Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH3:6][O:5][C:1]([CH2:2][CH2:3][N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:4]
Reactant: NCc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)Cc1ccccc1
Yield: 98 %

Procedure:
At room temperature, to a 500 mL three-necked bottle, 18.9 g (0.22 mol) of methyl acrylate and 100 mL of methanol were added, and a mixture solution of 10.7 g (0.1 mol) of benzylamine and 50 mL of methanol was slowly added dropwise to the three-necked bottle under stirring. The temperature was naturally elevated, and the addition rate was controlled so that the temperature of reaction system was not greater than 50° C. After the addition, the reaction was stirred at room temperature for 0.5 h, and reacted for 8 h under reflux. After completion of the reaction, the unreacted methanol and methyl acrylate were removed by vacuum distillation to obtain light yellow oily product N,N-bis(β-methoxy carbonylethyl)benzylamine, 27.3 g, yield 98%, by 174-176° C./533 Pa.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[C:13]([CH3:20])=[CH:12][S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: N#Cc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1csc2nc(-c3ccncc3)nc(Cl)c12

Procedure:
With the procedure of Example qq, the reaction of 4-cyanopyridine and 2-amino-4-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[C:23]([CH3:26])[N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[C:23]([CH3:26])[N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3c(C)csc3n2)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.35 (m, 2H), 0.52-0.58 (m, 2H), 1.18-1.22 (m, 1H), 2.64 (s, 3H), 3.76-3.78 (m, 2H), 7.01-7.14 (m, 3H), 7.25-7.28 (m, 1H), 7.49 (d, J=15.6 Hz, 1H), 8.10-8.16 (d, J=15.9 Hz, 1H); ESI-MS (m/z) 494.99 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:33][CH:34]=1
Reactant: NCc1ccc(N2CCCC2=O)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2ccc(N3CCCC3=O)cc2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl phenyl pyrrolidin-2-one (42.94 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin-1-yl)-benzylamide (48.9 mg, 40.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H36Cl2N4O2S+H [(M+H)+]: 603.2288. found: 603.2289.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH2:2]1.O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C([BH3-])#N.[Na+].O>C(O)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([S:7]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)(=[O:8])=[O:9])[CH2:2]2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(C1CCCNC1)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCC(S(=O)(=O)N3CCOCC3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
A mixture of the 4-(piperidine-3-sulfonyl)-morpholine (710 mg, 3.03 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1 eq, 605 mg) and Ti(OiPr)4 (1.25 eq, 1.12 mL) was stirred under nitrogen at ambient temperature for 1 hr. A solution of sodium cyanoborohydride (0.7 eq, 133 mg) in anhydrous ethanol (3 mL) was added and the clear solution was stirred overnight. Water (0.6 mL) was added followed by sufficient ethanol to permit stirring. The thick suspension was filtered through Celite® rising through with ethanol and the filtrate was evaporated to a cloudy oil which was redissolved in dichloromethane/ethanol, a few drops of water added and the mixture was filtered through Celite®. The filtrate was diluted with toluene, evaporated under vacuum and the residue purified by chromatography on silica gel eluting with 2.5% methanol-dichloromethane. The desired fractions were combined, evaporated under vacuum and the residue chromatographed on silica gel eluting with 2.5% methanol-dichloromethane to give 3-(morpholine-4-sulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (520 mg, 41%).
Reaction SMILES: [F:1][S:2]([C:5]([C:8](C(F)=O)([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[F-].[Cs+].[F:16][C:17]([F:25])([F:24])[C:18]1([F:23])[O:22][C:19]1(F)[F:20].C[O:27]CCOCCOC>>[F:1][S:2]([C:5]([C:8]([O:22][C:18]([C:19]([F:20])=[O:27])([C:17]([F:25])([F:24])[F:16])[F:23])([F:9])[F:10])([F:6])[F:7])(=[O:3])=[O:4]
Reactant: FC(F)(F)C1(F)OC1(F)F
Reactant: COCCOCCOC
Reactant: O=C(F)C(F)(F)C(F)(F)S(=O)(=O)F
Agent: [Cs+]
Agent: [F-]
Product: O=C(F)C(F)(OC(F)(F)C(F)(F)S(=O)(=O)F)C(F)(F)F
Reaction time: 1 h

Procedure:
FSO2CF2CF2COF obtained in Example 1-6, CsF powder and diglyme are charged into an autoclave, and hexafluoropropene oxide is introduced with stirring under cooling with ice. Stirring is continued for 1 hour, and the content in the autoclave is distilled under reduced pressure to obtain FSO2CF2CF2OCF(CF3)COF.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[CH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH:23]=[N:24][OH:25])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([O:25][N:24]=[C:23]([C:22]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:21]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(C=NO)cc1OC1CCCC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=NOC3(CCN(C(=O)OC(C)(C)C)C3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The compound obtained from step c above (170 mg, 0.0010 mole) and 3-cyclopentyloxy-4-methoxy-benzaldehyde oxime (236 mg, 0.0010 mole) were taken in dichloromethane (20%) in chloroform followed by the addition of pyridine (2 drops). The reaction mixture was stirred at room temperature for 10 minutes followed by the addition of sodium hypochlorite (2 mL) dropwise. The resulting reaction mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was evaporated under reduced pressure followed by diluting it with water. The compound was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 200 mg.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccccc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])c1ccccc1
Temperature: 80 °C
Reaction time: 21.5 h

Procedure:
Sitagliptin (5 g) and isopropanol (75 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 20 minutes to obtain a clear dissolution. Benzoic acid (1.49 g) is added and the reaction mixture is refluxed for about 1.5 hours. The reaction mixture is cooled to about 30° C. and stirred for about 21.5 hours. The separated solid is filtered, washed with isopropanol (5 mL), and dried under reduced pressure at about 40° C. for about 1.5 hours to afford the title compound. (Yield: 5.9 g; MC: 0.80% w/w; HPLC purity: 99.82%)
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28](O)([CH:30]=C)[CH3:29])[CH3:24])[CH3:19])[CH3:14].[C:33](O)(=O)C>CCOCC.CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([OH:7])[C:8]=1[CH3:33])/[CH:12]=[C:13](/[CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])\[CH3:14]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CO
Product: C/C(=C\Cc1c(C)c(O)c(C)c(C)c1O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: -78 °C
Yield: 47 %

Procedure:
The solution of trimethylhydroquinone (30, 7.5 g, 49.28 mmol), isophytol (12 g, 40.47 mmol), anhydrous zinc chloride (3 g, 22.01 mmol) and 0.4 mL of glacial acetic acid in 60 mL of absolute ether was refluxed for 1 h. The solvent was then removed in vacuo at 50° C. and the slurry obtained was dissolved in a mixture of 50 mL of petroleum ether and 20 mL of 70% aqueous methanol. The emulsion formed was destroyed by the addition of 20 mL of ether. The ether layer was dried (Na2SO4) and evaporated in vacuo to give a red solid paste that was triturated vigorously with 70 mL of petroleum ether. After cooling to −78° C., the suspension was centrifuged and the supernatant petroleum ether was decanted. Cold petroleum ether (10 mL) was added to the crystalline mass, and the operation was twice repeated to give 10 g (47%) of sticky white solid, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
4-Fluoroaniline (0.178 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.125 g, 0.268 mmol, 50%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:29]([N:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:30].Cl.C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C.C(Cl)Cl>[CH2:29]([N:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:30]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC
Reactant: CCN(CC)CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Temperature: 130 °C
Yield: 93.2 %

Procedure:
A solution of methyl 6-(2-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 96, 0.07 g) in acetonitrile (2.2 ml) was added to a solution of N,N-diethyl-1,3-propanediamine (0.225 g) in triethylamine (0.07 g) in a microwave vial. The mixture was heated in the microwave at 130° C. for 2 hours. After cooling, DCM and hydrochloric acid (1M) were added and the pH was adjusted to 8 by addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with DCM, washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM, methanol, acetic acid and water (350:20:3:2) to give methyl 6-[2-(3-diethylaminopropylamino)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.083 g) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.Cl.[OH-:25].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH2:42]>O1CCOCC1>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([C:1]([OH:42])=[O:25])[CH2:4][CH2:5]1)=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)c(Cl)c2)CC1
Reactant: O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of 356 (4.54 g, 12.78 mmol) and concentrated HCl (106.5 mL, 1278 mmol) was heated to reflux and stirred over the weekend. The reaction mixture was then cooled to RT, transferred to separatory funnel, and washed with Et2O (1×200 mL). The aqueous layer was concentrated in a rotovap under high vacuum. The resulting solids were dissolved in 10% NaOH (20.45 g, 51.12 mmol). To the solution was added dioxane (30 mL) followed by Boc2O (2.929 g, 13.42 mmol). After stirring overnight, the reaction was diluted with H2O (100 mL) and washed with ether (1×100 mL). The aqueous layer was acidified with solid KHSO4 and then extracted with DCM (200 mL). The combined extracts were dried (MgSO4), filtered, concentrated and dried under high vacuum to afford 1.98 g (41%) of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)piperidine-4-carboxylic acid (358) as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nn2ccc3c(c2c1CCN)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn2ccc3c(c2c1CCNC(C)=O)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 2-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (110 mg, 0.476 mmol) and triethylamine (133 μL, 0.954 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (90.0 μL, 0.952 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 μL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=90/10→100/0) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (67.8 mg, yield 52%).
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.CC.[Cl].[Cl]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[O:11][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:17]=2[CH:18]=1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: Oc1ccc(Br)cc1
Agent: CC
Agent: [Cl]
Product: CCOC(=O)c1c(C2CC2)oc2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 20.2 %

Procedure:
(t-BuO)2 (94 g, 640 mol) was added to a solution of ethyl 3-cyclopropyl-3-oxopropanoate (50 g, 320 mmol), 4-bromophenol (166 g, 9.6 mol) and FeCl.6H2O (5.8 g, 32 mmol) in Di-chlorine Ethane (316 g, 3.2 mol) under N2 gas at 25° C. The mixture was stirred at 80° C. for 6 hours. The solvent was removed and the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 5-bromo-2-cyclopropylbenzofuran-3-carboxylate (20.0 g, yield: 21%). 1H-NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.30 (d, J=7.2 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 3.01˜3.05 (m, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.24˜1.26 (m, 2H), 1.16˜1.19 (m, 2H). MS (M+H)+: 309/311.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:6][C:5]=2[CH:7]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc2sc(N3CCNCC3)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 0.49 mmol 2,5-dichlorobenzothiazole (CA=[2941-48-2]), 1.47 mmol of piperazine and 1.47 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][C:24](O)=[C:23]([CH3:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([I:20])=[CH:22][C:23]=2[CH3:28])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Cc1cc(I)ccc1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.89 g) synthesized in Example 4 and 4-iodo-2-methylphenol (3.0 g) were dissolved in tetrahydrofuran (30 mL), triphenylphosphine (3.36 g) and diethyl diazodicarboxylate (2.23 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=6:1) to give the title compound (4.4 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:24]N1C(=O)CCC1=O.C(OC(=O)C)C>CN(C)C=O>[Br:24][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(c2ccc(Br)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
N,N-bis(4-methoxyphenyl)aniline 1 (9.0 g, 29.5 mmol) was dissolved in 100 mL dimethylformamide in a 250 mL round bottom flask. N-bromosuccinimide (5.25 g, 29.5 mmol) was dissolved in 30 mL dimethylformamide and added dropwise to the reaction mixture. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography (TLC) (Reaction Time=23 h). The reaction mixture was quenched using 600 mL water and extracted with 4×150 mL dichloromethane. The organic layers were combined and washed with 4×150 mL saturated sodium thiosulfate solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified along with materials prepared previously using flash chromatography on silica gel eluting with 5:1 hexanes:ethylacetate (12.1 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 4H), 6.90 (d, J=9.0 Hz, 4H), 6.73 (d, J=9.0 Hz, 2H), 3.77 (s, 6H).