Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)CC)C.CS(Cl)(=O)=O.Cl>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][C:26]#[N:28])[CH:14]=[CH:15][C:16]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2ccc(CO)cc2OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(CC#N)cc2OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-(4-ethylbenzyl)benzyl alcohol (0.87 g) in dichloromethane (20 mL) were added triethylamine (0.44 mL) and methanesulfonyl chloride (0.22 mL) at 0° C., and the mixture was stirred for 2 hours. To the reaction mixture was added 0.5 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reducer pressure. The residue was dissolved in dimethyl sulfoxide (10 mL). To the solution were added potassium cyanide (0.68 g) and a catalytic amount of sodium iodide, and the resulting mixture was stirred at 80° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1–3/1) to give [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetonitrile (0.41 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:22])O)[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4](=[O:26])/[C:5](/[O:23][CH2:24][CH3:25])=[CH:6]/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1C)OCC
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a solution of 3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester (mixture of stereoisomers; 48.8 g, 136.2 mmol) in N,N-dimethylformarrd (500 ml) was added sulfuric acid (19.6 ml, 96%). The reaction mixture was heated to 100° C. for 2.5 h, cooled to ambient temperature, poured onto ice water/saturated aqueous NaHCO3 solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 46.1 g (135.4 mmol) of crude (Z)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylic acid ethyl ester which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 75.4 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (176 mg, 0.9 mmol) was treated with 60% NaH in oil (108 mg, 2.7 mmol) and tert-butyl bromoacetate (199.7 uL, 1.35 mmol) as above to yield 210 mg of a yellow solid. ES-MS calcd for C14H19N3O5 (m/e) 309.32, obsd 310.2 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[NH2:5][S:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(N)(=O)=O

Procedure:
300 mg (0.948 mmol) of methyl 2-[(tert-butylamino)sulfonyl]-6-nitrobenzoate in 8 ml of trifluoroacetic acid are stirred at room temperature for 4 h. The mixture is subsequently concentrated to dryness under reduced pressure and the residue is digested with diethyl ether. After filtration with suction and drying, 230 mg (93% of theory) of methyl 2-(aminosulfonyl)-6-nitrobenzoate of m.p. 227-229° C. remain.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]([CH3:12])([CH2:9][C:10]#[CH:11])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[CH3:12][C:4]([CH2:9][C:10]#[CH:11])([C:3]([OH:13])=[O:2])[C:5]([OH:7])=[O:6]
Reactant: C#CCC(C)(C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCC(C)(C(=O)O)C(=O)O
Temperature: 50 °C

Procedure:
23.7 g [53] (127 mmol) were dissolved in 200 ml methanol and a solution of 28.3 g (708 mmol) of NaOH in 50 ml water was slowly added dropwise. The mixture was heated to 50° C. in a water bath for two hours, the solvent was removed in a rotary evaporator and the residue was dissolved in water. The mixture was acidified with semi-concentrated hydrochloric acid and the free carboxcylic acid was exacted with chloroform, washed and dried.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]1[CH:11]=CC(C)=[CH:14][CH:15]=1.P(=O)(O)(O)O.C=CC(=C)C>O.CCCCCC>[CH3:9][C:10]1([CH3:11])[CH2:15][CH2:14][C:8]2[CH:7]=[CH:6][CH:5]=[C:3]([OH:4])[C:1]=2[O:2]1
Reactant: Cc1ccc(C)cc1
Reactant: Oc1ccccc1O
Agent: O=P(O)(O)O
Solvent: C=CC(=C)C
Solvent: O
Solvent: CCCCCC
Product: CC1(C)CCc2cccc(O)c2O1
Temperature: 100 °C
Reaction time: 7 h
Yield: 11 %

Procedure:
While a mixture of 10 g of catechol, 50 ml of p-xylene, 25 ml of hexane, 1 ml of phosphoric acid and 0.3 ml of water was heated at 100° C., 7.3 g of isoprene was added dropwise over 10 minutes, and the reaction was further carried out for 7 hours. After cooling, the resulting precipitate was separated by filtration. The filtrate was concentrated, and purified by column chromatography to give 1.7 g (yield 11%) of the product as a pale pink liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][OH:11])[C:6]=2[CH:12]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24](O)[CH:23]=[CH:22][CH:21]=2)=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24]([O:11][CH2:10][C:7]1[C:6]3[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17]
Reactant: OCc1coc2ccc(Cl)cc12
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 (4 g, 21.9 mmol), 102 (6.7 g, 21.9 mmol), triphenylphosphine (17.3 g, 65.8 mmol) and 40% diethyl azadicarboxylate solution (31.8 ml, 65.8 mmol) are dissolved in THF and cooled to 0° C. Then a solution of N-ethyldiisopropylamine (11.2 ml, 65.8 mmol) in THF is added dropwise. After the addition is completed, the mixture is stirred at room temperature for 2 h. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with saturated NaHCO3-solution and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (3:7), silicagel).
Reaction SMILES: [CH:1]1([CH2:5][C@@:6]2([CH3:19])[C:11](=[O:12])[O:10]C[C@H](C3C=CC=CC=3)[NH:7]2)[CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].C(O)C.O.FC(F)(F)C(O)=O>[NH2:7][C@@:6]([CH3:19])([CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:11]([OH:12])=[O:10]
Reactant: C[C@@]1(CC2CCC2)N[C@@H](c2ccccc2)COC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: C[C@](N)(CC1CCC1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.7 %

Procedure:
Pearlman's catalyst (0.5 g) was added to a solution of (3S,5S)-3-(cyclobutylmethyl)-3-methyl-5-phenylmorpholin-2-one (0.445 g, 1.7 mmol, Preparation 5) in ethanol (15 ml), water (2 ml) and trifluoroacetic acid (0.5 ml). The reaction was stirred under hydrogen gas (414 kPa, 60 psi) at room temperature for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (20 ml). The liquor was evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was removed and the aqueous phase was extracted with more dichloromethane (50 ml). The water layer was evaporated under reduced pressure to give a yellow solid. The product was purified by ion exchange chromatography on Dowex 50 WX8 resin, eluting with 0.88 aqueous ammonia:water (2:98 to 14:86) to give the title compound (0.034 g) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9]2=[CH:10][NH:11][CH:12]=[C:8]2[C:7](=[O:13])[N:6]([CH3:14])[C:5]1=[O:15].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1>[CH3:3][N:4]1[C:9]2=[CH:10][N:11]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:12]=[C:8]2[C:7](=[O:13])[N:6]([CH3:14])[C:5]1=[O:15]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cn(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60% in mineral oil, 335 mg, 8.4 mmol) was added to an ice cooled partial suspension of 1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate F step 2) (1.00 g, 5.6 mmol), SEM-Cl (1.485 mL, 8.4 mmol) and benzyl triethylammonium chloride (76 mg, 0.34 mmol) in THF (15 mL). The mixture was allowed to reach room temperature slowly and was stirred for 18 hours. The reaction mixture was quenched cautiously with sat ammonium chloride solution (80 mL, added dropwise), then was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with water (1×40 mL), brine (1×40 mL) then dried with magnesium sulfate and the solvent was removed under vacuum. The residue was triturated with iso-hexane and was dried under vacuum at 50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
4-Nitro-1H-pyrazole (1 g, 8.84 mmol) was dissolved in dimethylformamide (40 ml). Potassium carbonate (1.2 g, 8.68 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.2 g, 8.96 mmol) were added and the mixture was heated with stirring at 80° C. for 3 h. Once at room temperature, the reaction mixture was poured onto water and extracted with ethyl acetate (x3). The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to yield 2.27 g of the final compound as an oil. The product was used in the next synthetic step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(OCC)C>[OH:1][C@H:2]1[CH2:6][N:5]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
35.6 g (0.27 mol) of (2S,4R)-4-hydroxyproline were dissolved in 300 ml (0.60 mol) of 2N sodium hydroxide in a 750 ml sulphonation flask which was provided with stirrer, dropping funnel, thermometer and condenser. Thereupon, within 10 minutes there was added dropwise thereto a solution of 63 g (0.33 mol) of p-toluenesulphonyl chloride in 180 ml of diethyl ether. The temperature was held at 16°-20° C. by means of a water bath. After intensive stirring at room temperature for 16 hours, the reaction has finished. The aqueous phase (pH about 7) was separated and back-washed with 250 ml of diethyl ether. The ether phases were back-washed a further twice with 100 ml of deionized water each time. The combined aqueous phases were acidified to pH 2 with 25 ml of concentrated hydrochloric acid (27%) while cooling with ice at 5° C. and stirred for 1.5 hours at 5° C. The separated crystals were filtered off under suction, washed with 1 liter of deionized water and dried for 16 hours in a vacuum drying oven at 40° C./17 mbar. The resulting product (76.2 g of white crystals of melting point 142°-145° C.) was, for purification, dissolved in 200 ml of hot ethanol/water (1:4, v/v) and recrystallized while stirring and slowly cooling to 5° C. The white crystals obtained after drying (73.4 g) were again recrystallized from 150 ml of ethanol/water (1:4, v/v) as previously described and dried in a vacuum drying oven at 50° C./17 mbar. There were obtained 69.4 g (89.6%) of (2S,4R)-4-hydroxy-1-(p-tolylsulphonyl)-2-pyrrolidinecarboxylic acid of melting point 146°-147° C.; [α]D20 =-87.6° (c=1 in ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#[N:2].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:3]([C:1]2[NH:25][N:24]=[N:23][N:2]=2)[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(-c2nnn[nH]2)cc1Oc1ccc(F)cc1F
Temperature: 110 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (2.1 g), sodium azide (0.5 g) and ammonium chloride (0.43 g) in N,N-dimethylformamide (10 ml) was stirred for 6 hours at 110° C. The mixture was poured into a mixture of ice and diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo. The residual crystals were recrystallized from ethyl acetate to give colorless crystals of 2'-(2,4-difluorophenoxy)-4'-(5-tetrazolyl)methanesulfonanilide (2.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CC1(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 4 h

Procedure:
8.0 g of the product obtained in Step 2 dissolved in 200 ml of ethanol are hydrogenated for 4 hours at 20° C. and 5 bar in the presence of 1.0 g of 10% palladium-on-carbon. After filtering and concentrating to dryness, chromatography over silica gel (dichloromethane/tetrahydrofuran: 97/3) allows the expected product to be isolated (liquid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl (Z)-4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperazine1-carboxylate (0.0562 g, 0.139 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0203 g, 0.139 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperazine-1-carboxylate (0.0672 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:9][C:10]1[C:15]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Fc1cc(I)ccn1
Reactant: OB(O)c1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1cc(-c2cccnc2Cl)ccn1
Temperature: 100 °C

Procedure:
To 2-fluoro-4-iodopyridine (9.45 g, 42.4 mmol), 2-chloropyridine-3-boronic acid (10.0 g, 63.5 mmol), Na2CO3 (13.5 g, 127 mmol), Pd(OAc)2 (480 mg, 2.12 mmol) and P(tBu)3·HBF4 (1.23 g, 4.24 mmol) was added dioxane (125 mL) and water (45 mL). The mixture was heated overnight at 100° C. in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with n-Hexanes and dried to yield 2-chloro-2′-fluoro-[3,4′]bipyridinyl. MS m/z=209 [M+1]+. Calc'd for C10H6ClFN2: 208.62.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[S:10][C:11]=1[CH2:12][CH3:13].[C:19](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=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]>[CH3:18][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[S:10][C:11]=2[CH2:12][CH3:13])=[C:2]([CH3:19])[CH:3]=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: CCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: CN(C)C=O
Product: CCc1sc(C(=O)OC)cc1-c1c(C)cnn1C
Yield: 95.7 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (635 mg, 1.93 mmol), potassium carbonate (1.33 g, 9.64 mmol), PdCl2(dppf) (141 mg, 0.19 mmol) and trimethylboroxine (0.54 ml, 3.86 mmol) in N,N-dimethylformamide (3 ml) was stirred at 110° C. in a sealed tube for 2 h. This reaction mixture was concentrated and partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording the title compound (488 mg, 96%) as a yellow oil: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[C:31]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH3:26][N:25]1[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:28])[N:17]=[C:16]1[CH:15]=[CH:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([N:40]3[CH2:41][CH2:42][N:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:38][CH2:39]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)nc4)cc3)n(C)c(=O)c12
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: c1ccncc1
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(N5CCN(c6ccccc6)CC5)nc4)cc3)n(C)c(=O)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[2-[4-(6-chloronicotinoyl)-phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (333 mg) in pyridine (5 ml) was added 1-phenylpiperazine (156 ml) and the mixture was stirred at 90° C. for 4 hours. This reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed serially with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate (1:1)) to provide 162 mg of yellow powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccccc3OC)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3OC)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(2-methoxyphenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.86 g of 4,5-bis(4-methoxyphenyl)-2-(2-methoxyphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:17](O)[CH3:18]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH2:11][CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1c(CCC(=O)O)oc2cccc(O)c12
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1oc2cccc(O)c2c1C
Reaction time: 18 h

Procedure:
A mixture of 3-(4-hydroxy-3-methylbenzofuran-2-yl)propionic acid (400 mg, 1.8 mmole) in 1% sulfuric acid in ethanol was kept at room temperature for 18 hours. The mixture was concentrated. The residue was taken up in diethyl ether, washed with water twice, dried with Na2SO4, filtered, concentrated and chromatographed to obtain 280 mg of the title compound, m.p. 61°-63° C.