Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51])#[N:43]>C(#N)C>[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51])#[N:43]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3C#N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 87.8 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]-isoindolinone (0.115 g, 0.249 mmol) was dissolved in acetonitrile (5.0 mL), and the solution was treated with triethylamine (0.104 mL, 0.747 mmol) and 2-cyanobenzenesulfonyl chloride (0.0750 g, 0.374 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(2-cyanobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.137 g, yield 88%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1[CH3:13])=[CH:9][C:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[C:7]([CH3:27])[CH:6]=2)[CH3:2].[H-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>CC(N(C)C)=O>[C:31](=[O:32])([O:33][CH3:34])[O:14][C:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:27])=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)[CH:9]=2)[N:4]=[C:3]([CH2:1][CH3:2])[C:12]=1[CH3:13]
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 15 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Dimethyl acetamide (980 ml) and 98 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were charged into a glass flask equipped with a stirring device, a thermometer, a reflux condenser, and a calcium chloride tube and having a volume of 2000 ml under a nitrogen atmosphere, and the mixture was cooled to 15° C. 55% sodium hydride (18.2 g) was added thereto, and the mixture was stirred at 15 to 20° C. for one hr. Methyl chloroformate (32.1 g) was added dropwise, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 5 L of ice water contained in a 10-L plastic container, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by a suction filter and was washed with n-hexane and water. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (103.3 g, yield 91.4%).
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)=[CH:8][CH:7]=1
Reactant: COCc1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1ccc(Cn2ncc(N)n2)o1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-((5-(methoxymethyl)furan-2-yl)methyl)-4-nitro-2H-1,2,3-triazole (97 mg, 0.35 mmol), iron powder (59 mg, 1.04 mmol) and NH4Cl (94 mg, 1.74 mmol) in a mixture of EtOH (1.6 mL) and water (0.8 mL) was stirred at 90° C. for 2 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1N NaOH (10 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (95:5 CH2Cl2-MeOH) gave the title compound as a yellow oil: TLC: rf (95:5 CH2Cl2-MeOH)=0.39. LC-MS-conditions 07: tR=0.51 min, [M+H]+=209.34.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][CH2:14][C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: OCc1ccco1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCc2ccco2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 2-furanmethanol by the method of Example 10(b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (35 g, 194 mmol) and pyridine (17.5 ml) in dry dichloromethane (200 ml) at 0° C. was added methanesulfonyl chloride (20 ml , 258 mmol) dropwise. The mixture was stirred for 3 hours at room temperature. The mixture was washed with water and extracted with dichloromethane (2×100 ml). The organic layers were dried with MgSO4 and evaporated in vacuo. The residue was triturated and washed with methanol to give 1-(4-fluorophenyl)-4-(methanesulfonyl)piperazine (39.35 g) as white crystals.
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:23][C:24]1[CH:30]=[C:29]([O:31][C:32]2[C:41]3[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=3)[N:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:25]=1[NH2:26].C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[Cl:23][C:24]1[CH:30]=[C:29]([O:31][C:32]2[C:41]3[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=3)[N:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:25]=1[NH:26][C:21]([NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)=[S:22]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (32 mg, yield 41%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:5]([N:7]([C:21]([CH3:25])([CH3:24])[CH:22]=[O:23])[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH2:18][CH3:19])=[O:6].[O-:30][Mn](=O)(=O)=O.[K+].[OH-].[Na+].CCO>>[CH3:29][C:27]1[CH:26]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:28]=1)[C:5]([N:7]([C:21]([CH3:24])([CH3:25])[C:22]([OH:30])=[O:23])[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH2:18][CH3:19])=[O:6]
Reactant: CCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C(=O)O

Procedure:
2-[N-(3,5-Dimethyl-benzoyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazino]-2-methyl-propionic acid was prepared by oxidation of 2-ethyl-3-methoxy-benzoic acid N′-(3,5-dimethyl-benzoyl)-N′-(1,1-dimethyl-2-oxo-ethyl)-hydrazide with KMnO4. The corresponding ester could not be saponified to the acid shown, even with 40% NaO/CH3OH, or 50% aqueous NaOH+EtOH with reflux.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[NH:18]([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[F:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:13](=[O:15])[N:18]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:19]=[C:2]3[C:11]=2[CH:10]=1
Reactant: NNc1ncccn1
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Solvent: CCO
Product: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ncccn1

Procedure:
A solution of 2.0 of ethyl 4-chloro-6-fluoroquinolin-3-carboxylate and 0.95 g of 2-hydrazinopyrimidine in 40 ml of 95% ethanol is heated under reflux for 16 hours. The reaction mixture is filtered and the resulting solid is taken up in 20 ml of N sodium hydroxide and sufficient water to effect solution. Ammonium chloride (10.7 g) is added, the resulting precipitate is collected, washed with water and dried to yield 8-fluoro-2-(2-pyrimidyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, as a hydrate, m.p. above 350°; IR (KBr) 800, 829, 870, 880 cm-1.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].ClS(O)(=O)=O.[Br:23]Br.[OH-].[Na+]>C(O)(=O)C>[Br:23][C:2]([CH3:17])([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: BrBr
Reactant: CC(C)C(=O)c1ccc(N2CCCCC2)cc1
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(Br)C(=O)c1ccc(N2CCCCC2)cc1
Reaction time: 1 h

Procedure:
34.70 g (0.15 mol) of 2-methyl-1-(4-piperidinophenyl)-propan-1-one are dissolved in 200 ml of glacial acetic acid. 0.58 g (5.0 mmol) of chlorosulfonic acid (corresponding to 0.33 ml) are added as catalyst. 24.0 g (0.15 mol) of bromine are then added dropwise at room temperature with thorough stirring in the course of approximately one hour. The solution is then poured onto ice and is brought to about pH 6 with dilute sodium hydroxide solution. The precipitated crystals are extracted with toluene. The toluene solution is dried with Na2SO4 and is concentrated at 40° C. under the vacuum of a rotary evaporator. The slowly crystallising, orange liquid is then reacted further.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14](N(OC)C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14](=[O:15])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1sccc1OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1sccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a cold (0° C.) solution of 3-(benzyloxy)-N-methoxy-N-methyl-2-thiophenecarboxamide (3.47 g, 12.50 mmol) in THF (50 mL) was added a solution of methyl-magnesium bromide in THF (1 M, 35 mL). After being stirred at 0° C. for 1 hr, the reaction mixture was quenched with saturated aqueous NH4Cl solution, diluted with water, and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate/CH2Cl2=3/1/1) followed by recrystallization from n-hexane/ethyl acetate to give 1-[3-(benzyloxy)-2-thienyl]ethanone as a white solid (2.592 g, yield; 89%). [Starting Compound 2A]
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:15]([F:16])=[CH:14][C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:9]=2[C:10]=1[CH3:11])([O:3]CC)=[O:2].[OH-].[Na+]>CO>[CH3:11][C:10]1[C:9]2[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[C:15]([F:16])[C:8]=2[O:7][C:6]=1[C:1]([OH:3])=[O:2]
Reactant: CCCc1cc(F)c2oc(C(=O)OCC)c(C)c2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(F)c2oc(C(=O)O)c(C)c2c1O
Yield: 87 %

Procedure:
To a solution of 2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (1.0 gm, 3.6 mmoles) in methanol (100 mL) was added 2N sodium hydroxide (10 mL) and the resulting solution was refluxed for a period of 4.5 hours. The reaction mixture was concentrated in vacuo. The residue was acidified with 3N hydrochloric acid and then extracted with ethylacetate. The organic phase was dried (Na2SO4), concentrated in vacuo, and 3 methyl-4 hydroxy 5 propyl 7 -fluorobenzofuran-carboxylic acid (0.79 gm; 88%) was isolated by filtering the solid after suspending in hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[N+:13]([O-])=O>CO.[Pd]>[NH2:13][C:4]1[CH:5]=[CH:6][C:7]([C:9]([NH:11][CH3:12])=[O:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc(N)c(OC)n1
Yield: 97 %

Procedure:
The solution of 6-methoxy-N-methyl-5-nitropicolinamide (1 equiv) in methanol (0.43 M) was stirred with palladium on carbon 10% w/w (10% by mass) under hydrogen (45 psi) for 1 h. The reaction mixture was filtered over Celite and concentrated. The crude product was purified by silica gel column chromatography (20-90% ethyl acetate (with 1% 1N ammonia in methanol) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.73 (d, J=4.69 Hz, 3 H) 3.91 (s, 3 H) 5.49 (br. s., 2 H) 6.83 (d, J=7.81 Hz, 1 H) 7.35 (d, J=7.81 Hz, 1 H) 8.05 (q, J=4.82 Hz, 1 H); MS (ESI) m/z 182.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][NH:7]2.[C:14](Cl)(=[O:16])[CH3:15].O>ClCCl.N1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][NH:7]2)(=[O:16])[CH3:15]
Reactant: Cc1ccc(N)c2c1NCCC2=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2

Procedure:
In a mixed solvent of 20 ml of dichloromethane and 1.3 ml of pyridine was dissolved 2.0 gm of 5-amino-8-methyl-2,3-dihydroquinoline-4-one. 1.2 ml of acetyl chloride was added to the solution under ice-cooling while stirring, followed by further stirring for 4 hours. After the addition of water, the reaction mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was crystallized in ether to obtain 1.24 gm of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)nc(Br)c1
Temperature: 90 °C

Procedure:
To a solution of 2,6-dibromo-4-nitro-pyridine (1.0 g, 3.54 mmol) in glacial acetic acid (20 mL) was added Fe-powder (1.0 g, 17.74 mmol) at room temperature. The reaction mixture was refluxed for 90° C. for 30 min. After completion of reaction (TLC monitoring), water was added (100 mL), basified with 2N NaOH (pH 12-14). The resulting mixture was filtered through celite-bed and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried (Na2SO4), filtered and evaporated to dryness to get the desired product as an off white solid (0.80 g, 90%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1.[H-].[Na+].[CH3:19]I>O1CCCC1>[CH3:19][O:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)CC(COC)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A solution of 2.5 g (11.26 mmole) ethyl 2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate in 50 ml tetrahydrofuran was cooled under nitrogen to 0° C. and 595 mg (12.38 mmole) of a 50% by weight dispersion of sodium hydride in oil was added in portions. The mixture was stirred to 0° C. for 15 minutes, then a solution of 1.756 g (12.38 mmole) methyl iodide in 30 ml tetrahydrofuran was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo, the residue partitioned between ethyl ether and water. The ether extracts were combined, washed with brine, dried (MgSO4) and the solvent evaporated in vacuo to yield 2.28 g of product as an oil. 1H-NMR(CDCl3) showed singlet at 3.4 ppm, consistent with the presence of a CH2OCH3 group.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:17][CH2:16]2)[C:13]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]1([N:14]2[C:13]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:17][CH2:16]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of [(S)-1-(1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (414 mg, 1.3 mmol) in DCM (7 mL) was added TFA (3 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min and then the organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a yellow oil (166 mg, 58%). LCMS (Method C): RT 1.66 min [M+H]+ 220.1.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:34])[C@H:21]([CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:42][CH2:43][C:44](Cl)=[O:45]>C(OCC)(=O)C>[CH2:12]([O:19][C:20](=[O:34])[C@H:21]([CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[NH:22][C:44](=[O:45])[CH2:43][Cl:42])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCl)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
A solution of L-aspartic acid dibenzyl ester p-toluene sulfonic acid salt (150 g, 0.309 mol) and distilled triethylamine (93 mL, 0.67 mol) in ethyl acetate (1.1 L) was cooled to 0° C. Chloroacetyl chloride (25.5 mL, 0.32 mol) was added to the resulting solution at a rate such that the reaction temperature did not exceed 10° C. The reaction mixture was then stirred at room temperature for a period of 1.5 hours. The resulting heterogeneous mixture was filtered to remove triethylamine salts. The organic filtrate was sequentially extracted with aqueous 1N HCl (2×250 mL), water (about 300 mL), half-saturated aqueous sodium carbonate (250 mL), water (about 300 mL), and brine (about 300 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo to provide product 11 (115.6 g, 0.296 mol, 96%) as a viscous brown oil which crystallized on standing. Satisfactory 1H NMR data were obtained for this material. This material was not further purified but was instead used directly in the preparation of iodide 12.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCOCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:4](=[O:6])[C:3]3[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=3)[NH:1][C:31]2=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(=O)[nH]c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (1.50 g, 7.2 mmol) in triethylamine (2.50 mL, 18.0 mmol) and 1,4-dioxane (20 mL) was added 1-chloro-4-isocyanatobenzene (1.4 g, 9.3 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The mixture was then cooled to rt and the solid was filtered, then rinsed with ether (2×) to afford methyl 3-(4-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1.56 g, 66%). LC-MS: (FA) ES+ 331; 1H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.74 (dd, J=8.2, 1.4 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:16]1[CH2:17][CH2:18][CH2:19][N:20]=1>CCOCC>[ClH:1].[C:2]1([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[N:13]=[C:16]2[CH2:17][CH2:18][CH2:19][NH:20]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=NCCC1
Reactant: NC1CCCC1c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(C2CCCC2N=C2CCCN2)cc1
Reaction time: 144 h

Procedure:
A slurry of 3.0 g (0.0152 mole) of powdered 2-phenylcyclopentylamine hydrochloride and 3 ml of O-methylbutyrolactim is allowed to stand at room temperature with occasional stirring for 6 days after which the material is covered with absolute ether. The solution is allowed to stand at room temperature for an additional 6 days. A precipitate forms which is collected and recrystallized from acetone-methanol and dried to give 2-[(2-phenylcyclopentyl)imino]pyrrolidine hydrochloride, M.P. 155°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]2=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:9]3[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCC(Sc2ccc(F)cc2)C(=O)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CCc2sc3ccc(F)cc3c2C1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a room temperature solution of ethyl 4-[(4-fluorophenyl)thio]-3-oxocyclohexanecarboxylate (3.4 g, 11.5 mmol) in dichloroethane (100 mL) was added AlCl3 (3.7 g, 27.6 mmol). The mixture was heated to 80° C. for 1 hour. After cooling to room temperature, the reaction was diluted with water and acidified with 1 N HCl. The aqueous mixture was extracted with EtOAc. The organic layer was washed with water then brine, then was dried over MgSO4 and concentrated to an oil. Purification by chromatography on silica gel afforded 2.5 g (77%) of the title compound as semi-solid: MS (+) 278 (M)+.