Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: OCCCl
Reactant: CCOC(=O)C1=C(Nc2ccccc2O)OCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(Nc2ccccc2OCCO)OCC1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, 2-chloroethanol (0.038 mL, 0.57 mmol) and potassium carbonate (0.11 g, 0.80 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 90° C. for 2 days. Cooled to ambient temperature, ethyl acetate was added to the reaction mixture, the organic layer was washed with aqueous 5% citric acid solution, water and brine, dried over magnesium sulfate and concentrated. To the residue, tert-butyl methyl ether was added to precipitate the product. The precipitate was collected by filtration, washed with hexane then dried to afford ethyl 2-{[2-(2-hydroxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.041 g, y. 35%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]=[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([C:61]3[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=3)[CH:59]=2)[O:54][CH:53]=[CH:52]1>CN(C=O)C>[O:50]=[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([C:61]3[CH:62]=[C:63]([NH:67][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:64]=[CH:65][CH:66]=3)[CH:59]=2)[O:54][CH:53]=[CH:52]1
Reactant: Nc1cccc(-c2ccc3occc(=O)c3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5occc(=O)c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 98 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(4-oxo-4H-chromen-6-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.028 g of product in 100% yield: LCMS (ESI) m/z 440 (MH+).
Reaction SMILES: C([O:3][CH:4]1[CH:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][CH2:7][CH:6]([CH3:13])[CH2:5]1)=C>CO>[CH:6]1([CH3:13])[CH2:7][CH2:8][CH:9]([CH:10]([CH3:11])[CH3:12])[CH:4]([OH:3])[CH2:5]1
Reactant: C=COC1CC(C)CCC1C(C)C
Solvent: CO
Product: CC1CCC(C(C)C)C(O)C1
Reaction time: 2 h
Yield: 88 %

Procedure:
The reaction was conducted in the same manner as in Example 10 except that methanol was used instead of the solvent and the reaction time was altered to 2 hours. The obtained reaction solution was analyzed by GC, to find that 12% of the menthyl vinyl ether was left with an optical purity of 76% ee. Further, the reaction solution was purified by silica gel column chromatography to obtain the reaction product menthol in a yield of 88%. Also, the kre1 value showing the selectivity of reactions at this time was 2.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Cl)CC2)cc1
Temperature: 50 °C

Procedure:
To 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (4.07 g, 21.2 mmol) were added thionyl chloride (4.64 mL, 63.5 mmol) and DMF (64 μL). The mixture was heated at 50° C. for 45 minutes. The excess thionyl chloride was evaporated under reduced pressure and the resulting acid chloride was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40]>CC(N(C)C)=O>[CH:26]([O:25][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[N:13][N:14]=2)=[CH:24][C:21]=1[C:22]#[N:23])([CH3:28])[CH3:27]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NCCS(C)(=O)=O)s2)cc1C#N
Temperature: 90 °C
Yield: 31.1 %

Procedure:
To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) and DIEA (32 mg, 0.24 mmol) in DMA (1 mL) was added (methylsulfonyl)ethene (20 mg, 0.18 mmol). The reaction mixture was heated at 90° C. for 24 h. The solvent was evaporated and the product purified by preparative HPLC to afford 9 mg (31%) of (S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile 31 as half-white solid. LCMS-ESI (m/z) calculated for. C24H26N4O3S2: 482.1; found 483.1 [M+H]+, tR=2.49 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[C:10]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:38]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:38][C:17]1[C:18]2[C:23]3=[C:22]4[C:21](=[CH:20][CH:19]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:9][C:10]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:11]4[CH:12]=[CH:13][C:14]3=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)c3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixed solution of 1.5 g of the above-mentioned 1,3,6-tri(4-methylphenyl)pyrene, 0.68 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under nitrogen gas stream at a temperature of 60° C. for 6 hours. After cooling the mixed solution to room temperature, 50 ml of water was injected thereinto to extract therefrom with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography and thereafter vacuum dried under a temperature of 70° C. to obtain 1.5 g of 1-bromo-3,6,8-tri(4-methylphenyl)pyrene as pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:37])[C:31]2[CH:30]=[C:29](O)[C:28]3[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=3[C:26]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]1=2>>[C:12]1([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:11][C:29]3[C:28]4[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=4[C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]([CH3:37])([CH3:18])[C:31]=4[C:30]=3[CH:10]=[CH:9]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)c2ccccc2-c2c1cc(O)c1ccccc21
Reactant: C#CC(O)(c1ccccc1)c1ccc(F)cc1
Product: CC1(C)c2ccccc2-c2c1c1c(c3ccccc23)OC(c2ccccc2)(c2ccc(F)cc2)C=C1

Procedure:
The process from Step 3 of Example 1 was followed except that 1-(4-fluorophenyl)-1-phenyl-2-propyn-1-ol (from Step 1) was used instead of 1-ferrocenyl-1-(4-fluorophenyl)-2-propyn-1-ol. The 1-(4-fluorophenyl)-1-phenyl-2-propyn-1-ol was reacted with 7,7-dimethyl-7H-benzo[C]fluoren-5-ol (from Step 3 of Example 1) to provide 3-phenyl-3-(4-fluorophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran. Mass spectrometry analysis supported a molecular weight consistent with 3-phenyl-3-(4-fluorophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:28])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]4[CH3:27])[N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:28])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]4[CH3:27])[CH:16]=[C:17]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])[N:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Cyclopropyl-1-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea (1.83 g) was partially dissolved in DCM (50 mL) and triethylamine (1 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.56 mL) and the reaction was stirred for 45 mins at RT. The reaction was then washed with water (10 mL) and the organics dried over magnesium sulphate. The solution was vacuumed to dryness to give the desired material as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (0.5 g, 3.07 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (0.77 g, 3.22 mmol) in EtOH (15 mL) was added Et3N (0.62 g, 6.13 mmol) and the mixture was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the product as colourless oil (0.23 g, 21%).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27](=[NH:29])[NH2:28])[CH:23]=2)[CH:18]=1)(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.[Pd]>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:9]1([CH2:8][CH2:7][C:6]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27](=[NH:28])[NH2:29])[CH:23]=3)[CH:18]=2)=[O:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)C=Cc3ccccc3)ccc2c1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)CCc3ccccc3)ccc2c1
Yield: 75.5 %

Procedure:
In 30 ml of DMF, was suspended 1.2 g of 6-amidino-2-naphthyl cinnamate methanesulfonate. After addition of 0.4 g of 10% Pd-C, the mixture was subjected to catalytic hydrogenation. The reaction mixture was filtered and the filtrate was mixed with ethyl ether. The resulting precipitate was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 0.91 g of 6-amidino-2-naphthyl 3-phenylpropionate methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCc1cccnc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NCc1cccnc1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (40) (5 g) in methylene chloride (60 mL) was cooled to −78° C. and treated with 3-(aminomethyl)pyridine (2.8 g). The mixture was stirred at −78° C. for six hours, and concentrated in vacuo at RT to provide crude 2-chloro-5-nitro-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (41), which was used without further purification.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)Cc1ccc(Br)cc1

Procedure:
2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (22.5 g, 150 mmol). and 4-bromobenzyl bromide (25 g, 100 mmol). Yield 33.66 g, (99%); yellow oil; MS: 273.8 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>C1COCC1.C(O)C>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(CO)cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.7 %

Procedure:
To a solution of the 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (250 mg, 0.37 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (4 mL) at room temperature. The resulting suspension was stirred for 5 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×30 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded 4-[2-(2-carboxy-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (65 mg, 37%) as a white solid: ES(+)-HRMS m/e calcd for C33H40O9S (M+Na)+ 635.2285. found 635.2284.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:13]([C:15](=[O:25])[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:37].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:13]([C:15](=[O:25])[C:16]([N:18]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH3:37])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)C(=O)NC2CCCCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)C(=O)N(C)C2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]N-cyclohexyl-2-oxoacetamide (reference example 14-15) (860 mg) and N,N-dimethylformamide (6 mL) was added sodium hydride (60%, 92 mg). After stirring at room temperature for 20 minutes, iodomethane (0.48 mL) was added to the mixture. After stirring at room temperature for 8 hours, the mixture was poured into a mixture of 2 mol/L hydrochloric acid and ice-water. Ethyl acetate was added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-50% ethyl acetate/hexane, gradient elution) to give the title compound (605 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: CCc1ccc(CCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1ccc(CCCBr)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
Compound 39-2 (1.97 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.35 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.26 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.N#N.[H-].[Na+].Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[O:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:32]([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)=[O:33])[C:5]([CH3:26])=[CH:4]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3ccc4c(cc(C)n4C(=O)Oc4ccc([N+](=O)[O-])cc4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Compound 11 (300 mg, 0.85 mmol) in dry THF was sparged with N2, then NaH (68 mg of 60% dispersion, 1.7 mmol) was added in a single portion. While still sparging with N2, 4-nitrophenyl chloroformate (341 mg, 1.7 mmol) was added and the reaction stirred at room temperature for 1 hour. Solvent was evaporated by rotary evaporator and the product precipitated from ethyl acetate/diethyl ether and filtered. The crude solid was washed with methanol (20 mL) to yield Compound 12 as crude yellow solid, which was taken directly to the next reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1

Procedure:
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.4 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.2 g (77%); white solid; mp 188° C.; MS: 412 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:7].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:7]
Reactant: COCCN
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCCOC)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
2-Methoxy-ethylamine (1.55 mL, 17.8 mmol) was added to a stirred solution of 4-fluoro-3-nitro-benzoic acid ethyl ester (3.60 g, 16.9 mmol) and K2CO3 (4.67 g, 33.8 mmol) in 50 mL DMF. After stirring for 4 h the mixture was poured onto ice water, stirred for 10 min, filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3)cc2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
A mixture of 1.0 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 0.86 g of 4-(chloromethyl)pyridine hydrochloride, 2.54 g of potassium carbonate and 20 ml of DMF was stirred at 80° C. for 2 hours and subsequently at 150° C. for 3 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.91 g of 4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 3”).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C)cc(C)c1N(CCCl)CCCl
Agent: Cl
Product: Cc1cc(C)c(N(CCCl)CCCl)c(C(=O)O)c1
Yield: 97.6 %

Procedure:
A suspension of methyl 2-bis(2'-chloroethyl)amino-3,5-dimethylbenzoate (5.6 g, 0.018 mol) in concentrated HCl (37% w/w in H2O, 150 mL) was heated to reflux under N2 for 8 hours. The reaction mixture was treated with ice/H2O (200 mL), extracted with chloroform (3×150 mL). The organic solution was concentrated to give a white solid (5.1 g, 96%). 1H NMR (300 MHz, CDCl3): 8.01 (d, J=1.5 Hz, 1H), 7.23 (dd, J=1.5, 0.6 Hz, 1H), 3.6 (m, 8H), 2.43 (s, 3H), 2.35 (s, 3H). ESMS calcd for C13H17Cl2NO2 : 289.1.