Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:12][PH:13](=[O:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:35]/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([CH2:12][PH:13]([O:14][CH2:35][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:28][CH:29]=1)=[O:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(C[PH](=O)O)C(=O)OCc1ccccc1
Reactant: BrCc1ccc(Cc2ccccc2)cc1
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
(2-Benzyloxycarbonyl-4-methylpentyl)phosphinic acid (1.14 grams, 4.0 mmole), 4-benzylbenzyl bromide (1.31 grams, 5.0 mmole) and N,O-bis(trimethylsilyl) acetamide (2.44 grams, 12 mmole) were combined in dry methylene chloride (40 ml); the mixture was degassed with a stream of dry nitrogen, then stirred at room temperature for 18 hours and refluxed for 24 hours. The cooled solution was quenched with 1N hydrochloric acid (25 ml). The methylene chloride layer was separated and washed with 1N hydrochloric acid (2×25 ml), dried with magnesium sulfate, filtered and concentrated to a turbid oil. This was dissolved in methanol (10 ml)/toluene (40 ml) and treated with excess trimethylsilyldiazomethane (commercial hexane solution). After 30 minutes the excess trimethylsilyldiazo-methane was destroyed with acetic acid. The solution was concentrated to an oil which was chromatographed (75:25--ethyl acetate:hexane) to give 1.18 grams (62%) of 2-[(4-benzylbenzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]CN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+].CI>CN(C=O)C>[CH3:31][N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH2:28])=[O:27])=[CH:29][CH:30]=3)[N:18]=2)[CH2:13]1
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)c1ccc(-c2noc(C3CNCCN3C(=O)COc3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(C(=O)COc2ccccc2)C(c2nc(-c3ccc(C(N)=O)cc3)no2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.1 mmol of 4-{5-[1-(2-Phenoxy-acetyl)-piperazin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzamide are dissolved in 1 ml DMF and 1 eq. DIPEA and Na2CO3 added. To the suspension 1 eq. of MeI is added and the reaction stirred at room temperature overnight. The product is isolated via preparative HPLC.
Reaction SMILES: N[CH2:2][C:3]1([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:14][O:13][C:11]1[C:12]2[CH2:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2c1C(O)(CN)CCC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c1CC(=O)CCC2
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a suspension of 1-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.54 g) in 10% acetic acid was added dropwise a solution of sodium nitrite (1.27 g) in water (6.4 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1) to afford 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (1.08 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[CH3:21][Sn](C)(C)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.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C=O)ccc1C
Yield: 82.9 %

Procedure:
A mixture of methyl 5-formyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (4.88 g), tetramethyltin (10.8 g), tetrakis(triphenylphosphine)palladium (1.85 g) and toluene (150 mL) was heated under reflux for 20 hrs. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give methyl 5-formyl-2-methylbenzoate as colorless crystals (2.31 g, yield 83%) from a fraction eluted with ethyl acetate-hexane (1:8, v/v). Recrystallization from diethyl ether-hexane gave colorless prism crystals. melting point: 60-61° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12]Br.N>CC(O)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[C:10]([Br:12])[C:5]=2[N:4]=[CH:3]1
Reactant: BrBr
Reactant: Cn1cnc2cc(N)ccc21
Agent: N
Solvent: CC(=O)O
Product: Cn1cnc2c(Br)c(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-methyl-5-aminobenzimidazole (0.36 g, 2.4 mmol) in 10 ml of AcOH was added Br2 (0.12 ml). The reaction mixture was stirred for 1 h at 25° C. and concentrated in vacuo, yielding an oil which was subjected to column chromatography (NH3 sat'd 3% MeOH/CHCl,) to yield 0.27 g (1.2 mmol, 50%) of the desired product.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH3:6][C:7]1([CH3:15])[C:12](=O)[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8]1.C([BH3-])#[N:17].[Na+]>CO>[NH2:17][CH:12]1[CH:11]([CH3:14])[CH2:10][NH:9][CH2:8][C:7]1([CH3:15])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CC1CNCC(C)(C)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CNCC(C)(C)C1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 3,3,5-trimethyl-4-piperidone (0.8 g, 5.67 mmol) in methanol (20 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.25 g, 3.96 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-3,3,5-trimethylpiperidine. Yield 0.45 g (54%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:32]([OH:34])=[O:33].[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:23]4)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-[(1-methylethyl)oxy]-5-[3-(1,2,3,4-tetrahydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 3, 28.8 mg, 0.080 mmol), ethyl 4-bromobutyrate (45.8 μl, 0.32 mmol) and Cs2CO3 (130 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature for 1 h, and then irradiated to 60° C. for 5 min in the microwave. More ethyl 4-bromobutyrate (45.8 μl, 0.32 mmol) was added and the suspension was stirred at room temperature for 3.5 h. It was then filtered, concentrated in vacuo and purified by MDAP to give the title compound as a yellow film (8.0 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 8.42 (1H, d), 8.34 (1H, dd), 8.27 (br. s), 8.09 (1H, d), 7.39 (1H, t), 7.27 (1H, d), 7.13 (1H, d), 4.80 (1H, sept), 4.19 (2H, s), 4.13 (2H, q), 3.47 (2H, t), 3.28 (2H, t), 2.99 (2H, t), 2.44 (2H, t), 2.10 (2H, quin), 1.48 (6H, d), 1.25 (3H, t); m/z (ES) 475 [M+H]+.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([F:13])[F:12])[C:3]=1[C:4]#[N:5].[ClH:14].N([O-])=O.[Na+].[S:19](=[O:21])=[O:20]>C(O)(=O)C.O>[C:4]([C:3]1[C:6]([O:10][CH:11]([F:13])[F:12])=[CH:7][CH:8]=[CH:9][C:2]=1[S:19]([Cl:14])(=[O:21])=[O:20])#[N:5]
Reactant: O=S=O
Reactant: Cl
Reactant: N#Cc1c(N)cccc1OC(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(OC(F)F)cccc1S(=O)(=O)Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
2-Amino-6-difluoromethoxy-benzonitrile (6.4 g, 35 mmol) is dissolved in glacial acetic acid (50 ml). Hydrochloric acid (37%, 12.7 g) is added dropwise at ambient temperature. This mixture is cooled to 5° C. and a solution of sodium nitrite (2.5 g, 36.4 mmol) in Water (8 ml) is added dropwise. The reaction mixture is stirred at 0° C. for 1 hour. The resulting diazonium salt solution is added dropwise at ambient temperature to a mixture of glacial acetic acid (100 ml) saturated at ambient temperature with sulfur dioxide and a solution of CuCl2 (2.18 g, 16.2 mmol) in water (5 ml). The resulting mixture is stirred at ambient temperature for 2 hours. The reaction mixture is poured into an ice/water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated to give 2-Cyano-3-difluoromethoxy-benzenesulfonyl chloride (8.5 g, 91% yield) which is used without further purification. 1H-NMR (CDCl3, 400 MHz): 8.10 (d, 1H), 7.85 (t, 1H), 7.75 (d, 1H), 6.75 (t, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C(ONC([CH:16](C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=N)C>C(O)(=O)C>[NH:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCONC(=N)C(C)C(=O)OCC
Reactant: Nc1ccncc1N
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2cnccc2[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
A mixture comprising 3,4-diaminopyridine (51.7 g, 0.46 mol), ethyl 2-(N-ethoxyamidino)propionoate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 mL) was heated at 85° C. and stirred for 18 hours and then heated at 120° C. and stirred for an additional hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized by addition of an excess of 5M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated in vacuo to provide ethyl 1H-imidazo[4,5-c]pyridine-2-carboxylate (60.4 g, 58% yield); 1H NMR (300 MHz, CDCl3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3.90 (q, 1H), 1.75 (d, 3H), 1.25 (tr, 3H).
Reaction SMILES: [Cl-].[Cr+3:2].[Cl-].[Cl-].[C:5]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][SH:11])(=[O:7])[CH3:6]>O>[C:5]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][SH:11])(=[O:7])[CH3:6].[Cr:2]
Reactant: [Cr+3]
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: [Cl-]
Solvent: O
Product: [Cr]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
One half gram (1.85 mmole) of chromium chloride (CrCl3) was dissolved in 30 ml of deionized water to get a green solution. 1.5 g (9.2 mmole) of N-acetyl cysteine (NAC) was dissolved in 40 ml of deionized water were added, and the mixture was stirred for 3 hours at 40° C. until the solution turned dark green-blue.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.Cl.Cl[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(O)(=O)C>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:3][C:4]2[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:19]=1
Reactant: ClCc1cccnc1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(OCc2cccnc2)cc1
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
An aqueous solution of 2M NaOH (165 ml) was added to a solution of (E)-3-[4-hydroxyphenyl]-2-propenoic acid (16.4 g, 100 mmol) in ethanol (100 ml). The mixture was stirred for 10 minutes, and then 3-(chloromethyl)-pyridine hydrochloride (19.7 g, 120 mmol) was added in portions. The mixture was stirred for 20 hours, and the solvents were evaporated under reduced pressure. Water was added and the suspension heated to give a solution. To this solution was added acetic acid, and the resultant precipitate was filtered and recrystallised from methanol to give the title compound as a colourless solid (15.6 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20](Cl)=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>ClCCl>[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20]([NH:1][CH2:2][CH2:3][OH:4])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: NCCO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Reaction time: 1.25 h

Procedure:
2-Aminoethanol (1.2 g, 19.7 mmol) in dry dichloromethane (5 ml) was added dropwise to a solution of 9-fluorenylmethylchloroformate (5.0 g, 19.3 mmol) together with pyridine (1.5 g, 19.4 mmol). The mixture was stirred for a total of 1.25 hours then diluted with dichloromethane (50 ml), washed with water (25 ml), a saturated solution of ammonium chloride (25 ml), the organic phase was separated dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo to give a white solid. This material was crystallised from dichloromethane to give 2-(9-fluorenylmethoxycarbonyl)aminoethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO.CCOC(C)=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reaction time: 8 h
Yield: 95 %

Procedure:
Palladium on carbon (780 mg) was placed under an inert atmosphere and suspended in EtOH (15 mL). A solution of 5-nitroindazole-1-carboxylic acid tert-butyl ester (7.78 g, 29.5) in EtOH (100 mL) and EtOAc (100 mL) was added. The reaction mixture was placed under H2 atmosphere (1 Atm pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to yield a greenish foamy solid. The crude product was dissolved in CH2Cl2 and purified by Biotage Flash 40M (gradient from 30% to 50% EtOAc/hex) to give the title compound (6.55 g, 95%) as a white solid: TLC (50%EtOAc/hex), Rf=0.41; ES-LCMS (rel abundance) m/z 234 (MH+, 66%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I>CN(C)C=O>[CH3:38][O:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Methyl iodide (94 mg, 0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product in 50% yield.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[F:1][C:2]1[N:7]=[C:6]([NH:8][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(F)n1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cccc(F)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
6-fluoropyridin-2-amine (13.1 g, 117 mmol) was dissolved in anhydrous pyridine (100 mL), and cooled to 0° C. followed by fast dropwise addition of trimethylacetyl chloride (15.9 mL, 129 mmol) over 2 min. 5 min later, the resulting slurry was stirred over night at room temperature. Partial of the solvent was removed on rotary vacuum. The residue was partitioned between saturated ammonium chloride (200 mL) and EtOAc (200 mL). After separation, the organic layer was washed with brine (50 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜75% EtOAc/Hexanes (1400 mL) to afford the expected product as a white solid(21.4 g, 93% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 6.63 (dd, J=8.06, 2.01 Hz, 1 H), 7.76 (q, J=8.14 Hz, 1 H), 7.85 (s, 1 H), 8.09 (dd, J=8.06, 1.76 Hz, 1 H); Mass spec. 197.15 (MH+), Calc. for C10H13FN2O196.1
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH:31]([C:30]([OH:35])=[O:34])[CH3:33])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: CC(O)C(=O)O
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)cc1

Procedure:
A flask containing 10.0 g. 4-(15-carbomethoxypentadecylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 4 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[S:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C@@H:35]([C:37]2[N:38]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]([F:59])([F:58])[F:57])=[CH:50][CH:49]=3)[C:39](=[O:47])[C:40]3[CH:46]=[CH:45][CH:44]=[N:43][C:41]=3[N:42]=2)[CH3:36])[CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:34]([C@@H:35]([C:37]2[N:38]([C:48]3[CH:49]=[CH:50][C:51]([O:54][CH2:55][C:56]([F:57])([F:59])[F:58])=[CH:52][CH:53]=3)[C:39](=[O:47])[C:40]3[CH:46]=[CH:45][CH:44]=[N:43][C:41]=3[N:42]=2)[CH3:36])[CH2:33][CH:30]2[CH2:31][CH2:32][S:27][CH2:28][CH2:29]2)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@@H](NCC1CCSCC1)c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1)N(CC1CCSCC1)C(=O)Cc1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
The compound 4-fluoro-3-trifluoromethylphenylacetic acid (164 mg, 0.74 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (64 μL, 0.74 mmol) was added, then after 5 min, N,N-dimethylformamide (5.7 μL, 0.07 mmol) was added. The reaction stirred at 0° C. for 30 min. and room temperature for 1 h. The solution was added slowly to a mixture of D1 (208 mg, 0.43 mmol) and triethylamine (182 μL, 1.30 mmol) in dichloromethane at −78° C. The mixture was stirred for 30 min., then washed with saturated aqueous sodium bicarbonate and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by chromatography (2% methanol with 0.1% ammonium hydroxide in dichloromethane), yielding 265 mg of 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2C(OCC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].[CH2:28]([OH:30])C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:22][C:23]([C:28]([OH:30])=[O:26])=[CH:24][CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CCO
Reactant: CCOC(=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
847 mg (2.43 mmol) of ethyl (1-t-butoxycarbonyl-4-piperidyloxy)benzoate was dissolved in 50 ml of ethanol. 5 ml of 1 N aqueous sodium hydroxide solution was added to the solution, and they were stirred at room temperature for 3 days. The reaction liquid was concentrated and then treated with ethyl acetate as the extractant in an ordinary manner to obtain the title compound.