Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A reaction vessel was charged with 0.255 g of tetrakistriphenylphosphine palladium, 1.132 g of 4-fluorophenylboronic acid, and 3.122 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.095 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 8 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.399 g of 4-chloro-6-(4-fluorophenyl)pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13](OCC)[O:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2].[N:21]([Si](C)(C)C)=[N+:22]=[N-:23]>Cl[Sn](Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:21]=[N+:22]=[N-:23])[O:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(OCC(OCC)OCC)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCC)c1
Reaction time: 1 h

Procedure:
To a mixture of 3-(2,2-diethoxy-ethoxy)-benzoic acid ethyl ester (1.128 g, 4 mmol) and azidotrimethylsilane (0.584 ml, 4.4 mmol) was added SnCl4 (40 μl) at room temperature. After 1 hr, the precipitates were filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol, after 10 minutes, solvent was removed under reduced pressure. The residue was purified by a column chromatography (3×20 cm). The product was eluted with 10% petroleum ether (60-80° C.) in DCM. The title compound was obtained as a colourless oil (0.909 g, 81.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:17]1([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[N:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=Cc2ccc(-c3ccccc3)cc2)cc1

Procedure:
p-Toluidine (0.20 mole), 4-biphenylcarboxaldehyde (0.20 mole), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) were azeotropically refluxed in toluene (150 cc). The required amount of water had been removed after 3 hours. The solvent was removed on the rotary evaporator and the residue was recrystallized with 95% ethanol to yield N-(p-phenylbenzylidene)-p-methylaniline; m.p. 137°-139° C.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH3:21]
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)OC1=C(C)OC(C)C1=O
Yield: 29.3 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 44.0 g, 0.33 mole) and triethylamine (50.5 g, 0.5 mole) in methylene chloride (220 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.0 hours, a solution of methyl chloroformate (38.6 g, 0.41 mole) in methylene chloride (200 g), which is then stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 18 g of methyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product, b.p. 105° C.; IR (neat film) 2960(M), 1770(S), 1710(S), 1640(S), 1250(S), 1200(S) cm-1 ; 'H NMR δ 1.55 (d, J=8 Hz, 3), 2.28 (s, 3), 3.95 (s, 3), 4.70 (q, J=8 Hz, 1).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H][H]>[Pd].CO>[CH2:10]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NCc1ccccc1)c1ccccc1
Reaction time: 6 h

Procedure:
412 kg of methanol and 375.7 kg of (R)-1-phenylethylamine (ee=97.1%) are initially taken and 329 kg of benzaldehyde are added dropwise at 24° C. in the course of 120 minutes. Stirring is effected for 6 hours at 24° C., the completeness of the iminization is checked by GC, 6 kg of Pd/C (5% by weight) are added and the crude mixture is hydrogenated with hydrogen for 24 hours at atmospheric pressure. The sample is taken and the composition is investigated by GC analysis.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:4][CH:3]1[CH2:5][O:6]S(C)(=O)=O.C(OC([N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[Cl-:38].[Na+].O>CN(C=O)C>[ClH:38].[F:1][C:2]1([F:11])[CH2:4][CH:3]1[CH2:5][O:6][C:28]1[CH:27]=[CH:26][C:25]([CH:22]2[CH2:21][CH2:20][NH:19][CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Reactant: [Cl-]
Reactant: CS(=O)(=O)OCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: FC1(F)CC1COc1ccc(C2CCNCC2)cc1
Reaction time: 12 h

Procedure:
4.48 g (19.2 mmol, 80%) Methanesulfonic acid 2,2-difluoro-cyclopropylmethyl ester are added to 5.93 g (19.2 mmol, 90%) 4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 5.36 g (38.5 mmol) K2CO3 in 60 mL DMF. Stirring is continued for 12 h at 50° C. under inert gas atmosphere. After that time, brine (50 mL) is added and the mixture is extracted with EtOAc (3×50 mL). The organic layer is separated, washed with brine, dried over sodium sulphate and the solvent is removed by evaporation. The residue is purified by column chromatography (silica gel; gradient PE:EtOAc 20:1→10:1). The residue is taken up in 20 mL DCM and 100 mL 4N HCl in EtOAc are added dropwise at 0° C. The mixture is stirred for 12 h at rt. After that time, the solvent is removed in vacuo to yield the desired product.
Reaction SMILES: Br[C:2]1C=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=[O:24].[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>[CH3:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[O:24])[CH2:5][CH2:6][O:7][C:8]=3[CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc3c(c2)OCCC3=O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol), 3-methylbenzeneboronic acid (1.8 g, 13.2 mmol), Na2CO3 (2.8 g, 26.4 mmol) in dioxane (40 mL) and water (2 mL) was added Pd(PPh3)4 (509 mg, 0.4 mmol) at rt under N2. The reaction was stirred at 100° C. overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=12:1) gave 2.0 g (96%) of the title compound as a white oil. 1H NMR (300 MHz, CDCl3): δ 2.44 (3H, s), 2.86 (2H, t, J=6.6 Hz), 4.59 (2H, t, J=6.6 Hz), 7.20-7.29 (3H, m), 7.36-7.44 (3H, m), 7.87 (1H, d, J=8.1 Hz). [M+H] Calc'd for C16H14O2, 239. Found, 239.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](SC)=[C:4]([F:10])[CH:3]=1.O[O:12][S:13]([O-:15])=O.[K+].[CH3:17]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:13]([CH3:17])(=[O:15])=[O:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Br)cc1F
Reactant: CO
Agent: [K+]
Product: CS(=O)(=O)c1ccc(Br)cc1F
Yield: 78 %

Procedure:
Combine 4-bromo-2-fluorothioanisole (U.S. Pat. No. 6,307,047, 2.7 g, 12 mmol), oxone (38 g, 62 mmol) and methanol (200 mL) and stir for 12 hours. Filter through a pad of silica gel and elute with ethyl acetate (500 mL). Evaporate solvent and partition between dichloromethane (200 mL) and water (100 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Wash the crude solid with hexane (20 mL), ether (10 mL) and dry in vacuo to obtain 2.4 g of 4-bromo-2-fluoro-1-methanesulfonyl-benzene 78%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20].[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:23][CH:19]([CH2:21][CH3:22])[CH3:20])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(C)N
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCC(C)Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and sec-butylamine (282 mg, 3.85 mmol) suspended in 1-butanol (10 ml) were heated at 100° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 1N aqueous sodium hydroxide and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (71 mg, yield 62.8%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.N([O-])=O.[Na+].[ClH:16]>O>[Cl:16][C:2]1[S:3][C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1
Reactant: Cl
Reactant: Nc1nc2cn[nH]c(=O)c2s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (822 mg) obtained in Step 5 was suspended in 6N aqueous hydrochloric acid solution (6.6 ml), and sodium nitrite (1.69 g) was added in several portions at room temperature. After stirring the obtained suspension at room temperature for 30 min, the reaction mixture was diluted with water, and the solid was collected by filtration, washed with water and a small amount of acetone, and dried to give the title compound (770 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH:18]=[CH2:19])=[CH:4][N:3]=1.C[N+]1([O-])CC[O:24]CC1.[O-]S([O-])=O.[Na+].[Na+].[OH2:34]>C1COCC1.O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:18]([OH:24])[CH2:19][OH:34])=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(O)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 2-(2-chloro-5-vinylpyridin-4-yl)-4-fluoro-1H-indole (2 g, 7.35 mmol) in THF—H2O (26 mL-13 mL), NMO (2.15 g, 18.38 mmol) and OsO4 (56 mg, 0.22 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then Na2SO3 and water were added. The mixture was stirred at room temperature for 20 min and filtered. The filtrate was extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (DCM:MeOH=10:1) to give 1-(6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)ethane-1,2-diol (1.9 g, yield: 84.4%). 1H-NMR (Methanol-d4, 400 MHz) 8.61 (s, 1H), 7.63 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.08˜7.19 (m, 1H), 6.90 (s, 1H), 6.75 (dd, J=7.6, 10.0 Hz, 1H), 5.19 (t, J=6.0 Hz, 1H), 3.75˜3.82 (m, 1H), 3.67˜3.74 (m, 1H). MS (M+H)+: 307/309.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Oc3ccccc3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of the compound obtained in step 1 (0.50 g), phenol (0.21 g), potassium carbonate (0.76 g) and DMF (5 mL) was stirred at 100° C. for 3 days. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-benzyl-8-phenoxy-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.42 g, 66%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:25]([CH3:26])[C:21]=2[CH:20]=1>C1COCC1>[Cl:18][C:19]1[CH:32]=[CH:31][C:22]2[S:23][C:24]([S:27]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[C:12]([O:14][CH3:15])=[O:13])(=[O:28])=[O:29])=[C:25]([CH3:26])[C:21]=2[CH:20]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.5 %

Procedure:
Into 8 mL of THF was dissolved 115 mg of dimethyl 4-aminoisophthalate, followed by addition of 22 mg of sodium hydride (oily, 60%). After 20 minutes of stirring at room temperature, 130 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at the same temperature, followed by 30 minutes of stirring at room temperature. Further, 26 mg of sodium hydride (oily, 60%) was added and the whole was heated under refluxing for 6 hours. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 62 mg of the title compound as light yellow amorphous.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[C:14]([CH2:15][S:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3.O>CO>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]([OH:17])[C:9]3[C:14]([CH2:15][S:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3
Reactant: O=C1c2ccc(Cl)cc2SCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2ccc(Cl)cc2SCc2cccnc21
Reaction time: 0.67 h
Yield: 64.2 %

Procedure:
Add sodium borohydride (2.60 g, 0.0688 mol) portionwise over 15 minutes to a stirred suspension of 8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-one (15.0 g, 0.0573 mol) in methanol (150 mL) at 25°-35° C. and under an atmosphere of nitrogen. Stir the mixture for 40 minutes at 25°-30° C. Concentrate the mixture in vacuo to provide a suspension, and then pour it into water (150 mL), and extract with CH2Cl2 (3×100 mL). Combine the extracts, wash with water (3×75 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the crude product (18.4 g) via flash chromatography by eluting with EtOAc/hexanes (1:1) to obtain the title compound (9.70 g, 64% yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
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: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(F)cc1F
Temperature: 100 °C

Procedure:
To a stirred solution of 2-chloro-3-methyl-5-nitropyridine (prepared according to the procedure of Hawkins and Roe, J. Am. Chem. Soc., page 330, 1948) (17.6 g, 102 mmol, 1 eq.) in DMF (220 mL) was added 2,4-difluorobenzeneboronic acid (16.16 g, 102 mmol, 1 eq.) followed by Cs2CO3 (41.1 g, 122.7 mmol, 1.2 eq). The mixture was degassed with argon. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2 mmol, 0.02 eq). The mixture was degassed with argon and then heated to 100° C. under argon. After 18 h the mixture was cooled. The mixture was filtered and the filtrate concentrated under reduced pressure. The filtrate was partitioned between water and ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The material was purified by flash column chromatography eluting with 5:1 hekanes/acetone giving 7.5 g 2-(2,4-difluorophenyl)-3-methyl-5-nitropyridine. Mass spectrum (ESI) 251.3 (M+1). 1H NMR (500 MHz, CDCl3) δCHCl3: 9.35 (1H, s); 8.42 (1H, s); 7.47 (1H,m); 7.07 (1H, m); 6.97 (1H, m); 2.41 (3H, s).
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1.[Br-].[CH2:14]([N+:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:21]1[CH:30]=[CH:29][C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:22]1[CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C[n+]2ccc3ncccc3c2)cc1
Reactant: COc1ccc(CCBr)cc1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(CCC2c3cccnc3C=CN2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a suspension of 581 mg (23.9 mmol) magnesium in 24 mL THF was added 5.3 g (23.9 mmol) 4-methoxyphenethyl bromide. The mixture was refluxed for 2 h and then cooled in an ice bath and 2.4 g (7.97 mmol) 6-benzyl-[1,6]naphthyridin-6-ium bromide (Chemical & Pharmaceutical Bulletin, 32(7), 2522-9; 1984) was added at once. The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and quenched with a 20% NH4Cl solution. The mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 2.57 g (90%) of the title compound was yielded as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[Cl:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: c1ccc(COc2ccc(-c3cc4cc(OCc5ccccc5)ccc4[nH]3)cc2)cc1
Product: Clc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A flask was charged with 5-benzyloxy-2-(4-benzyloxy-phenyl)-1 H-indole No. 141 (8.0 g, 20.0 mmole) and CH2Cl2 (50 ml). The reaction was cooled to 0° C. and n-chlorosuccinimide (2.9 g, 22 mmole) was added. The reaction was stirred at 0° C. for 20 min. The reaction was then washed with 10% sodium sulfit solution, dried over MgSO4, and concentrated. To the resulting brown solid was added MeOH and the mixture was stirred for 15 min. The solid was filtered to give 6.8 g of a tan solid (78%). Mp=157-160° C.; 1H NMR (DMSO) 11.5 (s, 1 H), 7.80 (d, 2 H, J=7.0 Hz), 7.42−7.28 (m, 11 H), 7.17 (d, 2 H, J=8.7 Hz), 7.01 (d, 1 H, J=2.2 Hz), 6.88 (dd, 1 H, J=8.8 Hz, J=2.4 Hz), 5.17 (s, 2 H), 5.13 (s, 2 H); MS eI m/z 439 (M+).
Reaction SMILES: C(OC([N:8]1[C:13]2([C:16]([OH:18])=[O:17])[CH2:14][CH2:15][CH:9]1[CH2:10][O:11][CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:9]12[NH:8][C:13]([C:16]([OH:18])=[O:17])([CH2:14][CH2:15]1)[CH2:12][O:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1(C(=O)O)COC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C12CCC(COC1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a solution of 8-tert-butoxycarbonyl-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid (40 mg, 0.15 mmol) in DCM (3 mL) was added TFA (1 mL), The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to afford 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a (20 mg, 85%) which was used for next step without further purification. MS: calc'd (MH+) 158, measured (MH+) 158.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[C:15]=1[S:16]([OH:19])(=O)=[O:17].C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:32])=O>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[C:15]=1[S:16]([Cl:32])(=[O:19])=[O:17]
Reactant: CCOC(=O)c1cccn2c(S(=O)(=O)O)c(C)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Solvent: CC#N
Product: CCOC(=O)c1cccn2c(S(=O)(=O)Cl)c(C)nc12
Yield: 66.3 %

Procedure:
Ethyl 2-methyl-3-sulfo-imidazo[1,2-a]pyridine-8-carboxylate (1.7 g) and tri-n-propylamine (2.6 g) were added to acetonitrile (17 ml). Phosphorus oxychloride (1.1 ml) was added to the mixture, keeping the inner temperature to 50°-60° C. Then, the mixture was allowed to react at the same temperature for an hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated crystals were collected by filtration, washed with water and dried to obtain ethyl 2-methyl-3-chlorosulfonyl-imidazo[1,2-a]-pyridine-8-carboxylate (1.2 g, yield 66.3%) as crystals of m.p. 182°-183° C.