory); C14H22N2O3 (M=266.34); calc.: molecular ion peak (M+H)+: 267; found: molecular ion peak (M+H)+: 267; Rf value: 0.15 (silica gel, dichloromethane/methanol 9:1)).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH:28]1[O:32][CH2:31][CH2:30][O:29]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH:28]2[O:32][CH2:31][CH2:30][O:29]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCC1OCCO1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCC2OCCO2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 2-bromomethyl-1,3-dioxolane (0.11 ml, 1.1 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (73 mg, yield 28%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:28])[F:27])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][NH2:45].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[OH:6][NH:5][C:4](=[N:45][CH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=1)[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH2:15][C:14]([C:26]([F:29])([F:27])[F:28])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: NCc1ccccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=NCc1ccccn1)NO
Temperature: 75 °C
Yield: 44 %

Procedure:
To a solution of 2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (250 mg) in DMF (8 mL) was added N-chloro succinimide (84 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuoto ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-picolylamine (65 mg) and triethylamine (0.15 mL, 0.11 g) in THF (8 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (138 mg, 44%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:15]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC)cc1Cl

Procedure:
2-n-Butylbezofuran (5.7 g., 0.033 mol.) was acylated with 6.7 g. (0.033 mol.) of 2-chloro-4-methoxybenzoic acid chloride in the presence of 18 g. (0.07 mol.) of stannic chloride as described in the procedure of Example 10 to give 2-n-butyl-3-(2'-chloro-4'-methoxybenzoyl)benzofuran. The subsequent demethylation, epoxy compound formation and ring opening of the epoxide to give the title compound were carried out as previously described in Examples 9 and 7.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:28]>>[F:27][C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([C:8]4[CH:7]=[C:6]([C:4]([NH2:28])=[O:3])[O:10][N:9]=4)=[CH:16][CH:15]=3)[S:19][C:20]=2[CH:26]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Product: NC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Yield: 97.4 %

Procedure:
A mixture of 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (4.0 g; 10.44 mmol) and saturated methanolic ammonia (250 ml) was stirred to obtain a white solid. The solvent was evaporated, and the residue was stirred with light petroleum and filtered. The residue was washed with light petroleum and dried to obtain 3.6 g (97.4%) of the title compound. Mass (ES+), 355 (M++1); IR (KBr): 3463, 3123 (br), 1700, 1607, 1553 (br); 1447 (br); 1H NMR (DMSO-d6) δ: 7.18 (m, 1H), 7.54 (s, 1H), 7.64 (m, 1H), 7.76 (m, 1H), 7.87-7.90 (br, 4H), 7.98, 8.37(2×br, 2H, NH2).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.C(Cl)Cl.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29](=[O:31])[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
The above 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (88.5 mg, 0.19 mmol) was suspended in 8 ml of methylene chloride containing 10 equivalent of pyrrolidine, 2.0 equivalent of HBTU and 3.0 equivalent of triethylamine. The mixture was stirred at room temperature overnight and then evaporated to remove solvents. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded to a preparative HPLC for purification to give 6,7-Dimethoxy-1-[3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid as a fluffy solid (29 mg, 33%). ES-MS calcd for C25H24N2O7 (m/e) 464.5, obsd 465.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[N:17]=[CH:18][C:19]([C:22]([NH:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[O:23])=[N:20][CH:21]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[ClH:40]>O1CCOCC1>[ClH:40].[ClH:40].[NH:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:19]2[CH:18]=[N:17][C:16]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:39])([F:1])[F:38])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:21][N:20]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1cnc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A mixture of tert-butyl 4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxamido)piperidine-1-carboxylate (0.06 g, 0.11 mmol) and 4N hydrochloric acid in dioxane (1 mL) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated and washed with diethyl ether (2×1 mL) and then dried under reduced pressure to afford N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxamide dihydrochloride salt (compound 20) as a brown solid (0.56 g, 99%). 1H NMR (CD3OD, 300 MHz) δ 8.80 (s, 1H), 8.25 (s, 5H), 7.59 (m, 2H), 7.28 (m, 2H), 5.44 (m, 1H), 4.18 (m, 1H), 3.55 (m, 4H), 3.77 (m, 2H), 3.42 (m, 4H), 3.15 (m, 2H), 2.07 (m, 8H) ppm; MS (ES) 450.5 (M+1).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([CH2:26][N:27]([CH3:43])[C:28]4([C:39]([NH:41][CH3:42])=[O:40])[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>O1CCOCC1>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([CH2:26][N:27]([CH3:43])[C:28]4([C:39]([NH:41][CH3:42])=[O:40])[CH2:31][NH:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CNC1
Reaction time: 8 h
Yield: 130.7 %

Procedure:
A solution of HCl/1,4-dioxan (1/5) (2 ml) was added dropwise to a solution of tert-butyl 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylate (310 mg, 0.56 mmol) in 1,4-dioxan (6 ml). The reaction mixture was stirred overnight, then concentrated under reduced pressure. Three triturations in methanol/dichloromethane/diethyl ether afforded the isolation of a hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylazetidine-3-carboxamide as a solid (336 mg, 100%). 1H NMR Spectrum: (DMSO d6) 2.16 (s, 3H), 2.71 (d, 3H), 3.70 (s, 2H), 3.97 (m, 2H), 4.03 (s, 3H), 4.13 (m, 2H), 7.37 (m, 2H), 7.55 (t, 1H), 7.66 (t, 1H), 8.31 (brs, 1H), 8.90 (brs, 2H), 9.27 (s, 1H), 9.75 (brs, 1H); Mass Spectrum: (M+H)+ 459.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH3:19])[CH:5]=1)(=[O:3])[NH2:2].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([SiH](CC)CC)C.CN([CH:59]=[O:60])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:59]([C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][C:6]=1[CH3:19])=[O:60]
Reactant: Cc1cc(C(N)=O)cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Product: Cc1cc(C(N)=O)cc(C)c1C=O
Temperature: 75 °C
Reaction time: 6.5 h

Procedure:
Into a solution of trifluoro-methanesulfonic acid 4-carbamoyl-2,6-dimethyl-phenyl ester (1.49 g, 5 mmol), Pd(OAc)2 (0.037 g, 0.15 mmol), DPPP (0.062 g, 0.15 mmol) and TEA (1.74 mL, 12.5 mmol) in DMF (25 mL) was bubbled CO (gas) for 10 min, then triethylsilane (1.6 mL, 10 mmol) was added. The resulting mixture was stirred at 75° C. under a CO gas balloon for 6.5 hr. After cooling to room teperature, the reaction was quenched by addition of water, then extracted with EtOAc. The EtOAc extracts were washed with water, brine and then dried over MgSO4. After filtration and evaporation, the residue was purified by column chromatograpghy (eluent, EtOAc-hexanes˜1:1) to yield 4-formyl-3,5-dimethyl-benzamide (11c) as a yellowish solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14]3=[O:29])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH:21]1([C:17]2[CH:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14](=[O:29])[N:13]3[C:18]=2[C:19]([CH3:20])=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=2)[CH:11]=[CH:12]3)[CH2:22][CH2:23]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(C)=O)cc3)ccn2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(C)O)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
50 mg of ethyl 8-(4-acetylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 3) was dissolved in 1 ml of ethanol. 9 mg of sodium borohydride was added to the obtained solution, and they were stirred at room temperature for 14 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=100/3) to obtain 35 mg of ethyl 1-cyclopropyl-8-[4-(1-hydroxyethyl)phenyl]-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([NH:15][C:16](=[O:38])[CH2:17][N:18]1[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[N:19]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[O-:39][C:40]#[N:41].[K+]>CO.O>[C:40]([NH:2][CH2:3][CH:4]([NH:15][C:16](=[O:38])[CH2:17][N:18]1[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:27])[F:28])[C:20]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[N:19]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:14])[F:13])[CH:6]=1)(=[O:39])[NH2:41]
Reactant: NCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=O)NCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
Of the compound from Example 12, 180 mg (0.31 mmol) were introduced in 3 ml of methanol/water 1:1 and admixed with potassium cyanate (75 mg, 0.92 mmol) at RT. The mixture was heated at 40° C. for 90 min. The methanol was removed on a rotary evaporator and the aqueous residue was diluted with 20 ml of water. The precipitated solid was isolated by filtration, washed with a little water and dried in an HV. This gave 146 mg (76% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>CN(C=O)C.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:25]([C:28]#[C:29][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1)([CH3:27])[CH3:26]
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)Nc1nc2ccc(C#C[Si](C)(C)C)cc2s1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea (0.100 g, 0.33 mmol), Pd(PPh3)2Cl2 (0.012 g, 0.017 mmol, 0.05 eq), and triethylamine (0.20 mL, 1.42 mmol, 4.3 eq) in 1 mL of anhydrous DMF was bubbled with nitrogen gas for about 5 minutes, followed by the addition of trimethylsilyl acetylene (0.23 mL, 1.65 mmol, 5.0 eq). The mixture was heated at about 80° C. with stirring in a sealed tube for about 15 hours. The mixture was cooled down, taken up in 10 mL MeOH, and evaporated to dryness. Purification by HPLC gave pure desired compound 0.093 g (89%). LC/MS 318 (M+1); LC retention time 3.77 min.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:11]([O:13][C:14](=[O:16])[CH3:15])[CH3:12])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:14]([O:13][C@H:11]([CH3:12])[C@H:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]([OH:25])=[O:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Benzyl-3-acetoxy-2-(tert-butoxycarbonylamino) butanoate 11 (1.4 g, 3.98 mmol) was dissolved in EtOAc (40 mL), 10% Pd/C (600 mg) was added and reaction mixture was stirred under hydrogen atmosphere for 16 h. The reaction mixture was filtered over celite, solvent was evaporated in vacuo and the crude residue was triturated with hexane to yield (2S,3R)-3-acetoxy-2-(tert-butoxycarbonylamino) butanoic acid 12 (0.7 g, 70%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C:12]1[O:13]CC(C)(C)N=1)[C:2]#[CH:3].CI.[BH4-].[Na+].Cl>C(Cl)Cl.C(O)C.C1COCC1.O>[CH2:1]([S:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:12]=[O:13])[C:2]#[CH:3]
Reactant: C#CCSc1c(F)cccc1C1=NC(C)(C)CO1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: C#CCSc1c(F)cccc1C=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To the oxazoline from Step A (7.4 g, 28.1 mmol) in 10 ml of methylene chloride was added 10 ml of methyl iodide. After 5 days, the mixture was concentrated and then dissolved in 70 ml of methylene chloride and treated dropwise with sodium borohydride (1.28 g, 33.7 mmol) in 70 ml of ethanol. The reaction mixture was stirred overnight at RT and then poured into one liter of water and extracted twice with diethyl ether. The extracts were washed with water and then brine and dried over K2CO3 to afford the crude product. This crude product was dissolved in 95 ml of THF and then treated with 95 ml of a 2N HCl solution. The reaction mixture was then concentrated and extracted with ether. The organics were then washed with water and brine and dried over MgSO4 to afford the subtitle compound.