Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:15])=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH:9]1([CH2:8][C:7]2[CH:6]=[C:5]([CH3:15])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:3](=[O:21])[C:2]=2[NH:1][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cn1c(C)cc(CC2CCCCC2)c(N)c1=O
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cn1c(C)cc(CC2CCCCC2)c(NC(=O)OCc2ccccc2)c1=O
Yield: 57 %

Procedure:
1.12 g (3.83 mmol of methyl 3-amino-4-(cyclohexylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-1-acetate are reacted with phenylmethyl chloroformate under the conditions described in Example 3. 0.93 g of product is obtained after purification by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([CH3:16])=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([CH3:12])[CH:6]=2.C(Cl)(Cl)Cl>C(N)CN>[NH2:4][CH2:3][CH2:2][NH:11][C:2]1[C:3]2[N:4]([C:13]([CH3:16])=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([CH3:12])[CH:6]=2
Reactant: Cc1ccc2nc(Cl)c3ncc(C)n3c2c1
Solvent: NCCN
Solvent: ClC(Cl)Cl
Product: Cc1ccc2nc(NCCN)c3ncc(C)n3c2c1
Yield: 174.2 %

Procedure:
A solution of 4-chloro-1,8-dimethylimidazo(1,2-a)quinoxaline (compound 5) (4.8 g, 21 mmol) in ethylenediamine (300 mL) was heated at 60° C. under nitrogen gas (N2) for 16 hours. The solvent was evaporated under vacuum. The residue was diluted with EtOAc (200 mL), washed with saturated Na2CO3 and brine, dried over MgSO4, filtered and concentrated. Flash chromatography using methanol (MeOH) provided a solid, which was then dissolved with CHCl3 and filtered to remove any dissolved silica gel. The filtrate was concentrated under vacuum, providing the title compound 6 as a white solid (4.67 g). 1H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.31 (s, 1H), 3.63 (apparent q, J=5.9 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 2.88 (s, 3H), 1.38 (br, 2H); MS (ESI), m/z 256.15 [(M+H)+; calculated for compound 6, C14H17N5:255.15].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:1][CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccc(C(=O)O)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(O)c1cccc2ccc(CBr)cc12
Yield: 96.7 %

Procedure:
A suspension of N-bromosuccinimide (6.23 g, 0.035 mol) in a solution of 7-methylnaphthalene-1-carboxylic acid (6.2 g, 0.033 mol) in tetrachlomethane (200 mL) was refluxed in the presence trace amounts of benzoyl peroxide for 2 hours. The resulting white suspension was evaporated to dryness under reduced pressure, washed with hot water and dried to give the crude product (8.46 g, 95.8%). An analytical sample was recrystallized from benzene-ethanol mixture. M.p. 209.5-211° C. 1H NMR δ 13.20 (bs, 1H), 8.91 (bs, 1H), 8.30-7.95 (m, 3H), 7.72-7.54 (m, 2H), 4.92 (s, 2H). Anal. Calcd for C12H9BrO2: C, 54.37; H, 3.42. Found: C, 54.45; H, 3.44.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[N:25]=[CH:26][CH:27]=[N:28]2.[ClH:33]>>[ClH:33].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[N:25]=[CH:26][CH:27]=[N:28]4)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: BrCc1cccc2nccnc12
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccc3nccnc23)n1
Yield: 31.5 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 70 mg, 0.338 mmol), potassium carbonate (117 mg, 0.844 mmol) and 5-(bromomethyl)quinoxaline (75.3 mg, 0.338 mmol) [Hardie, M. J., Org. Biomol. Chem. (2004), 2(20), 2958] were reacted according to Example 3, Steps B and C, to provide N-(4-methylthiazol-2-yl)-3-(quinoxalin-5-ylmethoxy)pyridin-2-amine hydrochloride (41.1 mg, 31.5% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.12 (d, 1H), 9.07 (d, 1H), 8.26 (d, 1H), 8.16 (d, 1H), 8.04 (d, 1H), 7.93 (t, 1H), 7.73 (d, 1H), 7.15 (dd, 1H), 6.85 (s, 1H), 5.88 (s, 2H), 2.33 (s, 3H). Mass spectrum (apci) m/z=350.0 (M+H-HCl).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[C:14]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
tert-Butyl (3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with isobutyryl chloride (0.067 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give tert-butyl (3S)-3-(isobutyrylamino)pyrrolidine-1-carboxylate, LCMS [M+Na] 279.2. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the crude product (35 mg, 30%), which was used directly in the next step. LCMS calculated for C8H17N2O (M+H)+: m/z=157.1; Found: 157.2.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Li].[Cl-].[Cl-].[CH3:10][Ga+2:11]>CCCCC.C1C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Ga:11]([CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:10]
Reactant: [Li]CCCN(C)C
Reactant: C[Ga+2]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCC
Product: CN(C)CCC[Ga](C)CCCN(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 3-dimethylaminopropyllithium (53.7 mmol) are suspended in 40 ml of pentane, and a solution of 4 g of methylgallium dichloride (25.7 mmol) in 20 ml of benzene is added dropwise. The mixture is first stirred at room temperature for one hour and then boiled under reflux for 6 hours. After cooling, the lithium chloride and excess lithium salt are filtered off and the solvent is stripped off in vacuo. The residue which remains is sublimed in vacuo at an oil bath temperature of 60° C. Bis-(3-dimethylaminopropyl)methylgallium is obtained as a white solid of melting point 52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([CH3:25])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[NH2:18]>>[CH3:16][C:17]([NH:18][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[CH3:25]
Reactant: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(Cl)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 83 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=351.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:34](=S)=[S:35].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CCO.CN(C1C=CN=CC=1)C>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][N:28]=[C:34]=[S:35])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)=[CH:13][CH:12]=1
Reactant: S=C=S
Reactant: COc1ccc(C(OCc2cccc(CN)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C(OCc2cccc(CN=C=S)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4,4′-Dimethoxytrityloxymethyl)benzylamine (5) (613 mg, 1.39 mmol), carbon disulfide (0.85 mL, 13.9 mmol, 10 eq.), and triethylamine (0.20 mL, 1.39 mmol) were dissolved in EtOH (2 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The reaction mixture was stirred for 2 hours at a room temperature. Then, in an ice bath, to the mixture were added dropwise a solution of di-tert-butyl dicarbonate (3.06 mg, 1.40 mmol) in EtOH (0.6 mL) and a solution of DMAP (6.12 mg, 6 mol %) in EtOH (0.6 mL). The mixture was further stirred for 4 hours at a room temperature. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography (Hex:EtOAc=10:1) to isolate
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:11])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:35])[CH2:33][S:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: S=c1cc[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CSc1ccnc2ccccc12)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Quinoline-4(1H)-thione (3.50 g, 21.9 mmol) and potassium carbonate (3.95 g, 28.5 mmol) were suspended in dry acetone(350 ml). 1-Benzyloxy-4-bromoacetylbenzene (8.00 g, 26.3 mmol) was gradually added to the suspension under ice cooling and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added with water, extracted with ethyl acetate, washed with saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed by silica gel column chromatography (n-hexane:ethyl acetate=1:4) and recrystallized from ethyl acetate to obtain 5.43 g of the titled compound (64.4%) as yellow-white crystal.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Oc2ccc(Nc3cc(NC4CCNC4)ncn3)cc2)cc1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred solution of tert-butyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidin-1-carboxylate (0.1 g, 0.2 mmol) in dry CH2Cl2 (2.0 mL) at 0° C. was added CF3COOH (2 mL, 20 vol.) and the reaction mixture was kept at this temperature for 30 min. It was allowed to come to rt and stir at this temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was quenched with water (2 mL), basified with NaHCO3 solution, and was extracted with ethyl acetate (2×8 mL). The combined ethyl acetate extract was washed with water (2 mL) and brine (2 mL), was dried over Na2SO4 and was concentrated under reduced pressure to give N4-(4-phenoxyphenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine (0.025 g, 32.4%) as a light a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)=[O:5])[CH3:2]
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C)n1
Temperature: 140 °C
Yield: 36.7 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (300 mg, 1.36 mmol) and 6-methylpyridin-2-amine (176 mg, 1.63 mmol) were dissolved in acetonitrile (4.1 mL), then heated at 140° C. for 16 h. A second portion of 6-methylpyridin-2-amine (73 mg, 0.67 mmol) was added. After a further 2 d at 140° C. the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 5 to 40% ethyl acetate in hexanes) gave 6-chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (146 mg, 36%) as a light yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.68 (br. s., 1H) 9.21 (s, 1H) 7.59 (t, J=7.7 Hz, 1H) 6.90 (d, J=7.6 Hz, 1H) 6.76 (d, J=7.9 Hz, 1H) 4.57 (q, J=7.2 Hz, 2H) 2.57 (s, 3H) 1.51 (t, J=7.0 Hz, 3H); LCMS (EI/CI) m/z: 315 [M+Na].
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC(C)(C)C)O[CH2:35][CH:36]=[CH2:37]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][CH2:37][CH:36]=[CH2:35])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Reactant: C=CCOC(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCO[C@@H]1[C@@H](Cc2ccc(OC)cc2)CCC[C@H](N(COC)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
A solution of tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (350 mg, 0.775 mmol), palladium tetrakis(triphenylphosphine) (90 mg, 0.078 mmol), and allyl tert-butyl carbonate (758 mg, 4.79 mmol) in degassed THF (3876 μl) was heated to 60° C. and stirred for 4 h. The reaction mixture was cooled to room temperature and purified directly by column chromatography on SiO2 (EtOAc/Hex gradient) to afford the title product as a light yellow oil (200 mg, 52.5%): IR (neat) 2977, 2934, 2836, 1746, 1702, 1511, 1367, 1297, 1246, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 6.02-5.88 (m, 1H), 5.33 (dd, J=17.2, 1.6 Hz, 1H), 5.20 (dd, J=10.4, 1.5 Hz, 1H), 4.94-4.81 (m, 2H), 4.76 (t, J=10.3 Hz, 1H), 4.60-4.50 (m, 1H), 4.28 (dd, J=11.8, 5.6 Hz, 1H), 4.22-4.15 (m, 1H), 4.09 (dd, J=11.9, 5.3 Hz, 1H), 3.78 (s, 3H), 3.30 (d, J=14.5 Hz, 3H), 3.21 (t, J=9.0 Hz, 1H), 3.03 (dd, J=13.5, 3.4 Hz, 1H), 2.34-2.22 (m, 1H), 2.15-1.98 (m, 1H), 1.80 (s, 1H), 1.65-1.59 (m, 2H), 1.50-1.39 (m, 13H), 0.90-0.76 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.53, 157.82, 134.40, 134.36, 132.63, 129.69, 117.12, 113.73, 84.28, 84.24, 81.09, 74.62, 58.57, 57.06, 55.24, 55.22, 46.01, 35.97, 28.32, 28.23, 26.57, 19.22, 18.26; HRMS-ESI (m/z) ([M]+) calcd for C27H41NO7, 491.2883; found, 491.2862.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Reactant: BrCCCCBr
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCBr)ccc21
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To 11.6 g (46.5 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 200 ml acetone 18.6 g (134.8 mmol) K2CO3 (powdered) and 13.7 g (115.7 mmol) 1,4-dibromobutane were added. The mixture was stirred at reflux for 4 h and at RT over night. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. EtOAc and water were added, the inorganic phase was extracted with EtOAc and the combined organic phases were washed with water and dried over Na2SO4. The crude product was purified by column chromatography on silica gel with hexane/EtOAc 9:1 to yield 11.1 g (63%) 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil, MS: 383 (M, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Li].[CH3:26]COCC.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH3:26])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 39 %

Procedure:
Benzyl N-tert-butoxycarbonyl-(2S)-pyroglutamate (20.5 g, 64.2 mmol) was dissolved in THF (500 ml). Methyl lithium (a 1.04M ether solution, 61.7 ml, 64.2 mmol) was added dropwise at −78° C. The temperature of the reaction mixture was caused to rise back gradually to room temperature under stirring, and the resulting mixture was stirred for 18 hours. A saturated aqueous solution of ammonium chloride was added and the resulting mixture was concentrated under reduced pressure. The concentrate was extracted with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane/ethyl acetate (3/1) eluate fractions, benzyl (2S)-N-tert-butoxycarbonylamino-5-oxohexanoate (8.37 g, 39%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(OC)ccc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-4-methoxy-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-4-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.18 (s, —CO2H); 7.70 (m, 1 arom. H); 6.58 (m, 2 arom. H); 6.01 (m, —CH═CH2); 5.51, 5.24 (2 d-like, CH═CH2); 4.62 (d-like, CH2—CH═CH2); 3.81 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 166.45 (C═O); 163.45; 159.40; 133.25; 133.22; 116.91; 112.98; 105.37; 100.01; 68.63; 55.45.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)COc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.0 g, 9 mmol), (prepared as described for the starting material in Example 4), ethyl bromoacetate (1.11 ml, 10 mmol) and potassium carbonate (2.84 g, 20.6 mmol) in NMP (60 ml) was heated at 90° C. for 3 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and concentrated by evaporation. Hexane was added, the mixture was cooled and the precipitated solid was collected by filtration to give 4-(4-chloro-2-fluoroanilino)-7-(ethoxycarbonylmethoxy)-6-methoxyquinazoline (1.75 g, 48%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].C([NH:35][CH2:36][C:37](O)=[O:38])(OC(C)(C)C)=O>>[NH2:35][CH2:36][C:37]([NH:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4])=[O:38]
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: NCC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1

Procedure:
(2R)-2-Amino-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one (free-base) was acylated with Boc-glycine and deprotected according to Step 2 of Example 1 to furnish (2R)-2-(2-Aminoacetamido)-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one. Rt 2.23. MS (ESI+) [M+H]+ 419.
Reaction SMILES: [CH2:1]([C:5]([CH3:19])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([C:5]([CH3:19])([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C)(Cc1ccc(O)cc1)C(=O)OCC
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCC(C)(Cc1ccc(OCCOC2CCCCO2)cc1)C(=O)OCC
Yield: 95.4 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-butyl-3-(4-hydroxyphenyl)-2-methylpropionate (2.95 g), which is the product of Reference example 10(b), 2-(2-bromoethoxy)tetrahydropyran (4.66 g) and potassium carbonate (4.62 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (4.18 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14](OCC)=[O:15].O>CS(O)(=O)=O>[Cl:10][CH2:11][C:12]1[C:5]2[C:3](=[C:2]([CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:4][C:14](=[O:15])[CH:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1c(O)cccc1O
Agent: CS(=O)(=O)O
Solvent: O
Product: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 2-methylresorcinol (1 g) in 10 mL of methyl sulfonic acid is introduced into a flask and then 1.3 equivalents (1.42 ml) of ethyl 4-chloroacetoacetate are added dropwise. After 1 night of stirring at room temperature, the mixture is cooled to 0° C. and then 50 mL of water are added. The residue is then filtered, dried and washed with diethyl ether in order to obtain 1.63 g (90%) of the compound 5.