Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH:14]=[CH2:15])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[N+](=[CH2:18])=[N-]>C(OCC)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:14]1([C:13]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][C:6]3[CH2:10][O:9][C:8](=[O:11])[C:7]=3[CH:12]=2)[CH2:18][CH2:15]1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc2c(cc1CCO)COC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1OCc2cc(CCO)c(C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 ml flask containing a stir bar was added 5-(2-Hydroxyethyl)-6-vinyl-2-benzofuran-1(3H)-one (0.9 g, 4.41 mmol), and Palladium diacetate (0.049 g, 0.220 mmol), followed by addition of a freshly prepared diazomethane (3.7 g, 88 mmol) in diethyl ether (10 mL) over a course of 20 minutes. The resulting mixture was then stirred at room temperature in a shielded environment for 1 h. When the reaction was complete, the solvent was concentrated to dryness, dissolved in EtOAc, and washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The resulting residue was used for the next step without further purification.
Reaction SMILES: C([O:5][P:6]([C:13]([F:37])([F:36])[C:14]1[CH:35]=[CH:34][C:17]([CH2:18][CH:19]([C:30]([O:32][CH3:33])=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1)([O:8]C(C)(C)C)=[O:7])(C)(C)C.[H-].[Na+].Br[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:57])([F:56])[C:49]([O:51]C(C)(C)C)=[O:50])=[CH:44][CH:43]=1>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:37])([F:36])[P:6]([OH:7])([OH:8])=[O:5])=[CH:35][CH:34]=1)([C:30]([O:32][CH3:33])=[O:31])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]([F:56])([F:57])[C:49]([OH:51])=[O:50])=[CH:46][CH:47]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C(F)(F)C(=O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To starting 1-benzyl 3-methyl 2-{4-[(di-tert-butoxyphosphoryl) (difluoro)methyl]benzyl}malonate (0.12 g) in DMF(5.0 mL) was added NaH (55 mg). The reaction was stirred at r.t. for 30 min. Then tert-butyl 2-[4-(bromomethyl)phenyl]-2,2-difluoroacetate(0.085 g, prepared according the procedures described by J. W. Tilley et al, J. Med. Chem. 1991, 34. 1125) was added to the mixture. After stirring for 2 h, the mixture was quenched with H2O and extracted with EtOAc (50 mL). The extract was dried over Na2SO4 and evaporated to dryness. The residue was treated with a solution of TFA/H2O (3 mL, 9:1) for 3 h at r.t. and evaporated to dryness. The crude was purified on reverse phase HPLC to give 12 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-cyano-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 13; 200 mg, 0.75 mmol) in THF (2 ml) was added a solution of lithium hydroxide (94 mg, 2.25 mmol) in water (8 ml). The reaction mixture was stirred at room temperature overnight. The THF was removed and the mixture was adjusted to pH 7 with 2N HCl. The mixture was filtered and the residue dried to yield the title compound as a yellow solid. 160 mg.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21](O)=[O:22])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][N:26]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:22][N:31]=[C:29]([C:28]4[CH:33]=[CH:34][C:25]([NH2:24])=[N:26][CH:27]=4)[N:30]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccc(N)nc4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (diethyl ether) as a white solid (32 mg, 15%). MS (EI) 436.1 [(M)+]; mp 257° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[C:15]([OH:22])[C:14]=2[CH2:23][CH2:24][CH3:25])[N:6]=1)=[O:4].[OH-].[Li+]>CO.O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:14]([CH2:23][CH2:24][CH3:25])[C:15]=1[OH:22])(=[O:21])[CH3:20]
Reactant: CCCc1c(OCc2cccc(C(=O)OC)n2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCc2cccc(C(=O)O)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 64.1 %

Procedure:
Dissolve 6-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (3.77 g, 10.9 mmol) in MeOH (20 mL) and water (5 mL). Add 2N aqueous lithium hydroxide (10.9 mmol). After 12 hours, concentrate under reduced pressure and dissolve the residue in 4N hydrochloric acid in dioxane. Add water until white precipitate forms and collect by filtration to yield the title compound as a white solid (2.30 g, 6.99 mmol): 1H NMR (d6-DMSO) δ 0.89 (t, 3H), 1.50 (m, 2H), 2.56 (s, 3 H), 2.63 (t, 3H), 5.31 (s, 2H), 6.57 (d, 1H), 7.47 (m, 1H), 7.67 (d, 1H), 7.93 (m, 2H), 12.84 (s, 1H), (acid proton not observed); mass spectrum (m/e): 328 (M−1).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C:62](=[O:70])[C:63]([O:65]C(C)(C)C)=[O:64])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]([O:48]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:47])=[C:35]([CH2:71][CH3:72])[CH:34]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]C(C)(C)C)=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:14])=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl>>[C:1]([NH:4][C@H:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:17]([OH:19])=[O:18])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:14])=[O:7])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C:62]([C:63]([OH:65])=[O:64])=[O:70])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]([OH:48])=[O:47])=[C:35]([CH2:71][CH3:72])[CH:34]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C[C@H](NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)ccc1N(C(=O)C(=O)O)c1ccccc1C(=O)O

Procedure:
(2S)-2-[(5-{[2-(acetylamino)-3-(4-{2-[(benzhydryloxy)carbonyl][tert-butoxy(oxo)acetyl]anilino}-3-ethylphenyl)propanoyl]amino}pentanoyl)amino]-3-(4-tert-butoxyphenyl)propanoic acid was treated with trifluoroacetic acid/dichloromethane (1 mL, 1:1) at ambient temperature for 3 hours, concentrated under reduced pressure and purified by HPLC eluting with 5-100% acetonitrile/aqueous 0.1% trifluoroacetic acid to provide the titled compound. MS (ESI(+)) m/e 705 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12-13.5 (bs, 2H), 9.18 (s, 1H), 8.11-7.78 (m, 4H), 7.59-6.98 (m, 7H), 6.80-6.61 (m, 3H), 4.57-4.40 (m, 1H), 4.39-4.32 (m, 1H), 3.00-2.55 (m, 6H), 2.04-2.00 (m, 2H), 1.78, 1.75 (s, s, 3H), 1.40-1.36 (m, 2H), 1.35-1.20 (m, 2H), 1.35-0.91 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]>[OH-].[NH4+]>[NH2:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(C(=O)CCC(=O)O)cc1O

Procedure:
3-(3-Hydroxy-4-nitrobenzoyl)propionic acid in ammonium hydroxide solution was reduced with ferrous sulphate to give 3-(4-amino-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]1[C:17]([CH3:25])=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.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>[F:15][C:16]1[C:17]([CH3:25])=[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][O:13][CH3:14])[CH:19]=[CH:20][CH:21]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: Cc1c(F)cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1C
Temperature: 100 °C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (5.00 g, 19.3 mmol), 3-fluoro-2-methylphenylboronic acid (Combi-Blocks BB-3475, 4.46 g, 29.0 mmol), bis(triphenylphosphine)palladium(II) chloride (271 mg, 0.39 mmol) and cesium fluoride (8.79 g, 57.9 mmol) was prepared in dioxane (50 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled at RT, diluted with MTBE (250 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL). The aqueous layers were extracted with MTBE (150 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/n-hexane), the title compound was obtained as a colorless oil (4.85 g, 87%). HPLC (Method A), Rt: 5.0 min (purity: 99.5%). UPLC/MS, M+(ESI): 289.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH:18]3[C:20]4([C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[O:22][C:21]4([CH3:29])[CH3:28])[O:19]3)[CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[C:10]([CH:18]3[C:20](=[O:19])[C:21]([CH3:28])([CH3:29])[O:22][C:23]([CH3:27])([CH3:26])[C:24]3=[O:25])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
To an ice-cold solution of crude 2-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (2.59 g, 6.12 mmoles) in dichloroethane (25 ml) is added concentrated sulfuric acid (5 ml), followed by stirring at this temperature for 2 hours. The reaction mixture is poured into ice, extracted with dichloromethane (×2), and the combined organics are evaporated under reduced pressure to yield a brown gum. Purification by flash column chromatography (isohexane to 30% ethyl acetate in isohexane as eluant) then reverse phase preparative HPLC affords 4-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.370 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19]([O-])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.Cl.[OH-].[Na+]>C(OCC)(=O)C.O>[CH2:17]([O:16][C:14]([C:13]1[C:12](=[O:11])[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:8]=2)[NH:6][CH:19]=1)=[O:15])[CH3:18]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c[nH]c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 4-chloroaniline (156.7 mmol) and ethyl ethoxymethylenemalonate (156.7 mmol) was stirred at room temperature until homogeneous. The homogeneous solution was heated in an oil bath at 165° C. for 6 hours. The reaction mixture was cooled to room temperature and 1 N HCl (3 mL) was added. The reaction mixture was stirred and heated to 115° C. for 3 hours. The mixture was cooled to room temperature and then treated with 20 mL of water. The resulting suspension treated with 10 N NaOH solutions to reach the pH about 8. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane:ethyl acetate as solvent to afford title compound (28 g, 71% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C1(C)C=CC=CC=1.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.CO>[NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([F:23])[CH:25]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Reactant: COc1ccc(B(O)O)cc1F
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: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N)cc1
Temperature: 125 °C
Yield: 80 %

Procedure:
A mixture of methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)-isonicotinate (2.00 g, 5.48 mmol), 3-fluoro-4-methoxyphenylboronic acid (0.931 g, 5.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.316 g, 0.274 mmol) in a flask was flushed with nitrogen. Toluene (25 mL), MeOH (5 mL) and a 2 N aqueous solution of sodium carbonate (6.2 mL, 12.4 mmol) was added and the reaction was heated in a 125° C. oil bath for 2 hr. The reaction was partitioned between EtOAc and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)isonicotinate (1.8 g). MS (ESI) m/z 411.2 (M+H). 1H NMR (CDCl3) δ ppm 8.18 (2H, d, J=8.24 Hz), 8.06 (1H, s), 7.81 (2H, d, J=8.24 Hz), 7.74 (1H, dd, J=12.97, 1.98 Hz), 7.68 (1H, d, J=8.85 Hz), 6.99 (1H, t, J=8.70 Hz), 5.98 (2H, br. s.), 3.97 (3H, s), 3.96 (3H, s), 3.92 (3H, s).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[N:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cnc(Oc2ccc(I)cc2)nc1

Procedure:
In the same manner as in Reference Example 6, 4-iodophenol (220 mg) and 5-ethyl-2-chloropyrimidine (0.121 ml) were reacted in the presence of potassium carbonate (415 mg) to obtain 2-(4-iodophenoxy)-5-ethylpyrimidine (256 mg).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][CH:9]([CH3:10])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-oxopentanoate (5.00 g, 34.7 mmol) in chloroform (27 mL) at 0° C. was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, concentrated to give ethyl 4-bromo-3-oxopentanoate. 1HNMR (500 MHz, CDCl3), δ4.670-4.630 (dd, J=6.7 Hz, 1H), 4.251-4.208(dd, J=7.2 Hz, 2H), 3.883-3.851(d, J=16 Hz, 1H), 3.687-3.655(d, J=16 Hz, 1H), 1.804-1.791 (d, J=6.8 Hz, 3H), 1.323-1.295 (m, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:44]I>C1COCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:26][CH3:44])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (35.5 mg, 0.059 mmoles) in THF (0.3 mL) at 0° C. under nitrogen was added sodium hydride (4.8 mg, 0.12 mmoles, 60% dispersion in mineral oil). The reaction was stirred for 30 min., allowing it to warm to room temperature. The reaction mixture was then treated in a dropwise manner with methyl iodide (11 μL, 0.179 mmoles) at 0° C. The ice bath was removed after the addition and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified using silica gel chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to yield the title compound (30.1 mg, 83%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (m, 6H) 1.5 (m, 1H) 1.6 (m, 2H) 1.7 (m, 1H) 1.9 (d, J=12.9 Hz, 1H) 3.1 (s, 3H) 4.1 (d, J=7.1 Hz, 1H) 4.2 (s, 3H) 4.7 (d, J=15.8 Hz, 1H) 4.7 (s, 2H) 4.9 (d, J=16.2 Hz, 1H) 7.3 (s, 1H) 7.5 (d, J=7.9 Hz, 1H) 7.6 (d, J=8.3 Hz, 1H) 7.7 (s, 2H) 7.8 (s, 1H). MS (ES+) Calc: 609.2, Found: 610.4 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Yield: 79 %

Procedure:
Ex-36A: 2-(5-Formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as described in Ex-3A. Yellow oil, 79% yield. 1H-NMR (CDCl3) δ 10.36 (s, 1H), 8.15 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27–7.35 (m, 1H), 7.19–7.27 (m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(Cl)Cl.O>[CH:19]1([NH:22][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[N+:10]([O-:12])=[O:11])[C:5]#[N:6])[CH2:21][CH2:20]1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(NC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-fluoro-4-nitrobenzonitrile (2.0 g, 0.012 mol) in DCM (20 ml), was added K2CO3 (3.3 g, 0.024 mol) and cyclopropyl amine (6.7 ml, 0.096 mol) and the resulting solution was continued to stir at room temperature for 3 h. The reaction was diluted with cold water and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound 3-(cyclopropylamino)-4-nitrobenzonitrile as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 8.24-8.22 (d, J=8.8 Hz, 1H), 8.07 (bs, 1H), 7.64 (s, 1H), 6.94-6.92 (d, J=8.8 Hz, 1H), 2.59-2.58 (m, 1H), 1.25-0.97 (m, 2H), 0.71-0.58 (m, 2H). MS (M+1): 204.
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:16])=[C:12]([CH2:14][CH3:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)C=C.Cl[C:18]1[CH:23]=CC=C[C:19]=1Cl>>[CH2:23]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH3:15])=[C:11]([CH3:16])[C:10]=2[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1cccc2oc(CC)c(C)c12
Product: C=CCc1ccc2oc(CC)c(C)c2c1O

Procedure:
A mixture of 4-allyloxy-2-ethyl-3-methylbenzofuran (1.0 g; 4.8mmoles) and orthodichlorobenzene (40 ml) was refluxed for 4 hours. The mixture was chromatographed to obtain 1.0 g of the title compound as an oil. The oil was recrystallized from hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[CH:38]=[O:39].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[O:39])=[C:32]([F:31])[CH:33]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 88 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and (3-fluoro-4-formylphenyl)boronic acid (160 mg, 0.94 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (1.15 mL, 2.3 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (288 mg, 88%).