Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:16])[CH:3]=1.[C:17]([NH:20][C:21]1[S:22][C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:24]([CH3:26])[N:25]=1)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:20][C:21]1[S:22][C:23]([S:27]([NH:1][C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[C:4]([CH3:16])[CH:3]=2)(=[O:28])=[O:29])=[C:24]([CH3:26])[N:25]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Cc1cc(N)nc(NC(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2cc(C)cc(NC(=O)OC(C)(C)C)n2)s1
Temperature: 24 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a solution of tert-butyl (6-amino-4-methylpyridin-2-yl)carbamate (1.2 g, 6.0 mmol) in pyridine (30 mL) was added 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (1.5 g, 6.0 mmol). The resulting mixture was stirred at 24° C. for 16 hours. The reaction was concentrated in vacuo (˜25 mm Hg). Purification by high performance flash chromatography (0→5% methanol in dichloromethane) provided the intermediate (2.1 g, 80%). 1H NMR (400 MHz, CDCl3), δ: 7.43 (br s, 1H), 6.99 (s, 1H), 5.31 (s, 1H) 2.34 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 1.54 (s, 9H); LRMS (ESI) m/z: 342 [M-CO2C(CH3)3]+.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH3:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7]>C(OCC)C>[N+:1](=[CH:3][C:6](=[O:7])[C:5]([CH3:10])([CH3:9])[CH3:4])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Product: CC(C)(C)C(=O)C=[N+]=[N-]
Reaction time: 16 h
Yield: 100 %

Procedure:
To the diazomethane solution at 0° C. was added a solution of 1.23 mL (1.21 g, 10 mmol, Aldrich) of trimethylacetyl chloride in 1 mL of diethyl ether dropwise with stirring. The resulting mixture was kept at 0° C. for 16 h. The solution was sparged with argon to remove the excess diazomethane and diethyl ether was removed under reduced pressure to give 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone as a yellow liquid.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=O.C(C[C:31](=[O:33])C)C1C=CC=CC=1.C(OC1CC2CC1C1C=2CCC1)(=O)CC.C(OC1C2CC(C3C=2CCC3)C1)(=O)CC.CC1C(C=C(C)C(=O)C)C(C)(C)CCC=1.CC(CCC=C(C)CC)=CC#N.CC12CCC3C(C)(CCCC3(C)C)C1CCO2.C(O)(=O)CCCCCCCCCCC(O)=O.C1CCCCCCCCCCC(=O)CCCC=1.C1CCCCCCCC(=O)CCCCCCCC=1>>[CH3:31][O:33][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: O=C(c1ccc2ccccc2c1)c1ccc2ccccc2c1
Agent: CC(=O)C(C)=CC1C(C)=CCCC1(C)C
Agent: CC1(C)CCCC2(C)C1CCC1(C)OCCC12
Agent: CCC(=O)OC1CC2=C3CCCC3C1C2
Product: COc1ccc2ccccc2c1

Procedure:
β-naphthyl ketone; benzyl acetone:mixture of hexahydro-4,7-methanoinden-5-yl propionate and hexahydro-4,7-methanoinden-6-yl propionate;4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-methyl-3-buten-2-one; 3,7-dimethyl-2,6-nonadien-1-nitrile; dodecahydro-3a,6,6,9a-tetramethylnaphtho(2,1-b)furan; ethylene glycol cyclic ester of n-dodecanedioic acid; 1-cyclohexadecen-6-one; 1-cycloheptadecen-10-one; and corn mint oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:13][C:14]1([CH3:45])[CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:32]#[C:33][C:34]3[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=3)[CH:20]=2)[S:15]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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:2]1([C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:32]#[C:33][C:34]4[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=4)[CH:20]=3)[S:15][C:14]([CH3:13])([CH3:45])[CH:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CC(C)(C)S3)cc1
Temperature: 25 °C

Procedure:
A solution of bromobenzene (190.0 mg, 1.18 mmol) in 2.0 mL of THF was cooled to -78° C. and tert-butyllithium (151.2 mg, 2.36 mmol, 1.4 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (225.0 mg, 1.4 mmol) in 4.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-ylethynyl)-benzoate (Compound 224, 200.0 mg, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H20 and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 155.0 mg (91%), was isolated by column chromatography (5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.99 (2H, d, J=8.4 Hz), 7.52 (2H, d, J=8.4 Hz), 7.42-7.24 (8H, m), 5.78 (1H, s), 4.38 (2H, q, J=7.1 Hz), 1.50 (6H, s), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][CH2:19]Cl.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([N:25]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=2[CH2:18][CH2:19]1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C(C)CC
Yield: 95.6 %

Procedure:
The intended compound was obtained in 95.6% yield in the same manner as in Synthesis Example (5) using ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]pyrimidine-5-carboxylate and sec-butylamine.
Reaction SMILES: [CH2:1]1[CH:16]2[CH:5]([NH:6][C:7](=O)[CH2:8][NH:9][CH:10]3[CH2:21][CH:20]=[CH:19][CH2:18][CH:11]3[NH:12][CH2:13][C:14](=O)[NH:15]2)[CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C.[ClH:32]>O1CCCC1.C(OCC)C.CCCCCC>[ClH:32].[ClH:32].[ClH:32].[CH2:21]1[CH:10]2[CH:11]([NH:12][CH2:13][CH2:14][NH:15][CH:16]3[CH2:1][CH:2]=[CH:3][CH2:4][CH:5]3[NH:6][CH2:7][CH2:8][NH:9]2)[CH2:18][CH2:19][CH2:20]1
Reactant: O=C1CNC2CC=CCC2NCC(=O)NC2CCCCC2N1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CCC2NCCNC3CCCCC3NCCNC2C1

Procedure:
A mixture containing compound (C) (3.45 g., 11.3 mmol.) and 1M L/A/H4 (40ml.) in tetrahydrofuran (100 ml.) was refluxed for 21 hours under a dry nitrogen atmosphere. The solution was cooled and the excess LAH was decomposed by the careful addition of a saturated aqueous solution of Rochelles's salt (10 ml.). Absolute ethanol (50 ml.) was added to the suspension and the mixture was refluxed overnight. After filtration, the residual product in the filter cake was extracted by treatment of the solid with hot ethanol (2×100 ml.). The filtrates were combined and evaporated to afford 4.0 g. of a brownish mass. Crystallization from acetonitrile gave off-white crystals which dissolved in ethyl ether and hexane washes. A portion of this material (400 mg., 1.6 mmol.) was converted to the hydrochloride salt by treatment with methanolic hydrochloric acid (7 ml.).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[C:12]2=[C:13]([CH2:17][S:18][C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=[CH:9]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOCC.O>[CH2:32]([O:31][C:29]([N:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=[C:19]1[S:18][CH2:17][C:13]1[N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=[CH:9][S:8][C:12]=12)=[O:30])[CH3:33]
Reactant: c1ccc2[nH]c(SCc3nccc4ccsc34)nc2c1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(SCc2nccc3ccsc23)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 44.0 mg (1.10 mmol) of 60% NaH were added 7 ml of dry DMF and 299.2 mg (1.00 mmol) of 2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole. 1/10 H2O (Ia-1). After stirring for 10 min. at room temperature, the solution was added with 130.2 mg (1.20 mmol) of ClCOOEt and stirred for 30 minutes at room temperature. DMF was evaporated under reduced pressure. Water was added to the residue, and the solution was extracted with CH2Cl2. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, whereby 381.0 mg of pale greenish yellow cyrstals were obtained. After being subjected to silica gel column chromatography, the crystals were dispersed with 2 ml of ether, followed by filtration and washed with ether, whereby 335.7 mg (Yield : 90.9%) of the objective compound, 1-ethoxycarbonyl-2-[(thieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ib-1) was obtained as crystals.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:19]([OH:20])=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:19]([O:20][C:26]2[CH:31]=[N:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F
Product: N#Cc1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a yellow solid in the same method as in Example 251 (step 2) or in accordance with the method or by combining it with an ordinary method but using 5-(2-fluorophenoxy)-6-hydroxy-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 251 (step 1) and 5-bromo-2-cyanopyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:15]1([C:11]2[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]3[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]4[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:25]=4)=[CH:4][CH:5]=3)[N:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 4-[(4-chloromethylphenoxy)methyl]-2-phenyl-5-methyl-1,3-oxazole (2.85 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.64 g), potassium carbonate (1.20 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (3.49 g, 86%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([O:18][CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:21][CH2:22][NH:23][CH2:24][C@@H:12]23)[CH:17]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:20]1[N:14]2[C:15]3[C:11]([C@@H:12]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:13]42)=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])=[CH:17][C:16]=3[O:18][CH2:19]1
Reactant: COc1ccccc1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Temperature: 20 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of (6bR,10aS)-5-(2-methoxyphenyl)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (20 mg, 0.06 mmol) in CH2Cl2 (4 mL) under N2 was added a 0.91 M solution of BBr3 in CH2Cl2 (0.41 mL, 0.37 mmol). The reaction mixture was stirred at 20° C. for 16 h, and then quenched with water (1 mL). The aqueous layer was basified with 1 N NaOH to pH 7, and the reaction mixture was extracted with CH2Cl2 (3×30 mL). The organic solution was then dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil (10 mg, 50%). 1H NMR (CDCl3) δ1.88-2.01 (m, 2H), 2.10-2.22 (m, 1H), 2.60-2.79 (m, 2H), 2.90-2.99 (m, 1H), 3.18-3.37 (m, 3H), 3.36-3.43 (m, 2H), 3.61-3.66 (m, 1H), 4.39-4.44 (m, 2H), 6.70-6.79 (m, 1H), 6.80-6.99 (m, 2H), 7.08-7.18 (m, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)(C)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc(OC)c1OC
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine, Intermediate 3 (500 mg, 2.0 mmol), 5-bromo-1,2,3-trimethoxybenzene (494 mg, 2.0 mmol), Cl-BrettPhos-Pd precatalyst/BrettPhos admixture (53 mg, 0.040 mmol (1:1 mol: mol)) and cesium carbonate (912 mg, 2.80 mmol) in t-BuOH (15 mL) was heated at 110° C. for 16 hours. Upon cooling, the reaction mixture was diluted with EtOAc and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 2:3 hexanes:EtOAc) to obtain a clear glass (659 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([NH:13][CH:14]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([NH:13][CH:14]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH:6]=1
Reactant: CCOC(=O)c1ccc(C(Nc2ccc(-n3cc(Cl)c(C)n3)nc2)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(NC(c3ccc(C(=O)O)cc3)C3CCCC3)cn2)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of (+/−)-ethyl 4-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzoate (78.6 mg, 0.179 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added 1 N aqueous sodium hydroxide (0.36 mL, 0.36 mmol). The reaction was heated to 50° C. for 10 minutes. The heat was removed and the reaction was allowed to stir at room temperature for 1 hour. The reaction was concentrated. The residue was taken up in water and acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (68.3 mg, 93%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.19 (s, 1H), 7.92-7.96 (m, 2H), 7.66-7.69 (m, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.42-7.45 (m, 1H), 7.03 (dd, J=8.9, 2.8 Hz, 1H), 4.18 (d, J=9.2 Hz, 1H), 2.22 (s, 3H), 1.98-2.07 (m, 1H), 1.43-1.74 (m, 6H), 1.23-1.38 (m, 2H). MS (M+1) 411.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:40])=[C:16]([NH:18][C:19]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]4[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[C:32]([F:39])[CH:31]=4)=[CH:29][C:24]3=[N:23][CH:22]=2)=[O:20])[CH:17]=1)=[O:11].[NH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45]>>[CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:40])=[C:16]([NH:18][C:19]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]4[CH:38]=[CH:37][C:33]([C:34](=[O:36])[NH:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])=[C:32]([F:39])[CH:31]=4)=[CH:29][C:24]3=[N:23][CH:22]=2)=[O:20])[CH:17]=1)=[O:11]
Reactant: CC(C)(N)CO
Reactant: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1
Product: CC(C)(CO)NC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCCN5CCCC5(C)C)ccc4F)cnc3c2)cc1F

Procedure:
The title compound was prepared analogously to Example 7.4 from 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 3) and 2-amino-2-methylpropan-1-ol;
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:16]2[CH:12]([O:13][C:14]([CH3:18])([CH3:17])[O:15]2)[O:11][CH:10]1[CH:19]1[CH2:23][O:22]C(C)(C)[O:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([O:8][CH:9]1[CH:16]2[CH:12]([O:13][C:14]([CH3:18])([CH3:17])[O:15]2)[O:11][CH:10]1[CH:19]([OH:20])[CH2:23][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(C2OC3OC(C)(C)OC3C2OCc2ccccc2)O1
Solvent: CC(=O)O
Product: CC1(C)OC2OC(C(O)CO)C(OCc3ccccc3)C2O1
Yield: 80 %

Procedure:
To a flask charged with 6-Benzyloxy-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole was added 75% aqueous solution of acetic acid. The reaction was stirred, extracted, washed, dried and the solvent was evaporated to provide the titled compound in 80% yield.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[OH-].[K+]>C1COCC1.[H][H]>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: [H][H]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
Boc-Gly-Pro-Nleu-OEt (4.3 g, 0.0104 mol.) was dissolved in 80 ml THF/H2) (v/v, 1:1) and the solution was chilled to 0° C. on a water-ice bath. KOH (1.1 g dissolved in 20 ml H2O) was added while stirring the solution. After a while, the bath was removed and the stirring was continued for one more hour. The THF was removed under reduced pressure. The aqueous solution was extracted by ethyl acetate 2×50 ml. Then, the aqueous layer was chilled to 0° C. and was acidified to about pH=3 by addition of concentrated HCl while swirling the solution vigorously at the same time (the aqueous layer was covered by 50 ml ethyl acetate). The product was extracted from the aqueous layer by ethyl acetate 3×50 ml. The organic layer was combined and dried by Na2SO4. The ethyl acetate was removed under reduced pressure. Column chromatography (E/H:5:2) was carried out to obtain the pure product (white solid, 3.6 g, 92%). TLC Rf=0.44 (developing solvents: CMA, 85:15:3). FAB-MS, observed (M+H)+=386. Analytical RP-HPLC chromatogram, single peak, retention time RT=13 min. (25-60% B in 30 min.). 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ12.50 (s, 1H, carboxyl), 6.62 (m, 1H, Gly-NH), 4.92 (d, Pro-α), 4.72 (d, Pro-α), 4.56 (d, Nleu-α), 4.48 (d, Pro-α), 4.12 (m, Nleu-α), 4.00-3.90 (m, Nleu-α), 3.83-3.66 (m, Nleu-α, Gly-α), 3.64-3.50 (m, Gly-α, Nleu-α), 3.50-3.33 (m, Pro-δ), 2.34-1.60 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 1.38 (s, 9H, Boc-CH3), 0.88 (dd, Nleu-δ), 0.75 (dd, Nleu-δ).
Reaction SMILES: [C:1]([N:8]([CH3:29])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[N:35][CH:36]=1>>[CH2:24]([O:23][C:22]1[CH:21]=[CH:20][C:19]([C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:29])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1)[CH3:25]
Reactant: CCOc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(Br)cn1
Product: CCOc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 11 (812 mg, 2.0 mmol) is coupled to 5-bromo-2-methylpyridine (344 mg, 2.0 mmol) using Method A to give the title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[CH:15]=[CH:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=3[NH:10][C:9](=[O:21])[C:8]2=[O:22])CCCCC1.BrC1C2C=CC=CC=2C2N=C(C3CCCCC3)C=NC=2C=1>>[CH3:1][N:7]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11]=2[NH:10][C:9](=[O:21])[C:8]1=[O:22]
Reactant: O=c1[nH]c2c3ccccc3ccc2n(C2CCCCC2)c1=O
Agent: Brc1cc2ncc(C3CCCCC3)nc2c2ccccc12
Product: Cn1c(=O)c(=O)[nH]c2c3ccccc3ccc21

Procedure:
In exactly the same manner 4-cyclohexylbenzo[f]quinoxaline-2,3(1H,4H)-dione was made from 6-bromo-2-cyclohexylbenzo[f]-quinoxaline. M.p. 288° C. (Compound 27k).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: Cc1ccc(B(O)O)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: [K+]
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(O)ccc2O3)cc1

Procedure:
A vial was charged (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (282 mg, 0.809 mmol), p-tolylboronic acid (220 mg, 1.618 mmol), potassium carbonate (559 mg, 4.04 mmol), tetrakis(triphenylphosphine)palladium (46.7 mg, 0.040 mmol). The vial was flushed with Ar (g), then Dioxane (4044 μL) and water (2 mL) were added in sequence. The vial was sealed and placed in an 80° C. oil bath for 1 hour. The mixture was partitioned between brine and 10% iPrOH/EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on an 80-g Redi-Sep column, eluting with 0-80% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an orange solid.