Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:2].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[C:1]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:21])=[O:2]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3.67 g, 15.03 mmol, 1 eq) was dissolved in acetone (50 ml) and the solution diluted with water (50 ml). To the reaction mixture was added sulfamic acid (2.04 g, 21.04 mmol, 1.4 eq) and 80% sodium chlorite (1.78 g, 15.8 mmol, 1.05 eq) and allowed to stir for 1 hour at room temperature in an open vessel. Removal of acetone in vacuo yielded crude product as a precipitate in the remaining aqueous solution. The solid was collected, washed with absolute ethanol and dried (3.32 g, 85%). m.p. 173-175° C.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:9]1[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][N:13]=1)=[CH:5][N:6](C)C.[NH:19]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:22]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[N:27]1([C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:19]3[C:3](=[O:18])[C:4]([C:9]4[S:10][C:11]([C:14]([F:15])([F:16])[F:17])=[N:12][N:13]=4)=[CH:5][NH:6]3)[CH:22]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: NNc1cc(N2CCOCC2)ncn1
Reactant: COC(=O)C(=CN(C)C)c1nnc(C(F)(F)F)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: O=c1c(-c2nnc(C(F)(F)F)s2)c[nH]n1-c1cc(N2CCOCC2)ncn1

Procedure:
2.43 g (8.62 mmol) of the compound from Example 2A, 1.53 g of the compound from Example 16A and 182 mg (784 μmol) camphor-10-sulfonic acid are dissolved in 35 ml anhydrous methanol and the mixture is heated under reflux overnight. After cooling, the mixture is concentrated, the residue is taken up again in 325 ml methanol, 0.5 ml (8.62 mmol) of a 25% strength methanolic sodium methylate solution is added and the mixture is heated again under reflux overnight. After cooling, the precipitate formed is filtered off with suction, washed with diethyl ether and suspended in a little water, an excess of 1 M hydrochloric acid is added and the suspension is concentrated again. The residue is washed with water and diethyl ether and dried. 1.34 g (43% of th.) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[O:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[C@H:2]1[O:4][CH2:3]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:4][C@@H:2]([CH2:3][N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH2:31][CH2:32]1)[CH2:1][O:5][C:6]1[C:11]2[O:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: CCOC(=O)c1cc2cccc(OC[C@@H]3CO3)c2o1
Product: CCOC(=O)c1cc2cccc(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)c2o1
Yield: 77.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 11 using ethyl (S)-7-(glycidyloxy)benzo(b)furan-2-carboxylate (5.3 g) and 4-(naphthalen-2-yl)piperidine (3.0 g), the title compound (5.2 g) was obtained as a brown oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].Cl>O1CCCC1>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: ClCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCl)C(=O)OCC
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To 458 ml of dry tetrahydrofuran (THF) was added 13.4 g of 60% sodium hydride, and 160.6 g of diethyl malonate was added dropwise with stirring under ice-cooling. After addition, stirring was continued for 15 minutes, and 57.3 g of 1-bromo-4-chlorobutane was added. The mixture was stirred for 50 hours at room temperature. The reaction solution was poured into ice-cold water, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to provide 26.8 g of the objective compound as colorless oil. B.p. 127–130° C. (5 mmHg).
Reaction SMILES: CO.[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:24])([F:23])[C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15].[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C(O)(=O)C>[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Reactant: Cc1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CNC2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol) and N-trifluoroacetyl-4-piperidone (from reaction step 1) (5.065 g, 25.9 mmol) were added to a 250 ml round-bottomed flask and dissolved in the methanol/acetic acid (150 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBH3 (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a reparatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO4. Concentration afforded, 4-(4-methylbenzylamine)-1-(trifluoroacetyl) piperidine. UV/MS 60/53 (M+ 301), tr (A, MS) 3.267.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)CCCCOCc1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCCCOCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (162 mg, 0.600 mmol) was dissolved in pyridine (10 mL), 5-(benzyloxy)pentanoyl chloride (150 mg, 0.662 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (105 mg, yield 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:27][CH2:9][C:6]1[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CBr)nc1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 3-methoxy-6-methyl-2-(4-(trifluoromethyl)phenyl)pyridine (0.59 g, 2.2 mmol) in CCl4 (40 mL) was added NBS (440 mg, 2.5 mmol) and AIBN (33 mg, 0.20 mmol). The reaction mixture was heated to reflux for 13 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered through a pad (1.5 cm) of silica, and concentrated. The product 6-(bromomethyl)-3-methoxy-2-(4-(trifluoromethyl)phenyl)pyridine was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]([CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[OH:24])[CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)(C)(C)C.Cl>CCOC(C)=O>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:17])[N:18]([CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[OH:24])[CH:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=1
Reactant: CC(C)N(CC(O)c1ccc(Cl)c(Cl)c1)C(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)N(CC(O)c1ccc(Cl)c(Cl)c1)C(=O)Nc1ccc(CN)cc1
Yield: 92.5 %

Procedure:
Through a solution of 3 g (6 mmol) (4-{3-[2-(3,4-Dichloro-phenyl)-2-hydroxy-ethyl]-3-isopropyl-ureido}-benzyl)-carbamic acid tert-butyl ester in 100 mL EtOAc was gently bubbled HCl gas for 15 min. The reaction mixture was then concentrated in vacuo and to the resulting residue was added 15 mL 1N LiOH solution. This was extracted 3×70 ml EtOAc and the combined extracts were washed with 10 ml brine, dried over Na2SO4, filtered and concentrated to give 2.2 g 3-(4-Aminomethyl-phenyl)-1-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-1-isopropyl-urea as a white solid which was used without further purification. 1H NMR(300 mHz, CD3OD) 7.71 (d, 1H, J=2 Hz); 7.53 (d, 1H, J=8 Hz); 7.37 (dd, 1H, J=8 and 2 Hz); 7.28 (m, 4H); 4.88(m, 1H); 4.34 (sept, 1H, J=7 Hz); 3.78 (s, 2H); 3.48(dd, 1H, J=9 and 16 Hz); 3.22 (m, 2H); 1.25 (d, 3H, J=7 Hz); 1.12 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]C)=[O:24])=[CH:16][C:15]=2[CH:27]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=2[CH:27]=1)[CH3:2]
Reactant: CCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
Into a solution of methyl 7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.64 g) in THF-methanol (6-3 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.9 ml), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (385 mg) as light yellow crystals.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(C)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefins): δ 0.73 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 15 H), 1.90 (tdd, J=7.0, 7.0, 1.0, 2 H), 2.36 (s, 3 H), 3.30-3.50 (m, 21 H), 4.40 (d, J=4.0 Hz, 2 H), 5.20-5.40 (m, 1 H), 5.95 (dt, J=16.0, 1.0 Hz, 1 H), 6.90 (m, 2 H), 7.10-7.30 (m, 2 H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.34 (10% ethyl acetate/n-hexane). mp 94-97° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1COc2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCl
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)COc2ccccc21
Yield: 96.4 %

Procedure:
3(S)-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one (1.9 g) obtained in Example 14 is reacted with 1.1 g of tert-butyl chloroacetate in a manner similar to that of Example 4 to give 2.5 g of tert-butyl 3(S)-benzyloxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a pale yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([O:17]O)(C)(C)C.C(OCC)C>[OH-].[Na+].O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:17])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)CCCC2
Reactant: CC(C)(C)OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc2c(c1)CCCC2
Temperature: 70 °C
Reaction time: 72 h

Procedure:
1,2,3,4-Tetrahydro-6-naphthaldehyde (2.0 g) was suspended in 0.5M aqueous sodium hydroxide solution (125 ml), stirred vigorously and a 70% w/w solution of tertiary butyl hydroperoxide in water (10.3 ml) added. The mixture was heated at about 70° C. for 4 hours and then left to stand at room temperature for 3 days. A frther quantity of a 70% w/w solution of tertiary butyl hydroperoxide in water (10 ml) was added and the mixture heated at about 70° C. for a further 24 hours. The mixture was cooled, diethyl ether (100 ml) added and the phases separated. The aqueous phase was acidified to pH 1 with 2N aqueous hydrochloric acid solution and extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 1:1 changing to 1:0, by volume, diethyl ether:pentane to give 1,2,3,4-tetrahydro-6-naphthoic acid (0.62 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Br:12][C:13]1[CH:18]=[N:17][C:16]([OH:19])=[CH:15][N:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](OS(C)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:19][C:16]2[CH:15]=[N:14][C:13]([Br:12])=[CH:18][N:17]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1cnc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc(Br)cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 96.7 %

Procedure:
Cesium carbonate (372 mg) was added to a DMF solution (2 ml) of 2-bromo-5-hydroxypyrazine (100 mg) and 1-t-butoxycarbonyl-4-(methanesulfonyloxy)piperidine (192 mg), and stirred at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane:ethyl acetate=1:11) to obtain the entitled compound (198 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[N:34]1.C(=O)=O.CC(C)=O>C1COCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reaction time: 0.03 h

Procedure:
A solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.271 g, 0.632 mmol; Intermediate 16) in THF (6 mL) was stirred under argon at ˜−70° C. while n-BuLi (1.63 M in hexanes, 0.368 mL, 0.6 mmol) was added dropwise by syringe over 1 minute. After another 2 minutes, a solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (0.128 g, 0.664 mmol; Intermediate 43) in THF (6 mL) was added dropwise over 2 minutes, and the reaction was allowed to warm to room temperature overnight as the dry ice/acetone bath slowly warmed (11 hours). The resulting yellow mixture was quenched in one portion at 0° C. with 5 M aqueous NH4Cl (1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a DCM to 100% EtOAc gradient to yield the impure title compound. This was then triturated from ˜0.5 mL DMSO+˜2 mL MeOH at 70° C., and the opaque milky mixture was allowed to cool to room temperature, filtered, and the white filter cake washed with MeOH (2×2 mL). The filter cake was air dried at 110° C. to provide the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=2.53 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J=4.55 Hz, 2H), 7.46 (dd, J=2.27, 8.84 Hz, 1H), 7.36 (d, J=8.59 Hz, 2H), 7.19 (s, 2H), 6.51 (s, 1H), 4.30 (s, 2H), 4.06 (s, 3H), 3.84 (s, 6H); MS m/e 542.3 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=3)[C:12](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:27])[N:5]=2)[CH3:3])=[N:34][CH:33]=1
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(Cl)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 28 h
Yield: 14.6 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-chloro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (80 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 28 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 15 mg of the title compound (15% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1I)=[CH:9][CH:8]=[CH:7][CH:6]=2.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[N:24]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[CH2:26][CH2:25]1
Reactant: c1cc2c(cn1)CCN2
Reactant: Fc1cnc2ccccc2c1I
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cnc2ccccc2c1N1CCc2cnccc21
Temperature: 80 °C
Yield: 68.2 %

Procedure:
3-Fluoro-4-iodo-quinoline (0.2 g, 0.73 mmol) was placed in a 25 ml round bottomed flask and to it was added tetrahydrofuran (15 ml), xantphos (0.015 g, 0.02 mmol), cesium carbonate (0.476 g, 1.4 mmol), 5-azaindoline (0.087 g, 0.73 mmol). The mixture was degassed for 5 mins. Tris(dibenzylidineacetone) dipalladium(0) (0.0025 g, 0.0025 mmol) was added and the mixture was heated to 80° C. for 48 hrs. Water was and compound extracted into ethyl acetate, dried over sodium sulfate and concentrated in rotary evaporator to yield desired compound (0.132 g, 67%). MS (ES) 266.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccncc3)c12
Temperature: 85 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (258 mg, 0.68 mmol) was mixed with K2CO3 (207 mg, 2.2 eq), pyridine-4-boronic acid (110 mg, 1.3 eq), Pd(Ph3)4 (43 mg, 0.05 eq), 3 mL of 1,2-dimethoxyethane and 0.5 mL of water. The mixture was heated and stirred in an 85° C. oil bath for 5 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of solvent gave the crude product, which was purified by column chromatography to give 156 mg of 3-methyl-4-pyridin-4-yl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([N+:14]([O-])=[O:15])([CH3:13])[CH3:12].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N+:14]([C:11]([CH3:13])([CH3:12])[CH3:10])[O-:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccc(F)cc1

Procedure:
To a suspension of 4-fluorobenzaldehyde (325.0 mg, 2.62 mmol), 1,1-dimethylnitroethane (542.3 mg, 5.26 mmol) and zinc (516.0 mg, 7.89 mmol) in ethanol (3.0 ml) was added acetic acid (941.7 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 4.5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1-1/1).