Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:13]2[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C>C(O)C.[C].[Pd]>[F:19][C:14]1[C:13]([C:4]2[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)c1c(Cl)[nH]c(-c2cccnc2F)c1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2cccnc2F)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 2-chloro-5-(2-fluoropyridin-3-yl)-4-methyl-1H-pyrrole-3-carboxylate (10.0 g) and triethylamine (5.5 mL) in ethanol (250 mL) was added 10% palladium carbon (50% containing water, 1.43 g), and the mixture was stirred under a hydrogen atmosphere at 60° C. for 3 hr. After cooling, the reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as colorless crystals (yield 7.93 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH3:11])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
3-Nitro-1-propyl-1H-pyrazole (92 mg, 0.59 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on carbon, wet (˜50 mg) was added to the mixture. The vial was charged with hydrogen gas (via balloon) and the mixture stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo followed by purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 1-propyl-1H-pyrazol-3-ylamine (54 mg, 73%) as a golden oil: LC-MS (ESI) m/e calcd for C6H11N3 [M+] 125.10, found 126.3 [M+H+], 251.3 [2M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]2[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:17]=[C:18]([CH3:19])[C:3]=12.Cl.C([OH:29])C>>[CH3:19][C:18]1[C:3]2[C:2](=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[NH:5][C:4]=2[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccc(C(F)(F)F)cc3c(Cl)c12
Reactant: CCO
Agent: Cl
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccc(C(F)(F)F)cc3c(=O)c12
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 4-chloro-3-methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]quinoline (6.50 g, 17.9 mmol) in ethanol (300 mL), 6N hydrochloric acid (10 mL, 60 mmol) was added and the mixture was heated under reflux for 5 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried, and recrystallized from ethanol to give the title compound (4.69 g, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([NH:6][C@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[CH2:8]2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1.C(O[C:26](=[O:28])[CH3:27])(=O)C>N1C=CC=CC=1>[C:11]([O:12][C@@H:11]1[C@H:7]([NH:6][C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N+:19]([O-:21])=[O:20])[CH2:8][C@H:9]([CH2:14][O:15][C:14](=[O:15])[CH3:9])[C@@H:10]1[O:13][C:26](=[O:28])[CH3:27])(=[O:12])[CH3:10]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1C[C@H](CO)[C@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 89 %

Procedure:
(1R, 2S, 3R, 5R)-5-(4,5-Dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol (1.30 g, 3.86 mmol) was stirred in pyridine (10 mL)-acetic anhydride (2.2 mL) at ambient temperature for 2 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and saturated aqueous sodium bicarbonate. The chloroform layer was dried (sodium sulfate) and concentrated to an oil which was chromatographed on silica gel. Elution with 2% methanol-chloroform gave (1R, 2S, 3R, 5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate as yellow needles (1.60 g, 89%), after crystallization from ethyl acetate-hexanes, m.p. 125°-130° C.; 1H-NMR(DMSO-d6) and mass spectrum (CI) consistent with structure; [α]20589 -130.5°, [α]20578 -140°, [α]20546 -178° (c=0.275, methanol).
Reaction SMILES: [NH:1]([CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[NH2:2].[N:18]1[CH:23]=NC=N[CH:19]=1>C(O)C.C(OC)(C)(C)C>[CH3:17][N:15]([CH2:14][CH2:13][C:7]1[C:6]2[CH:5]=[C:4]([CH2:3][N:1]3[N:2]=[CH:23][N:18]=[CH:19]3)[CH:12]=[CH:11][C:10]=2[NH:9][CH:8]=1)[CH3:16]
Reactant: CN(C)CCc1c[nH]c2ccc(CNN)cc12
Reactant: c1ncncn1
Solvent: CCO
Solvent: COC(C)(C)C
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Yield: 157.2 %

Procedure:
A solution of [2-(5-Hydrazinomethyl-1H-indol-3-yl)-ethyl]-dimethyl-amine (3.1 g, 85% purity, 11.9 mmol) and 1,3,5-triazine (0.69 g, 8.5 mmol) in ethanol (50 ml) is refluxed over night. The solution is then diluted with tert-butyl methylether (TBME), and the precipitated ammonium salts are filtered off. Removal of the solvent on the rotavapor produces 3.6 g of an oil which is chromatographed on silica (CH2Cl2: MeOH:NH4OH 98:2:1 to 95:5:1 v:v:v) to give 1.75 g (55%) of the product, dimethyl-[2-(5-[1,2,4]triazol-1-ylmethyl-1H-indol-3-yl)-ethyl]amine (Rizatriptan). HPLC retention time: 4.0 min.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[H][H]>CO.[C].[Pd]>[N:6]1[CH:7]=[CH:2][C:3]([CH:8]([N:11]2[C:12](=[O:21])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])[CH2:9][CH3:10])=[N:4][CH:5]=1
Reactant: CCC(c1ncncc1Br)N1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(c1ccncn1)N1C(=O)c2ccccc2C1=O
Yield: 66.6 %

Procedure:
2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione (568 mg, 1.64 mmol), triethylamine (0.228 mL, 1.64 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in methanol (10 mL) in a hydrogen atmosphere at room temperature for 1 day. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) give the desired product (292 mg, 66% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[C:6]2[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([N:17]1[CH2:16][CH2:15][N:14]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:19][CH2:18]1)=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc2c(N3CCNCC3)ncnc2cc1C
Reactant: S=C=NCc1ccccc1
Product: COc1cc2c(N3CCN(C(=S)NCc4ccccc4)CC3)ncnc2cc1C
Yield: 37 %

Procedure:
Substantially the same procedure as in Example 1 was repeated, except that 6-methoxy-7-methyl-4-(1-piperazinyl)quinazoline was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline in Example 125, and the corresponding benzyl isothiocyanate was used in place of phenyl isocyanate, to give the desired compound.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:30][CH2:31]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(NS(=O)(=O)CCO)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide (0.30 g, 0.64 mmol) in methylene chloride (6 mL) was added a solution of boron tribromide (0.12 mL, 1.29 mmol) and 2,6-lutidine (0.15 mL, 1.29 mmol) in methylene chloride (1 mL) dropwise. The reaction mixture was stirred at 0° C. for 2 h and at ambient temperature for 1 h, then cooled to 0° C. and quenched with saturated sodium bicarbonate solution (15 mL). The mixture was diluted with methylene chloride (15 mL), layers were separated, and the aqueous layer was extracted with methylene chloride (2×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 75% gradient of ethyl acetate in hexanes to afford the title compound as colorless solid (0.07 g, 25%): 1H NMR (300 MHz, CDCl3) δ 8.71 (br. s, 1H), 7.64-7.52 (m, 1H), 6.64-6.50 (m, 1H), 4.22-4.07 (m, 2H), 3.86-3.74 (m, 2H), 3.56 (s, 2H), 2.57 (s, 11H), 2.09-1.99 (m, 4H), 1.84-1.63 (m, 12H), 1.00-0.89 (m, 2H), 0.69-0.59 (m, 2H); MS (ES+) m/z 452.3 (M+1).
Reaction SMILES: [B:1](OCCCC)([O:7]CCCC)[O:2]CCCC.C([O:19][CH:20](OCC)[C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)C.C(OC)(C)(C)C.S(=O)(=O)(O)O>O1CCCC1>[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([B:1]([OH:7])[OH:2])=[CH:23][CH:22]=1)=[O:19]
Reactant: CCOC(OCC)c1ccc([Mg]Br)cc1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=Cc1ccc(B(O)O)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
Using a method based on that in Liebigs Ann. 1995, 1253-1257, a solution of 120 g of tri-n-butyl borate in 250 g of dry tetrahydrofuran was placed under nitrogen in a dried 2 l flask fitted with a dropping funnel and cooled to -50° C. 535 g of a 26.5% strength solution of 4-diethoxymethylphenylmagnesium bromide in THF are then added dropwise at such a rate that the internal temperature does not exceed −40 to −50° C. The mixture is subsequently stirred at −50° C for another 1 hour. 1 l of methyl t-butyl ether (MTBE) is subsequently added and the mixture is hydrolyzed at 5-10° C. using 650 g of 1M sulfuric acid. The aqueous phase was separated off and extracted three times with 500 ml each time of methyl t-butyl ether. The solvent was distilled off under reduced pressure and the crude boronic acid was once again taken up in 0.5 l of water and 185 ml of 5N aqueous potassium hydroxide (pH 14) at 5° C. The aqueous phase was extracted once with 250 ml of MTBE and subsequently, at 5° C., brought to a pH of 1 using 400 ml of 1M sulfuric acid. The precipitate was filtered off, washed twice with 150 ml of ice water and dried. This gives 66.1 g of 4-formylphenylboronic acid (88% of theory) comprising, according to HPLC, 89% of 4-formylphenylboronic acid, 4% of 4-carboxyphenylboronic acid, 3.8% of 4-hydroxymethylphenylboronic acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH3:14]>>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH2:13][CH3:14])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: CCBr
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Product: CCOc1cccc([N+](=O)[O-])c1C#N
Yield: 50 %

Procedure:
Prepared in a similar manner as Example 115c from 2-hydroxy-6-nitrobenzonitrile (Example 115d) and ethyl bromide to provide 2-nitro-6-ethoxybenzonitrile (192 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:16]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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>[CH3:16][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(C(F)(F)F)c(C)c1
Yield: 33.6 %

Procedure:
To a solution of methyl 5-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate (1173 mg, 4.13 mmol) in 1,4-dioxane (25 ml) stirred under N2 was added K2CO3 (1712 mg, 12.39 mmol), trimethylboroxine (0.866 ml, 6.19 mmol) and tetrakis(triphenylphosphine)palladium (0) (239 mg, 0.206 mmol). The reaction mixture was stirred heating under reflux for 24 h. HPLC showed starting material remaining, more tetrakis(triphenylphosphine)palladium (0) was added until starting material was not detected by HPLC. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a 40 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded methyl 5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (304 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[NH:27][S:28]([CH3:31])(=[O:30])=[O:29]>[Cu](I)I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]([C:13]1[N:27]([S:28]([CH3:31])(=[O:30])=[O:29])[C:20]2[C:19]([CH:14]=1)=[CH:24][CH:23]=[C:22]([C:25]#[N:26])[CH:21]=2)([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)Nc1cc(C#N)ccc1Br
Reactant: C#CC(C)(C)c1cc(OC)ccc1C(=O)OC
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1C(C)(C)c1cc2ccc(C#N)cc2n1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To the DMF (2 ml) solution of 2-(1,1-dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester (Compound AA3, 134 mg, 0.577 mmol) and N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA3, 167 mg, 1.05 eq.), copper iodide (9 mg, 0.08 eq.) and TEA (129 μl, 1.6 eq.) were added, degassed and flushed with nitrogen gas, added with dicholorobis(triphenylphosphine) palladium (20 mg, 0.05 eq.), and then degassed and flushed again with nitrogen gas. After stirring for 2 hr at 90° C., the reaction solution was added with water, extracted with ethyl acetate. The organic layer was washed with an brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white solid, 152 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(SC)cc3)ccc2c1
Yield: 71.1 %

Procedure:
Stir a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (1.98 g, 6:68 mmol), 4-fluoro-nitrobenzene (0.78 mL, 7.34 mmol) and phosphazene base P4-t-butyl (6.7 mL of 1M in hexane, 6.7 mmol) in N,N-dimethylformamide (30 mL) at ambient temperature for 4 hours. Dilute the reaction with dichloromethane, wash with 1N aqueous hydrochloric acid, water, dry with solid magnesium sulfate and chromatograph on silica gel with hexane/ethyl acetate mixtures to give 2.18 g of 6-methoxy-2-(4-methylsulfanyl-phenyl)-1-(4-nitro-phenoxy)-naphthalene (78%)
Reaction SMILES: Cl(O)(=O)(=O)=O.[Br:6][C:7]1[C:8]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:9]=2[S:10][C:11]=1[CH:12]([OH:17])[C:13]([O:15][CH3:16])=[O:14]>C(OC(C)(C)C)(=O)C>[Br:6][C:7]1[C:8]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:9]=2[S:10][C:11]=1[CH:12]([O:17][C:8]([CH3:21])([CH3:9])[CH3:7])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(O)c1sc2cccc(C)c2c1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1sc2cccc(C)c2c1Br
Reaction time: 1 h
Yield: 149.4 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 1.33 mL) was added at −10° C. to a solution of methyl (3-bromo-4-methyl-benzo[b]thiophen-2-yl)-hydroxy-acetate (23h) (250 mg, 0.79 mmol) in tert-butyl acetate (10 mL). After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (2×30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (23i) as a white solid (220 mg, 0.59 mmol, 75%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2S[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O[O:22][S:23]([O-:25])=O.[K+].OS([O-])(=O)=O.[K+]>CO>[Br:1][C:2]1[S:6][C:5]([CH:7]2[S:23](=[O:25])(=[O:22])[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)s2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)s2)S(=O)(=O)CC1
Reaction time: 4 h

Procedure:
To a solution of 7-(5-bromo-2-thienyl)-4-tert-butoxycarbonylperhydro-1,4-thiazepine (73.8 g) in methanol (500 ml) was added an aqueous solution (500 ml) of OXONE (2KHSO5.KHSO4.K2SO4) (156 g) under ice-cooling. After being stirred for 4 hours, the reaction mixture was concentrated in vacuo to remove methanol. The residue was extracted with ethyl acetate (1000 ml) and the extract was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed with hexane to afford 7-(5-bromo-2-thienyl)-4-tert-butoxycarbonylperhydro-1,4-thiazepine 1,1-dioxide (64.6 g) as a solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])#[N:4]>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:2][CH3:1])=[O:9])#[N:4]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C#N)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 40% aqueous methylamine solution (20 ml) and THF (30 ml) was cooled to 5° C., and 3-cyanobenzoyl chloride (1.89 g) was slowly added. The mixture was stirred for one hr. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (1.14 g) as colorless needle crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cccc(OCCCCCCCl)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: CC(=O)c1cccc(OCCCCCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(6-chlorohexyl)oxy]phenyl}ethanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 463.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)[CH3:33].Cl.C(N)C>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)[CH3:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and ethanamine hydrochloride (15.9 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 27.4 mg (34%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 10.03 (br. s., 1H), 8.64 (s, 1H), 8.35 (t, J=5.2 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 7.83 (s, 1H), 6.90-7.11 (m, 2H), 4.40-4.71 (m, 3H), 4.26 (s, 2H), 3.98 (d, J=11.1 Hz, 1H), 2.96-3.57 (m, 8H), 2.61-2.74 (m, 1H), 2.08 (d, J=11.9 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.73 (m, 4H), 1.11 (t, 3H). [M+H] calc'd for C24H31N7O2, 450. found, 450.