Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)nc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)nc1
Yield: 86 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 384 mg of 2-[1-(2-phenyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 17), 537 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 393 mg of triphenylphosphine and 261 mg of diethyl azodicarboxylate, 698 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1.N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.O>ClCCl.C(OCC)(=O)C>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:2][CH:3]2[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]2)=[O:22])=[CH:19][CH:18]=1
Reactant: CC1=CCC(N)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=CCC(NC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-amino-4-methylcyclohex-3-ene hydrochloride (0.103 g) in dichloromethane (5 ml) were added in turn pyridine (0.14 ml) and 4-fluorobenzoyl chloride (83 μl) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was chromatographed on silica gel (50 ml) eluting with 0-20% ethyl acetate in n-hexane to give 1-(4-fluorobenzoylamino)-4-methylcyclohex-3-ene (98 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:29])[C:16](=[O:28])[CH2:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH3:19])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([N:15]([CH3:29])[C:16](=[O:28])[CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH3:19])[CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(Br)cc1)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 185 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1,N2-dimethylglycinamide (50 mg, 0.100 mmol) was dissolved in 500 uL of 1,4-Dioxane and combined with (4-chlorophenyl)boronic acid (23 mg, 0.150 mmol), Pd(dppf)2Cl2 (2 mg, 0.003 mmol), and 300 uL of 1M Na2CO3 in water in a glass reaction tube (0.5-2.0 mL Smith Process Vial) that was equipped with a magnetic stir bar. The tube was fitted with a rubber septum and hermetically sealed with a crimped metal foil seal. Using a Personal Chemistry Emrys Optimizer microwave unit, the reaction mixture was magnetically stirred and irradiated with microwave energy of dynamically adjusted power in order to maintain a temperature of 185° C. for 360 seconds. Ethyl acetate (2 mL) and brine (2 mL) were added and the reaction mixture was filtered. The organic layer was separated and the solvent was removed under reduced pressure. The residue was dissolved in 1.0 mL DMSO and purified by preparative HPLC (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 25 mg (47%) of the title compound as a tan solid. MS (ES) m/e 530/532 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:29][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][N:50]([NH2:75])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C@H:69]([CH2:71][CH3:72])[CH3:70])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:45][CH:44]=2)=[N:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:29][C:30]([N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][N:50]([NH:75][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:51][C@H:52]([OH:74])[C@@H:53]([NH:61][C:62](=[O:73])[C@H:63]([C@H:69]([CH2:71][CH3:72])[CH3:70])[NH:64][C:65]([O:67][CH3:68])=[O:66])[CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:47][CH:48]=2)=[N:39]1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH3:31]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 128 mg (0.67 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 243 mg (1.27 mmol) of EDC and 114 mg (0.84 mmol) of HOBT are dissolved in 2 ml of DMF. After 15 min, 0.35 ml (2.5 mmol) of TEA and 286 mg (0.42 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane hydrochloride in 1.5 ml of DMF are added. After 20 hours, the mixture is worked up as described under Example 25. Chromatography (SiO2 ; ethyl acetate/toluene/methylene chloride 2:1:1) yields the title compound: TLC: Rf =0.22 (methylene chloride/ethyl acetate 1:1); HPLC20-100 : tRet =17.3; FAB MS (M+H)+ =814.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH2:11])=[CH:7][C:6]=2[CH:12]=1.[NH2:13][C:14]1[N:22]=[C:21]([CH2:23][O:24][CH3:25])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C)C=O>[NH2:13][C:14]1[N:22]=[C:21]([CH2:23][O:24][CH3:25])[CH:20]=[CH:19][C:15]=1[C:16]([NH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:12][C:6]=2[CH:7]=1)=[O:17]
Reactant: NCc1cc2cc(Br)ccc2o1
Reactant: COCc1ccc(C(=O)O)c(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(C(=O)NCc2cc3cc(Br)ccc3o2)c(N)n1
Reaction time: 12 h
Yield: 40.6 %

Procedure:
To an N,N-dimethylformamide (10 mL) solution of C-(5-bromo-benzofuran-2-yl)-methylamine (455 mg, 2.01 mmol) described in Production Example 56-1-4 were added 2-amino-6-methoxymethyl-nicotinic acid (293 mg, 1.61 mmol) described in Production Example 4-1-5, triethylamine (700 μL, 5.03 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.41 mmol) at room temperature, which was stirred for 12 hours. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate, filtering and concentrating the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (255 mg, 33%) as a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:14][C:15]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:53])[CH2:43][CH2:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:38][CH:37]=1)([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([NH:14][C:15]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42](=[O:53])[CH2:43][CH2:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:40][CH:41]=1)([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:20])[CH3:19])[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])(=[O:13])[CH3:12]
Reactant: CC(=O)NC(CCc1ccc(C(O)CCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of dimethyl sulfoxide (0.73 ml) in dichloromethane (8 ml) was added oxalyl chloride (0.23 ml) under a nitrogen atmosphere at −78° C., and then 2-acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-(1-hydroxy-5-phenylpentyl)phenyl)ethyl)propane (1.1 g) in dichloromethane (7 ml), and the mixture was stirred at said temperature for 1 hour. Then, triethylamine (1.2 ml) was added thereto and the temperature of the mixture was raised to room temperature. The reaction mixture was poured into water and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=4:1) to give the title compound (0.91 g) as a colorless transparent oily substance.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:36]([F:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[F:37][C:36]1[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:38])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:21][CH2:22]3)=[CH:28][CH:27]=2)=[N:30][CH:31]=[C:32]([CH:35]=1)[C:33]#[N:34]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncc(C#N)cc5F)cc4)CC3)n2CCS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncc(C#N)cc5F)cc4)CC3)n2CCS1
Yield: 89.9 %

Procedure:
A solution of the compound (451 mg, 0.82 mmol) obtained in Example 71-1) and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.98 mL) in tetrahydrofuran (4 mL) was stirred at room temperature for 18 h. Saturated aqueous ammonium chloride was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (321 mg, 90%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]3=[O:22])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:23])[CH2:2][CH3:3].[BH4-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([N:14]3[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[CH:18]3[OH:19])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:23])[CH2:2][CH3:3]
Reactant: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3O)cc21
Reaction time: 3 h
Yield: 69.1 %

Procedure:
1.15 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2,5-dioxo-2,5-dihydropyrrole was dissolved in 100 ml of methanol, and 0.09 g of sodium borohydride was added at room temperature. The mixture was stirred at this temperature for 3 hours. One drop of acetic acid was added, and methanol was evaporated. The concentrated residue was extracted with dichloromethane, washed with water and dried. The solvent was evaporated, and the precipitated crystals were recrystallized with ethanol to give 0.8 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole. m.p. 124°-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-chloro-3-(cyclopentylamino)benzoate (0.550 g, 1.65 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.08 g, 3.31 mmol) and methyl iodide (1.17 g, 8.25 mmol). The reaction mixture was heated at 80° C. for 12 h. On completion, the reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated and purified by column chromatography to afford methyl 5-bromo-2-chloro-3-(cyclopentyl(methyl)amino)benzoate (0.350 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.[BH4-].[Li+].C(O)C.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([CH2:6][OH:7])=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COC(=O)c1cc(C#N)c(N)cc1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(N)c(C#N)cc1CO
Temperature: 25 °C
Reaction time: 120 h
Yield: 81 %

Procedure:
To a solution of methyl 4-amino-5-cyano-2-methoxybenzoate (intermediate 129; 0.59 g, 2.88 mmol) in tetrahydrofuran (40 mL) was added dropwise lithium tetrahydroborate 2M (21.7 mL, 43.4 mmol) at 0° C. under nitrogen atmosphere. After 5 minutes was added dropwise ethanol (7.5 mL). The mixture was stirred for five days at room temperature. Then the crude was poured into a saturated solution of ammonium chloride and ice, and stirred for 10 minutes. The crude was extracted with ethyl acetate and washed with water and brine, dried and the solvent was removed under reduced pressure to obtain the title compound as a white solid (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:28]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:28])[C:11]2[CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[N:14]=[CH:15][C:16]=2[CH:17]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cc2c(=O)[nH]c(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a slurry of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (50 mg, 0.1 mmol) in tetrahydrofuran (0.5 mL) at 0° C. was added trifluoroacetic anhydride (0.04 mL, 0.29 mmol) dropwise over 2 minutes. The mixture was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as a yellow solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 10.33 (s, 1H), 9.51 (s, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 7.62-7.52 (m, 1H), 7.53-7.38 (m, 3H), 2.08 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=3.759 min, M+H+=340.0.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[CH:17][N:16]([Si](C(C)C)(C(C)C)C(C)C)[C:13]3=[N:14][CH:15]=2)[C:6](=[O:29])[CH2:5]1)[CH2:2][CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.O>C1COCC1>[CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[C:6](=[O:29])[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CC(=O)N(Cc2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC1CC(=O)N(Cc2cnc3[nH]ccc3c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256 (0.7 g, 1.7 mmol) is dissolved in absolute THF (7 ml). A 1 M solution of tetrabutylammonium fluoride in THF (1.7 M, 1 eq) is added. The obtained solution is stirred for 10 min at room temperature and poured into a mixture of ether (100 ml) and water (20 ml). The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is purified by chromatography on silicagel (dichloromethane/isopropanol) to yield 0.43 g of 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one 241.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(Cl)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>C(#N)C>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:18]2[NH:17][CH:21]=[CH:20][N:19]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
5.9 g diphenyl-chloroacetonitrile (prepared from diphenyl-chloroacetamide, Ber. 41, 3593 by heating in phosphorus oxychloride; b.p. 130°C./0.4 mm Hg) are heated with 5 g imidazole in 50 ml acetonitrile at boiling temperature for 18 hours. After treating with 20 ml of water, the mixture is extracted with methylene chloride. The solvent is distilled off after drying in a vacuum. The solid residue is recrystallized from ethyl acetate/petroleum ether. Diphenyl-imidazolyl-acetonitrile i.e. diphenyl-imidazolyl-acetic acid nitrile of m.p. 98°C. is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3Br)[CH2:5][C:4]=2[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[N:25]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(N(C)C)=O>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[N:25]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1Br)C2
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2C2CC(=O)c3c(C)nc(N)nc3C2)n1
Temperature: 150 °C
Yield: 53.5 %

Procedure:
To a 5 mL microwave vial was added 2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one (1F (Example 1), 56 mg, 0.163 mmol, 1.0 eq.), 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (77 mg, 0.325 mmol, 2.0 eq.), Pd(dppf)Cl2 (11 mg, 0.013 mmol, 0.08 eq.), 2.0 M aqueous K2CO3 (162 μL, 0.325 mmol, 2.0 eq.), and dimethylacetamide (2 mL). The vial was sealed and heated in a microwave at 150° C. for 10 min. LC/MS analysis showed the reaction was completed. The reaction mixture was filtered through Celite and purified via preparative-HPLC to give the product 13A as a white solid (33 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H) 2.62 (ddd, J=15.73, 3.03, 2.72 Hz, 1H) 2.84-3.04 (m, 2H) 3.15-3.31 (m, 1H) 3.60-3.73 (m, 1H) 3.78 (s, 3H) 6.81 (d, J=8.34 Hz, 1H) 7.15 (d, J=7.07 Hz, 1H) 7.22 (dd, J=9.60, 2.78 Hz, 1H) 7.33 (td, J=8.59, 2.78 Hz, 1H) 7.55 (br. s., 2H) 7.71 (dd, J=8.84, 5.81 Hz, 1H) 7.81 (dd, J=8.34, 7.33 Hz, 1H). ESI-MS: m/z 379.3 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(OC(=O)C)(=O)C.[Br:16]Br>C(O)(=O)C>[Br:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=1
Reactant: BrBr
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(Br)cc1N
Temperature: 65 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
In 64 ml of acetic acid, 8.0 g of o-phenylene diamine was dissolved, to which 15.3 ml of acetic anhydride was added drop-wise under cooling. Then the mixture was heated for 30 minutes in an oil bath at 65° C. After cooling to room temperature, a solution of bromine (4.6 ml bromine in 16 ml acetic acid) was quickly added, followed by heating for 40 minutes in an oil bath at 50° C. About 10 minutes after adding bromine, crystals started to precipitate. The reaction mixture was cooled to room temperature, and poured into 300 ml ice water containing 4.0 g sodium hydrogen sulfite. The resulting white precipitates were collected by filtration, washed with water and dried under reduced pressure (14.0 g; yield 70%). Into a 150 ml solution of water: methanol (2:1) containing 33.6 g potassium hydroxide, the white solid was dissolved and heated with stirring for 12 hours in an oil bath at 75-80° C. After cooling the reaction mixture, and adding 400 ml water thereto, the mixture was extracted with 100 ml ether five times. The ether phase was washed with 200 ml of saturated salt water two times, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate=3:1 to 1:1) so as to obtain compound 13 as colorless crystals (5.5 g, total yield 40%).
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[CH:12]=[N:13][CH:14]=1>O1CCOCC1.CO>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)c1cncc(-c2ncccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cncc(-c2ncccn2)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.21 mL) was added to a solution mixture of the obtained methyl 5-(pyrimidin-2-yl)pyridine-3-carboxylate (30 mg) in dioxane (0.3 mL) and methanol (0.3 mL) at room temperature, followed by stirring at the same temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and water and toluene were added to the residue. The aqueous layer was separated and adjusted to a pH of 3.8 with 1 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 7.0 mg of 5-(pyrimidin-2-yl)pyridine-3-carboxylic acid as a white solid.