Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14](N)=[CH:15][CH:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[I:31]I>CC(O)=O.O.Cl>[I:31][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([CH:1]=[CH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:10][N:11]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 113.7 %

Procedure:
To a solution of 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine (1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl (1.67 mL) cooled to 2° C. was added a solution of NaNO2 (304 mg, 4.4 mmol) in water (0.5 mL) over 5 min. The resulting dark red solution was stirred at 2° C. for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) and I2 (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keep the internal temperature below 5° C. After 2 h at 2° C. the reaction was allowed to stir at 23° C. for 17 h. The reaction was quenched with 3 N NaOH (aq), diluted with EtOAc (50 mL) and H2O (15 mL), the phases were separated and the aqueous was extracted 2×15 mL EtOAc. The pooled organic phase was washed 3×20 mL 5% NaHSO3, brine (15 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (eluting with 1:1 hexane:EtOAc) to give 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a white solid (1.3 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.30–7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, J=6.0 Hz), 0.96 (t, 2H, J=6.0 Hz), 0.0 (s, 9); 13C NMR (75 MHz, CDCl3) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4, 119.6, 119.5, 92.9, 78.1, 66.9, 18.0, −1.2. Anal. Calc'd: C, 52.94; H, 5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:11]([CH3:13])[CH3:12].[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19][N:20]([CH3:24])[CH2:21][CH2:22]O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][N:11]([CH3:13])[CH3:12])[CH3:24])=[CH:25][CH:26]=1
Reactant: CN(CCO)Cc1ccc(Cl)cc1
Reactant: CN(C)Cc1cc(C#N)ccc1O
Product: CN(C)Cc1cc(C#N)ccc1OCCN(C)Cc1ccc(Cl)cc1

Procedure:
The title compound (b.p. 100° C. at 0.1 mbar) was prepared by reacting 4-hydroxy-3-(dimethylaminomethyl)benzonitrile (7.32 g) with N-(4-chlorobenzyl)-N-methylethanolamine (8.29 g) in a similar manner to Example 4.
Reaction SMILES: [OH-].[NH4+:2].Br[CH2:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]=1)=[O:6]>CO>[NH2:2][CH:8]=[C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][CH2:4][C:5]1=[O:6]
Reactant: [NH4+]
Reactant: O=C(CBr)c1coc2ccccc2c1=O
Agent: [OH-]
Solvent: CO
Product: NC=C1C(=O)COc2ccccc2C1=O
Reaction time: 1 h

Procedure:
Concentrated ammonium hydroxide (1300ml) was added to a stirred mixture of 108g (0.041 mole) of 3(bromoacetyl)chromone and 500ml of methanol. All solid went into solution. There was a mild exotherm. After several minutes the product began to separate. After one hour, the reddish-tan solid was filtered, washed well with water and dried; wt. 70g (86%); m.p. 149°-151°. Recrystallization from ethyl acetate gave pure, orange crystals; m.p. 151°-153°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Yield: 95 %

Procedure:
To a solution of 2-fluoro-4-nitro-1-phenoxybenzene (3.2 g, 13.72 mmol, 1.00 equiv) and methanol (100 mL) was added 10% palladium on carbon (0.5 g) catalyst. The reaction mixture was stirred under 1 atmosphere of hydrogen at room temperature for 4 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 2.65 g (95%) of 3-fluoro-4-phenoxybenzenamine as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.29-7.19 (m, 2H), 7.03-6.83 (m, 4H), 6.52-6.36 (m, 2H), 3.63 (s, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[SH-:18].[Na+]>O>[CH:15]([C:4]1[CH:3]=[C:2]([SH:18])[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)c1nc2nc(C(C)C)cc(Cl)n2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2nc(C(C)C)cc(S)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
The product obtained in Step 2 (40 g) was added at 0° C. to a solution of sodium hydrosulfide (40 g) in one liter of water with stiring under a nitrogen stream. The mixture was stirred at 0° C. for one hour, then at room temperature for three hours, and the resulting yellow solution was washed with 200 ml of ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid to pH 2.0, and the formed crystals were collected by filtration and washed with 100 ml of ethanol, affording 36 g of the objective compound as faint yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][CH:17]([NH:24][C:25](=[O:29])[C:26](O)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:25]([NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][OH:15])=[O:29]
Reactant: O=C(O)C(=O)NC(CO)c1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)NC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), 2-(2-hydroxy-1-phenylethylamino)-2-oxoacetic acid (0.250 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.440 g of N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(2-hydroxy-1-phenylethyl)oxalamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:16]1[C:17]([Cl:21])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH3:2]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOC(=O)c1ccccc1N
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-benzoic acid ethyl ester was prepared from 2-amino-benzoic acid ethyl ester and 2,4,5-trichloro-pyrimidine in an analogous manner to Example 308b. Product isolated as a white solid (2.28 g, 27%). m.p.=156-157° C.; LCMS (m/e) 312 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.68 (bs, 1H), 8.91 (d, 1H, J=8.6 Hz), 8.28 (s, 1H), 8.14 (d, 1H, J=8.0 Hz), 7.70-7.62 (m, 1H), 7.22-7.13 (m, 1H), 4.45 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[Cl:14][C:15]([CH2:17]Cl)=[CH2:16]>>[Cl:14][C:15](=[CH2:16])[CH2:17][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C=C(Cl)CCl
Product: C=C(Cl)Cn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as pale yellow crystals in 77.5% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 2,3-dichloro-1-propene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:36][C:35]1[CH:34]=[CH:33][C:32]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:38][CH:37]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2cc1OC
Yield: 71.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 222.3 mg (1.2 mmol) of 4-phenoxyaniline to give 283.0 mg (71.3%) of the product as a light yellow solid, m.p. 239-241° C., mass (electrospray, m/e): M+H 397.9.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[CH2:10][C:11]([O-:13])=[O:12].[Na+].Cl>O1CCCC1.O>[CH2:2]([CH:3]([O:6][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH3:5])[CH3:1]
Reactant: O=C([O-])CCl
Reactant: CCC(O)CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of 198 mg of 3-pentanol in tetrahydrofuran (4 ml), 180 mg of sodium hydride was added in nitrogen atmosphere at 0° C., and stirred for an hour at room temperature. To the solution 261 mg of sodium chloroacetate was added, followed by 2 hours' stirring at 100° C. The reaction solution was cooled to room temperature, diluted with water, acidified with 1N hydrochloric acid and extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 103 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[NH:17]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2ccc(N)cc2[nH]1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COC(=O)c1cc2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide 2-chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineamine which was used without further purification. LCMS: purity: 65%; MS (m/e): 322(MH+).
Reaction SMILES: [ClH:1].C1(OC)C=CC=CC=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C@H:20]([NH:26]C(=O)OC(C)(C)C)[C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:11]1>C(OCC)(=O)C>[ClH:1].[NH:25]1[C:21]([C@@H:20]([NH2:26])[CH2:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[N:22][N:23]=[N:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nnn[nH]1
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1c[nH]c2ccccc12)c1nnn[nH]1
Reaction time: 1 h

Procedure:
Ethyl acetate (30 mL) was saturated with HCl gas at 0° C. at which point anisole (7.4 mL) was added followed by (S)-[2-(1H-indol-3-yl)-1-(1H-tetrazol-5-yl)ethyl]carbamic acid, 1,1-dimethylethyl ester (1.24 g., 3.77 mmol.) dissolved in ethyl acetate (7 mL). The resulting solution was stirred at 0° for one hour at which time TLC showed that no starting material remained. The reaction mixture was evaporated and chased with methylene chloride and ether and finally pumped to 0.95 g. of (S)-α-(1H-tetrazol-5-yl)-1H-indol-3-ethanamine, hydrochloride as a light brown solid.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])([O:3][CH3:4])=[O:2].[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1>>[C:1]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)(=[O:12])=[O:11])([O:3][CH3:4])=[O:2]
Reactant: c1cc[nH]c1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: COC(=O)c1sccc1S(=O)(=O)n1cccc1
Yield: 50 %

Procedure:
N-(2-carbomethoxythiophene-3-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A by reacting 2-carbomethoxythiophene-3-sulfonyl chloride with pyrrole, 50% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.Cl[CH2:29]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:29][O:21][C:20]([C@H:10]1[C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)=[O:22]
Reactant: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (7.0 g, 22.0 mmol) were dissolved in methanol (75 mL) and at ambient temperature treated with sulfuric acid 97% (2.4 mL). The reaction mixture was stirred at 60° C. for 18 h. At 0° C. dichloro methane (150 mL) was added followed by aqueous sodium carbonate 10% (150 mL) (final pH 11) under vigorous stirring. The phases were separated. The aqueous phase was washed with dichloro methane, the combined organic phases with water and brine and then dried on sodium sulfate. After filtration and evaporation of the solvent the title product was obtained as a light brown oil (7.0 g, 96%) which was directly used in the next step. ES-MS m/e: 330.8 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:25]
Reactant: COC(=O)CC(=O)Cl
Reactant: Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Product: COC(=O)CC(=O)Nc1c(C)cc(Cl)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-5-chloro-3-methyl-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. Brown oil. MS (ESI): 346.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:34](=[O:36])[CH3:35])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.8 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and acetyl chloride (59 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 6 h. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and concentration afforded the title compound (162 mg, 72%) as a yellow solid. MS: m/e=391.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:13][C:12]=1[C:23]1[CH:24]=[C:25]([O:30][CH3:31])[C:26]([NH2:29])=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:12]([C:23]3[CH:24]=[C:25]([O:30][CH3:31])[C:26]([NH2:29])=[N:27][CH:28]=3)[N:13]=2)=[CH:17][CH:18]=1
Reactant: COc1cc(-c2nc(-c3ccc(F)cc3)oc2Br)cnc1N
Reactant: OB(O)c1ccncc1
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: COCCOC
Product: COc1cc(-c2nc(-c3ccc(F)cc3)oc2-c2ccncc2)cnc1N
Yield: 56.6 %

Procedure:
A mixture of 4-pyridineboronic acid (113 mg, 0.9 mmol) and 5-(5-bromo-2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine (135 mg, 0.4 mmol), and in DME (1.0 mL) and 2.0 M aqueous Na2CO3 (1.0 mL, 2.0 mmol) was sparged with Ar. Tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) was added and the mixture was again sparged with Ar. The reaction was irradiated at 120° C. for 15 min in a microwave reactor. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over (SiO2, 100:0-0:100 hexanes-EtOAc). Enriched fractions were concentrated in vacuo and further purified by column chromatography (SiO2, 100:0-80:20 DCM-MeOH) to afford 82 mg of the title compound: LC/MS (m/z): 362.9 (MH+), tR=0.54 min.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl>[OH-].[K+]>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C:16]([CH3:22])([CH3:21])[C:17]([OH:19])=[O:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C(C)(C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(=O)O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 58.9 %

Procedure:
A solution of methyl 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoate (520 mg, 0.95 mmol) in 4N aqueous potassium hydroxide (5 mL) was stirred at 50° C. for 1 hour. Using concentrated aqueous hydrochloric acid, the reaction mixture was acidified to pH 5, and then partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 mg, 0.56 mmol (59%) of 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoic acid as a white solid. 1H NMR (400 MHz, DMSO): 8.49 (s, 1H), 7.57-7.52 (m, 1H), 7.37-7.25 (m, 2H), 7.17-7.13 (m, 1H), 6.68-6.58 (m, 1H), 3.98-3.94 (m, 2H), 3.80-3.77 (m, 1H), 3.55-3.52 (m, 1H), 0.88 (s, 6H). MS (EI) for C20H18F3IN2O4: 535 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[S:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[N:19]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(N(C(C)C)CC)(C)C>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[N:10]=[C:11]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:19]=2)[N:12]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)thiazole (100 mg, 0.22 mmol) in diisopropylethylamine (10 mL) was added 1-methylpiperazine (2 mL, 2.2 mmol). The mixture was stirred at 80° C. for 16 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to give the title compound as an oil; MS (ES+) C24H24F3N7OS requires: 515. found: 516. [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.58 (s, 1H), 7.29 (d, J=8.1 Hz, 2H), 6.43 (d, J=5.2 Hz, 1H), 6.40 (s, 1H), 5.34 (s, 2H), 3.61-3.49 (m, 4H), 2.57-2.44 (m, 7H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[CH3:28].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([O:20][CH2:27][CH3:28])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCBr
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 0.3 g (1.04 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 5 mL of anhydrous dimethylformamide was added 255 mg (0.78 mmol) of cesium carbonate in one portion, followed by addition of 103 uL (1.7 mmol) of ethyl bromide. The reaction was stirred at room temperature overnight. The reaction was added to 100 mL of ethyl acetate. The organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified by silica chromatography with EtOAc/hexane (3:7) to afford 0.21 g (67%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.68(s, 1H), 7.00(s, 1H), 6.42(s, 1H), 5.63 (q, J=7.2 Hz, 1H), 5.38(s, 1H), 4.28(m, 2H), 2.54(q, J=7.2 Hz, 2H), 1.31(t, J=7.2 Hz, 3H), 1.20(t, J=7.6 Hz, 3H), MS (ESI+) 317 (M+1, 100).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6](Br)[N:7]=1.[CH:21]1[CH2:26][CH:25]=[CH:24][CH2:23][CH:22]=1>[Pd].O1CCCC1>[CH3:5][N:4]([CH3:9])[CH2:3][CH2:2][N:7]([CH2:6][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][N:7]=1
Reactant: C1=CCC=CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(-n2ccnc(N(CCN(C)C)Cc3ccccc3)c2=O)c1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 129 mg), W-benzyl-N,N-dimethylethylenediamine (0.1 mL), N,N-diisopropylethylamnie (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 15 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated within a microwave for 60 minutes at 120° C. before being cooled to room temperature. The mixture was filtered and the filtrated concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (50 mg).