Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC>C1C=CC=CC=1.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.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: c1ccccc1
Product: Cc1c(-c2ccco2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 30 h
Yield: 100 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (100 mg, 0.34 mmol) was dissolved in benzene (3 ml), then 2-tributylstannylfuran (117 μl, 0.37 mmol) and 2,6-di-tert-butylcresol (1 mg) and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.003 mmol) were added, followed by hearing under reflux for 20 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was fractionated with ethyl acetate and water, followed by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was dissolved in methylene chloride, potassium fluoride (20 mg) and water (0.1 ml) were added, followed by vigorously stirring at room temperature for 30 hours. The insoluble matter was separated by filtration through Celite, followed by fractionation with methylene chloride and water and by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography, eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-6-(2-furyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (96 mg) as a white solid. This was dissolved in dimethyl sulfoxide (2 ml), triethylamine (119 μl, 0.85 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 22 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to preparative thin-layer silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v) to obtain the entitled compound (37 mg, 29%) as a white solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+:15].[OH-]>C1COCC1>[OH:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:4].[Li+:15]
Reactant: COC(=O)c1ccc(C(C)(C)O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(=O)[O-])cn1
Yield: 99.9 %

Procedure:
To a stirred solution of methyl 6-(1-hydroxy-1-methylethyl)pyridine-3-carboxylate (479 mg, 2.45 mmol) in THF, (10 mL) was added LiOH (2M aqueous solution, 1.35 mL, 2.70 mmol). After 4 hours the solvent was removed at reduced pressure to give the title compound (458 mg, 100%) that was used without further purification.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[CH2:15]([NH:17][CH2:18][CH2:19][OH:20])[CH3:16].O>C(OCC)(=O)C>[CH2:15]([N:17]([CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2)[CH3:16]
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Reactant: CCNCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCO)c1ccc2cc(C(C)=O)ccc2c1
Yield: 12 %

Procedure:
A mixture of 1-(6-hydroxy-2-naphthyl)ethanone (744 mg, 3.92 mmol), sodium hydrogen sulfate(IV) (1.66 g, 16 mmol), 2-ethylaminoethanol (2 mL) and water (5 mL) was heated in a steel bomb at 130-140° C. for 3 days. After cooling, the mixture was distributed between water and ethyl acetate, and the organic layer was washed with brine, dried and evaporated. The residue was dissolved in acetone and loaded onto a 4 mm dry silica plate for radial chromatography. The plate was eluted with a 1:1 mixture of petroleum ether and ethyl acetate. Appropriate fractions were collected and evaporated to give 125 mg (12%)of 1-{6-[ethyl-(2-hydroxylethyl)-amino]-2-naphthyl}ethanone.
Reaction SMILES: [C:1](=[N:4][O:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2].[CH3:11][CH2:12][O-].[Na+].CC(=NO)C.BrC(C)C(OCC)=O>>[C:1](=[N:4][O:5][CH:6]([CH3:10])[C:7]([O:9][CH2:11][CH3:12])=[O:8])([CH3:3])[CH3:2]
Reactant: CC[O-]
Reactant: CC(C)=NOC(C)C(=O)O
Agent: CC(C)=NO
Agent: CCOC(=O)C(C)Br
Agent: [Na+]
Product: CCOC(=O)C(C)ON=C(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
The synthesis of (±)-α-(isopropylideneaminooxy)propionic acid (2) was adapted from Melvin, S et al., Organic Syntheses, 1973, Coll. Vol. 5, 1029-37. Briefly, to a freshly prepared 1 M NaOEt solution (35 g in 1 L) was added acetone oxime (110 g, 1.505 mol) and cooled to 0° C. Ethyl α-bromopropionate (175 mL, 1.347 mol) was added at a rate that such that the temperature of the reaction mixture did not rise above 20° C. After 18 hr at rt, the mixture was filtered and the filtrate was concentrated to approximately 500 mL. Water (500 mL) was added and the mixture was extracted with 1:1 benzene:Et2O (3×150 mL). The combined extracts were washed with water (500 mL), dried over Na2SO4 and the solvent was removed and the oily residue was distilled to afford 197 g of ethyl α-(isopropylideneaminooxy)propionate as a clear oil (83%) 1H NMR (CDCl3): δ 4.5 (q, 1H, J=6.9 Hz, CH), 4.1 (m, 2H, J=7.2 Hz, O—CH2-Me), 1.84 (s, 3 H, CH3), 1.61 (s, 3 H, CH3), 1.22 (d, 3 H, J=6.9 Hz, CH—CH3), 1.17 (t, 3H, J=7.2 Hz, —CH3); B.P. 62-64° C. (4 mm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[NH:22])[NH:12][C:13]2[C:18]([Br:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2Br)[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:22][C:14]3[CH:15]=[C:16]([F:20])[CH:17]=[C:18]([Br:19])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C(=N)Nc2c(Br)cc(F)cc2Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3c(Br)cc(F)cc3[nH]2)c1
Temperature: 80 °C
Yield: 16.6 %

Procedure:
A mixture of 1-[N-(2,6-dibromo-4-fluoro-phenyl)-carbamimidoyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.134 g, 0.290 mmol), CuI (6.00 mg, 0.0290 mmol), Cs2CO3 (0.464 g, 1.43 mmol), and DMF (2 mL) was heated to 80° C. for 1 h. The mixture was cooled to 23° C., diluted with EtOAc (3 mL), filtered through Celite®, and rinsed with EtOAc. The filtrate was washed with aqueous 1M HCl and water, dried (MgSO4), filtered, and concentrated under reduced pressure. Dichloromethane was added and the resulting precipitate was collected by filtration to yield the titled compound (17.0 mg, 17%). MS (ESI/CI): mass calcd. for C13H10BrFN4O2, 353.2; m/z found, 354.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.86 (s, 1H), 8.95 (s, 1H), 8.36 (s, 1H), 7.45 (dd, J=9.6, 2.3 Hz, 1H), 7.32 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[N+:19]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[C:25](OC1C=CC=CC=1)=[O:26])([O-:21])=[O:20].Cl>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([C:25](=[O:26])[C:24]2[CH:34]=[CH:35][CH:36]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(Oc1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: Cc1[nH]c2ccccc2c1CCCC(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of 4-(2-methylindol-3-yl)butyric acid (600 mg) in N,N-dimethylformamide (10 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 243 mg) in N,N-dimethylformamide (5 ml) at 20° C. and the mixture was stirred at 20° C. for 1 hour. A solution of phenyl 3-nitrobenzoate (671 mg) in tetrahydrofuran (10 ml) was added to the mixture at -35° C. and the resulting mixture was stirred at the same temperature for 2 hours. The mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was chromatographed on a silica gel (25 g) column with a mixture of hexane and ethyl acetate (10:1 to 1:1) to give 4-[2-methyl-1-(3-nitrobenzoyl)indol-3-yl]butyric acid (749 mg) as yellow crystals.
Reaction SMILES: N[C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2.[OH-:14].[Na+]>C(O)(=O)C>[OH:14][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2
Reactant: Cc1nccc2[nH]c(=O)c(N)cc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(O)cc12
Temperature: 25 °C

Procedure:
This compound was prepared by heating 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one following in part the procedure described in Example E-4 without purification of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one by reacting said unpurified 3-amino compound with aqueous sodium hydroxide solution or by similarly reacting said purified 3-amino compound with aqueous sodium hydroxide solution. These procedures are described as follows. Following the procedure described in Example E-4 using 27 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, 60 ml of concentrated sulfuric acid, 200 ml of water and 9.1 g of sodium nitrite and after concentrating the reaction mixture to dryness on a rotary evaporator, the residue containing the corresponding said 3-amino compound was treated with 75 ml of 35% sodium hydroxide solution and 100 ml of water and the resulting aqueous mixture was heated on a steam bath for 30 hours and then acidified with acetic acid. The acidified mixture was allowed to stand at room temperature overnight and the resulting product that separated was collected, washed with water and air-dried. It was then recrystallized from 400 ml of boiling dimethylformamide, filtering off the insoluble material, concentrating the filtrate to a volume of about 200 ml and then allowing it to stand at room temperature for 3 hours. The yellow crystalline solid was collected, washed with methanol and dried at 100° C. to yield 7.6 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one, m.p. >320° C. The same compound was also prepared by heating a mixture containing 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one with 25 ml of 10% aqueous sodium hydroxide solution on a steam bath for 7 hours and then cooled to room temperature. The reaction mixture was acidified with acetic acid and the resulting white crystalline precipitate was collected, washed with water and dried at 95° C. to yield 1.2 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one, m.p. >320° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:14][CH:13]=2)[CH:23]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1cccc(-c2cccs2)c1
Product: CCOc1cccc(-c2ccc(Cc3cc(Br)ccc3F)s2)c1

Procedure:
2-(3-Ethoxyphenyl)thiophene obtained in Reference Example 69-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 391/393 (M+H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1.N.C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([NH2:32])=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CO[C@@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CO[C@@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.1 g racemic 4-[2-((cis)-3-methoxycyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7 M in methanol) using TBTU instead of HATU in DMF as solvent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][NH2:27])[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:26][NH:27][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:17])=[N:12][C:11]=1[CH3:13])=[O:16]
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Reactant: NCc1ccc(F)c(F)c1
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 88 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (3,4-difluorophenyl)methanamine, the title compound was obtained as a colorless solid in 88% yield: mp 294-296° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.50 (br s, 1H), 8.77 (t, J=5.8 Hz, 1H), 8.59 (d, J=8.0 Hz, 1H), 7.40-7.28 (m, 2H), 7.15-7.10 (m, 1H), 6.26 (dd, J=8.0, 2.6 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 162.1, 161.6, 154.2, 150.5, 137.7, 132.6, 124.5, 123.3, 117.8, 117.6, 116.8, 116.6, 104.4, 98.0, 42.2, 17.5; MS (ES+) m/z 378.2 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([C@H:7]([C:31]([O:33]C)=[O:32])[CH2:8][N:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[S:10]([CH3:13])(=[O:12])=[O:11])[CH3:6].Cl.CCCCCC>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]([C@H:7]([C:31]([OH:33])=[O:32])[CH2:8][N:9]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)[S:10]([CH3:13])(=[O:11])=[O:12])[CH3:6]
Reactant: COC(=O)[C@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)N(C)CCCCl
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(CCCCl)[C@@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a mixture of N-{(2S)-2-[N-(3-Chloropropyl)-N-methylamino]-2-methoxy-carbonylethyl}-N-[4-(4-trifluoromethylphenoxy)phenyl]methanesulfonamide (350 mg, 0.67 mmol) from Step D in THF (1.5 mL) was added lithium hydroxyl (1.0 M in H2O, 1.34 mL, 1.34 mmol) at room temperature. The mixture was stirred at rt for 3 h. Then, HCl(aq) (2 N, 0.67 mL, 0.67 mmol) and hexane (15 mL) were added sequentially. The resulting solid was filtered and was washed with H2O (50 mL) and hexane (100 mL). The solid was then dried to give 317 mg of the titled compound (92%) as a pale brown solid. 1H NMR (300 MHz, d6-DMSO) δ 12.60 (br s, 1H), 7.76 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 3.96-3.80 (m, 2H), 3.59 (t, J=9.0 Hz, 2H), 3.20 (t, J=7.5 Hz, 1H), 3.00 (s, 3H), 2.67-2.46 (m, 2H), 2.20 (s, 3H), 1.82-1.70 (m, 2H); MS (EI) 509 (M++1), 507 (M+−1, 100).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:45])=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:45])=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Yield: 69.8 %

Procedure:
Prepared in 69.8% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S,24Z)-16,17-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. 1H NMR (500 MHz, CDCl3) δ 8.21 (dt, J=7.9, 1.3 Hz, 1H), 8.01 (s, 1H), 7.90 (t, J=1.5 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.38-7.33 (m, 2H), 7.14-7.06 (m, 1H), 6.72-6.68 (m, 1H), 6.07 (br. s., 1H), 4.51-4.45 (m, 1H), 4.04-3.95 (m, 1H), 3.77 (t, J=10.8 Hz, 1H), 3.71 (s, 3H), 3.56-3.50 (m, 1H), 3.50-3.45 (m, 1H), 3.09 (d, J=10.1 Hz, 1H), 2.71 (d, J=7.7 Hz, 1H), 2.48 (d, J=0.9 Hz, 3H), 2.00-1.92 (m, 2H), 1.85-1.71 (m, 8H), 1.30 (s, 3H), 1.27 (s, 9H), 1.13 (d, J=6.1 Hz, 3H); LCMS (ESI, M+1): 676.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[C:9](=[O:25])[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH:27]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[C:9](=[O:25])[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:27])[CH:12]=3)[CH:7]=1
Reactant: Cc1ccc(N)cc1-c1cc2cnc(Cl)cc2n(-c2ccccc2)c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2-c1ccccc1
Temperature: 140 °C

Procedure:
A vial is charged with 19 (208 mg, 0.575 mmol), Pd2(dba)3 (26 mg, 0.028 mmol) and Ph3P (37 mg, 0.14 mmol). The vial is evacuated and refilled with N2. Dioxane (12 mL) is added to the vial and the solution is treated with AlMe3 (0.86 mL of a 2M solution in hexane, 1.72 mmol). The mixture is heated in a microwave oven at 140° C. for 20 min. The vial is cooled down to rt and the mixture is extracted with ethyl acetate. The organic phase is washed with 1N NaOH solution, saturated NaHCO3 solution and brine. The solvent is removed in vacuo and the crude product is purified using flash chromatography (hexane:ethyl acetate=2:1) to give 3-(5-amino-2-methyl-phenyl)-7-methyl-1-phenyl-1H-[1,6]naphthyridin-2-one 20. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.75 (s, 1H), 7.58-7.63 (m, 2H), 7.52-7.56 (m, 1H), 7.28-7.30 (m, 2H), 7.03 (d, 1H), 6.67 (d, 1H), 6.64 (d, 1H), 6.38 (s, 1H), 5.32 (s, 1H), 3.60 (brs, 2H), 2.46 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.N1C=CC=CC=1.[C:16]1([NH:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[C:16]1([NH:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH:34][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 104 %

Procedure:
2-Amino-4-chloropyridine (500 mg, 0.446 mmol) was dissolved in N-methylpyrrolidone (5.0 ml); pyridine hydrochloride (750 mg) and 5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol) was added thereto; the reaction mixture was stirred at 100° C. for 6.5 hours. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane-ethyl acetate-methanol system). The obtained pale yellow oil was solidified with diethyl ether; and the crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (188 mg, 0.464 mmol, 35.7%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](=[N:28][NH2:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[C:16]1([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:28][NH:29][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NN=C(c1ccccc1)c1ccccc1
Yield: 63.9 %

Procedure:
A solution of 20.0 g (0.10 mole) of t-butyloxycarbonyl-L-serine, 19.6 g (0.10 mole) of benzophenone hydrazone, and 24.7 g of 2-ethoxy-1(2H)-quinolinecarboxylic acid ethyl ester in 250 ml of methylene chloride was stirred at room temperature for 16 hours. The solution was extracted with successive 100 ml portions of 1N hydrochloric acid, water, saturated sodium bicarbonate solution, water and brine, then dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulting syrup was dissolved in ethyl acetate and crystallized by the addition of hexane to afford 24.5 g (64%) of product, mp 150.0°-152.5° C.