Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccccc1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-fluoroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: NO
Reactant: N#Cc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2ccccc2)cc1

Procedure:
In ethanol (5.0 mL), was combined 4-phenoxybenzonitrile (200 mg, 1.02 mmol) and hydroxylamine (250 μL, 4.09 mmol). The mixture was refluxed for 3 hours. The reaction was cooled and then concentrated in vacuo to give the product, which was taken to the next step without further purification (quantitative yield). 1H NMR (500 MHz, CDCL3) δ(ppm): 4.87 (2H, bs), 7.01 (2H, d, J=9.0 Hz), 7.03 (2H, dd, J=8.7, 1.1 Hz), 7.15 (2H, tt, J=7.4, 1.1 Hz), 7.36 (2H, dd, J=8.6, 7.3 Hz), 7.59 (2H, d, J=9.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 118.6 (CH), 119.6 (CH), 124, 127.3, 127.6 (CH), 130.1 (CH), 152.5, 156.6, 159.3. MS (FAB+): 229 (MH+). HRMS for C13H12N2O2 (MH+): calculated: 229.0977; found 229.0977.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.38 g of methyl α-[p-(p-chlorophenoxy)phenyl]acetate in 15 ml of carbon tetrachloride is added 0.92 g of N-bromosuccinimide and a small drop of concentrated HBr. The mixture is maintained at reflux for 72 hours and cooled to room temperature. Filtration through 50 g of aluminum oxide, evaporation of the solvent and bulb-to-bulb distillation of the residue (166° at 0.05 mm) affords the product as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)#[N:2].C[Si]([N:23]=[N+:24]=[N-:25])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>CO>[N:2]1[NH:23][N:24]=[N:25][C:1]=1[CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: N#CC[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of trans-benzoic acid 4-cyanomethyl-cyclohexyl ester (3.42 g) obtained in Example (44a), trimethylsilyl azide (3.7 mL), di-n-butyltin oxide (348 mg), and toluene (30 mL) was heated at 110° C. for 48 hours. The progress of the reaction was stopped using methanol, and the reaction mixture was concentrated. The residue was diluted with ethyl acetate, followed by extraction with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was acidified (pH=2) by the addition of 1 N hydrochloric acid, followed by extraction with ethyl acetate (×2). The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated to obtain the title compound (2.57 g, 64%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:31][CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:5][CH2:6]1
Reactant: COc1ccc2ccccc2c1CC=O
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
70 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 115 mg of (2-methoxynaphthalen-1-yl)acetaldehyde were dissolved in 2 ml of tetrahydrofuran. Thereafter, 0.03 ml of acetic acid and 91 mg of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol), so as to obtain 72 mg of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2[nH]cc(C3CCNCC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.062 mMol) acetyl chloride, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH2:12]>CS(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C(O)c1ccc(Br)nc1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Br)nc1
Reaction time: 24 h
Yield: 59 %

Procedure:
N,N′-Carbonyldiimidazole (480 mg, 2.96 mmol) was added to a solution of 6-bromonicotinic acid (480 mg, 2.96 mmol) in dimethylsulfoxide (2 mL) and the mixture was stirred for 24 hours. Methylamine (2M in THF, 6 mL, 12 mmol) was then added and the mixture was stirred for a further 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was diluted with water (25 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound as a colourless solid in 59% yield, 300 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[C:11](=[O:18])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:16])([CH3:17])[C@@H:11]([OH:18])[CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)C(=O)CC(c2cc(F)cc(F)c2)NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C(=O)N[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reaction time: 2.5 h

Procedure:
To a solution of 6-(3,5-difluorophenyl)-3,3-dimethylpiperidine-2,4-dione from Step A (20.18 g, 80 mmol) in THF (600 mL) and CH3OH (25 mL) at 0° C. was added NaBH4 (4.57 g, 121 mmol). After 2.5 h, the reaction mixture was quenched with H2O (200 mL) and concentrated in vacuo. The residue was partitioned between H2O (600 mL), saturated aqueous NaHCO3 (200 mL) and EtOAc (1 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (600 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 88:12, to give the title compound, which contained approximately 20% of the corresponding trans-isomer. MS: m/z=256 (M+1).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH3:39][O:40][C:41]1[CH:63]=[CH:62][C:44]([CH2:45][C@H:46]([CH2:50][C:51]([N:53]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH3:54])=[O:52])C(O)=O)=[CH:43][CH:42]=1>>[CH2:26]([NH:25][C:23](=[O:24])[C@H:22]([CH3:30])[CH2:21][C@H:20]([OH:31])[C@@H:19]([NH:18][C:16](=[O:17])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:6](=[O:7])[C@H:46]([CH2:45][C:44]1[CH:62]=[CH:63][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)[CH2:50][C:51]([N:53]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:54])=[O:52])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(C[C@H](CC(=O)N(C)Cc2ccccc2)C(=O)O)cc1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccc(OC)cc1
Yield: 69.7 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 150 mg (0.27 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-N-butyl-6-cyclohexyl-4-hydroxy-2-methylhexanamide [prepared as described in Example 6(a)] and 92 mg (0.27 mmole) of 2(R)-(4-methoxybenzyl)-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 146 mg of the title compound as a white powder, melting at 112°-114° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([O:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1

Procedure:
0.19 g (1.01 mmol) 4,6-dichloro-2-methoxypyrimidine, 0.18 g (1.04 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one and 0.15 g (1.09 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. Then water was added and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCC1
Yield: 34.5 %

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (3 g, 11.15 mmol) was dissolved in acetonitrile (30 mL) and K2CO3 (1.85 g, 13.38 mmol) and cyclopentyl bromide (3.35 g, 22.30 mmol) was added to it. The reaction mixture was refluxed for 3 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (1.3 g, 50%).
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.CO[CH:13](OC)[N:14](C)C.O.Cl.NO>CO>[CH:1]1([C:4]2[O:10][N:14]=[CH:13][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: O
Product: O=C(O)c1cnoc1C1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-cyclopropyl-3-oxopropanoate (0.28 g, 2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.24 g, 2 mmol) was mixed and heated for 20 h at 60° C. The bright yellow oil was dissolved in methanol (2 mL) and H2O (1 mL) and hydroxylamine hydrochloride (0.14 g, 2 mmol) was added, resulting in a pH of ca 5. The reaction was heated for 90 min at 60° C. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCl (3+3 mL) for 4 h. The mixture was stored at room temperature for 2 days and the solid was filtered off and dried in vacuum to yield the title compound as a grey solid. This compound is also commercially available. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.18-1.28 (m, 2 H) 1.28-1.35 (m, 2 H) 2.78-2.90 (m, 1 H) 8.45 (s, 1 H)
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([O:14]CC)(=S)[C:10]([NH2:12])=O>C(O)C>[NH2:12][C:10]1[C:9](=[O:14])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: CCOC(=S)C(N)=O
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Nc1nc2ccccc2[nH]c1=O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 1,2-phenylenediamine (324 mg, 3.00 mmol; Aldrich Co.) and ethyl thiooxamate (400 mg, 3.00 mmol; Aldrich Co.) in 7.5 mL of ethanol was heated to reflux. The resulting solution was stirred under reflux for 3 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 85 mg (18%) of 3-aminoquinoxalin-2(1H)-one as a pale yellow solid (McKillop et al., Tetrahedron Lett. 23:3357 (1982)): mp dec.>320° C. 1H NMR (300 MHz, DMSO-d6) δ 7.261-7.075 (m, 4H, H-5+H-6+H-7+H-8). LRMS: 161 (M+, 100%), 133 (50%).
Reaction SMILES: C(C(CC)(OC1C=CC(CCN[C:17]([C:19]2[S:27][C:26]3[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=3[CH:20]=2)=[O:18])=CC=1OCC([O-])=O)C([O-])=O)C.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:48]=1>ClCCl>[C:17]([C:19]1[S:27][C:26]2[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:22][C:21]=2[CH:20]=1)(=[O:18])[CH3:48]
Reactant: c1cc[nH+]cc1
Reactant: CCC(CC)(Oc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1OCC(=O)[O-])C(=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.67 h
Yield: 92 %

Procedure:
To the solution of the compound prepared in (a) (847 in dichloromethane (30 ml) was added Molecular Sieves 4A (3 g), followed by pyridinium chlorochromate (966 mg) under ice-cooling. The mixture was stirred for 40 minutes. After the reaction mixture was filtered through FLORISIL, the filtrate was concentrated to give 772 mg of 2-acetyl-5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (yield, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.CC1(C)C2C=[CH:37][CH:36]=[C:35](P(C3C=CC=CC=3)C3C=CC=CC=3)[C:34]=2[O:33]C2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(O)CCC>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([CH:34]([CH:35]4[CH2:37][CH2:36]4)[OH:33])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(Nc1nc2c(C(O)C3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 100 °C

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (50 mg, 0.100 mmol), palladium(II) chloride (0.355 mg, 1.999 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.157 mg, 1.999 μmol), triethylamine (18.11 μl, 0.130 mmol) and 1-butanol (1000 μl) were combined in a 40 mL vial and sparged with nitrogen for 5 minutes. The cap on the vial was removed and the atmosphere changed to carbon monoxide by pressurizing to 30 psi and releasing the pressure 3 times inside a stainless steel pressure vessel. Then, the pressure of CO was adjusted to 100 psi and heated to 100° C. for 5 h. Then, the reaction was cooled to room temperature, the reaction was then poured into ethyl acetate, washed with saturated NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a white solid. 1H NMR (500 MHz, C2D6SO) δ 11.68 (d, 1H, J=6.0 Hz), 10.04 (d, 1H, J=2.0 Hz), 8.50 (d, 1H, J=9.0 Hz), 7.83 (d, 1H, J=7.0 Hz), 7.78 (d, 1H, J=7.5 Hz), 7.68 (d, 1H, J=8.5 Hz), 4.81 (m, 1H), 4.22 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.17 (m, 6H), 0.93 (s, 9H). LRMS (ESI) calc'd for (C23H29BrN3O3) [M+H]+ 476.1; found 476.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[N:21][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)nn2)cs1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(OC(F)(F)F)cc3)nn2)cs1
Yield: 79.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 213-1 and 4-trifluoromethoxyphenylboric acid (300 mg) were dissolved in dioxane (6 mL) and 2 mol/L sodium carbonate (3 mL), tetrakis(triphenylphosphine)palladium (70 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:2) to give the title compound (520 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH:29]C(OC(C)(C)C)=O)[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.O1CCOCC1.[ClH:52]>>[ClH:52].[CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH2:29])[CH:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-N-(2-indanyl)glycyl-L-proline benzylester (2.72 g, 4.95 m mole) was dissolved in 4N hydrogen chloride dioxane solution (50 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was distilled under reduced pressure from the solution, and thereby a sticky residue was obtained. After addition of ethyl ether the solution was filtered and a crystalline residue was obtained on the filter paper, and immediately dried in a desiccator to obtain a white powder of L-alanyl-N-(2-indanyl)glycyl-L-proline benzylester hydrochloride (2.31 g, 4.76 m mole, yield: 96%). This product had a hygrospic nature, and gave a single spot with Rf =0.42 by silica gel thin layer chromatography (developing solvent, chloroform:methanol:triethylamine=40:2:1, Colour forming method: spraying of 0.1% ninhydrin and heating).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH3:9])=[C:4]([OH:10])[N:3]=1.[OH-].[Na+].[CH3:13]I>>[CH3:9][C:5]1[C:4]([OH:10])=[N:3][C:2]([S:1][CH3:13])=[N:7][C:6]=1[OH:8]
Reactant: Cc1c(O)nc(S)nc1O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-mercapto-5-methylpyrimidine-4,6-diol (2.08 g, 13.14 mmol) in 2 N aq. NaOH-solution (19.7 mL, 39.41 mmol) was cooled to 0° C., then MeI (2.07 mL, 32.84 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for 1 h 40 and at rt for 2 h. The reaction mixture was concentrated to yield 5-methyl-2-(methylthio)pyrimidine-4,6-diol as a white solid which was used in the next step without further purification. LC-MS conditions
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][C:12]=1[O:13][CH2:3][C:2]#[CH:1])[CH:6]=[O:5]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=O)cc1OC
Yield: 86.4 %

Procedure:
Propargyl bromide (219 mL, 80% w/v, 1.48 mol) was added to a suspension of vanillin (150 g, 0.986 mol) and potassium carbonate (408 g, 2.96 mol) in acetone (1.50 L) and treated according to Procedure 3. 3-Methoxy-4-propargyloxybenzaldehyde (162 g, 86%) was obtained as yellow crystalline solid; mp 95° C.; δH (400 MHz, CDCl3) 2.56 (t, J=2.5 Hz, 1H, C≡CH), 3.95 (s, 3H, OCH3), 4.86 (d, J=2.5 Hz, 2H, OCH2), 7.14 (d, J5,6=6.8 Hz, 1H, H5), 7.44 (d, J2,6=1.4 Hz, 1H, H2), 7.47 (dd, J5,6=6.8, J2,6=1.4 Hz, 1H, H6), 9.87 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.0, 56.6, 77.2, 77.4, 109.4, 112.5, 126.3, 130.9, 150.0, 152.1, 190.9; HRMS (ESI) Calculated for C11H10O3 [M+H]+ 191.0703. found 191.0706; vmax 1006, 1130, 1259, 1586, 1677, 2119, 2845, 2932, 3266 cm−1.
Reaction SMILES: C([O-])(=O)C.[K+].C(Cl)Cl.CC1(C)C(C)(C)[O:13][B:12](B2OC(C)(C)C(C)(C)O2)[O:11]1.Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[F:38])[N:34]=[C:33]([NH2:39])[C:32]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[CH:31]2>CN(C=O)C>[NH2:39][C:33]1[C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:31][C:30]2[C:35](=[CH:36][C:37]([F:38])=[C:28]([B:12]([OH:13])[OH:11])[CH:29]=2)[N:34]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Nc1nc2cc(F)c(Br)cc2cc1N1CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc2cc(F)c(B(O)O)cc2cc1N1CCOCC1
Temperature: 125 °C

Procedure:
A microwave vessel was charged with potassium acetate (0.34 g, 3.46 mmol), [1,1′-bis(dppf)]dichloropalladium(II) complex with CH2Cl2 (0.038 g, 0.052 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.211 g, 0.831 mmol), 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine (0.226 g, 0.693 mmol), and DMF (2.2 mL). The vessel was purged with argon, sealed, and heated by microwave radiation for 30 min at 125° C. The reaction was diluted with EtOAc (10 mL), and the suspension was filtered through celite rinsing with EtOAc. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (25 mL) which had been deactivated with Et3N (2.5 mL) using 3% MeOH/DCM to afford 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid.