Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1)=S.C(=O)([O-])[O-].[K+].[K+].N#CBr>C(#N)C>[CH2:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]2[N:3]3[CH:4]=[CH:5][N:1]=[C:2]3[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=2)[CH2:17][CH2:18]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)N1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1
Agent: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Cc3nccn32)CC1
Temperature: 25 °C

Procedure:
To a solution of 8.9 g of 1-[2-(2-imidazolylmethyl)phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine in 70 ml of acetonitrile, cooled to 0°, is added 2.4 g of solid potassium carbonate while stirring, followed by dropwise addition of a solution of 2.5 g of cyanogen bromide in 10 ml of acetonitrile; the mixture is allowed to warm up to room temperature overnight. The solids are filtered off, washed with ethyl acetate, and the filtrate is evaporated to dryness. The residue is dissolved in methylene chloride, the solution is washed with water, dried over MgSO4, decolorized with charcoal and evaporated to dryness. The residue is chromatographed with 250 g of silica gel using ethyl acetate-methanol (9:1) as eluant to give 5-(4-ethoxycarbonyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine, m.p. 137°-139°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16](OC)=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[Br-].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][Zn+].CC([N:35](C)C)=O>[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[Cl:23])=[C:14]([C:16]([NH2:35])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Reactant: Clc1ccccc1C[Zn+]
Agent: [Br-]
Agent: [Zn]
Product: NC(=O)c1nc2n(c1Cc1ccccc1Cl)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (150 mg, 0.33 mmol) in dry dimethylacetamide (DMA, 1.0 mL) was sparged with nitrogen gas and treated with PdCl2-[P(o-Tol)3]2 (27 mg, 0.033 mmol). A degassed solution of 2-chlorobenzylzinc bromide (0.61 M, 0.96 mL, 0.59 mmol) was added over 5 min dropwise. The flask was sealed under nitrogen and heated at 50° C. An additional 0.5 mL, of the zinc reagent was added under nitrogen sparge. After 30 min, LCMS indicated complete consumption. The mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. The crude residue was dissolved in DMF (2 mL) and treated with formamide (1 mL) then sodium methoxide (0.5 mL, 25 wt % in methanol). After 20 min at 50° C., complete conversion to the amide was evident by LCMS. The mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. The amide was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[C:9]1([S:15][CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([C:12]1[CH:13]=[CH:14][C:9]([S:15][CH3:16])=[CH:10][CH:11]=1)=[O:4]
Reactant: CCCC(C)C(=O)Cl
Reactant: CSc1ccccc1
Product: CCCC(C)C(=O)c1ccc(SC)cc1

Procedure:
Following the procedure described for Example 1, Step 1, the title compound was prepared from 2-methyvaleryl chloride and thioanisole.
Reaction SMILES: CS(N)(=O)=O.[CH3:6][O:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:41]1([C:44]2[C:45]([O:54][CH2:55][C:56]34[C:62]([F:64])([F:63])[CH:61]3[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[CH2:43][CH2:42]1>>[CH:41]1([C:44]2[C:45]([O:54][CH2:55][C:56]34[C:62]([F:64])([F:63])[CH:61]3[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49]([NH:13][S:10]([CH2:9][CH2:8][O:7][CH3:6])(=[O:12])=[O:11])=[O:50])[CH2:43][CH2:42]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with 2-methoxyethanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.045 g, 74%): 1H NMR (300 MHz, DMSO-d6) δ 11.92 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.8 Hz, 1H), 4.23-3.92 (m, 2H), 3.72 (s, 3H), 3.39-3.28 (m, 2H), 3.23-3.18 (m, 2H), 2.08-1.58 (m, 6H), 1.38-1.16 (m, 4H), 0.96-0.84 (m, 2H), 0.74-0.64 (m, 2H); MS (ES+) m/z 463.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)cc1
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Yield: 92 %

Procedure:
A solution of 4-chlorophenyl-2-(pyridin-4-yl)ethan-1-one (20.0 g, 86.4 mmol) and N,N-dimethylformamide dimethylacetal (57.6 mL, 0.43 mole) was heated at 100° C. for 3½ hours. The reaction mixture was concentrated in vacuo, and the residue crystallized from methyl butyl ether to give 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 93%). 1H NMR (CDCl3/300 MHz) δ8.52 (d, 2H), 7.38 (d, 2H), 7.29 (d, 2H), 7.08 (d, 2H), 2.83 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH4-].[Na+].[ClH:31]>CO>[ClH:31].[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][CH:10]([CH3:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCc1ccccc1
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Cc1cccc(C(F)(F)F)c1)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-2-propanone (102 mg, 0.50 mmol), 3-phenyl-1-propylamine (86 mg, 0.64 mmol), glacial acetic acid (8 mg, 0.13 mmol), and MeOH (2 mL) was allowed to stir at room temperature for 0.5 h. To this mixture was added over a 4-h period sodium borohydride (19 mg, 0.50 mmol) and the mixture was allowed to stir at room temperature for 20 h. The solvents were removed by warming under reduced pressure to give a small amount of an oil which was cooled and treated with 10% HCl. The crude product separated as a white solid, 122 mg (68%), mp 135-145° C. The crystals were dissolved in H2O and the solution was extracted with Et2O. The H2O portion was separated, the H2O was evaporated, and the crystals reformed; recrystallization from acetone gave 66 mg (37%) of colorless crystals, mp 167-169° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[O:17])[NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)[CH3:2].[Br:19]Br>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([Br:19])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:17])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)Nc1cccc2cccnc12
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of the product from Example 81 (20 g, 82 mmol) in 200 mL acetic acid was treated with a solution of bromine (15.7 g, 0.198 mol) in 50 mL of acetic acid and stirred at room temperature for 1 hour. The solid was collected by filtration and washed with ether to give the title compound (23.5 g, 69% yield).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]/[C:10]/1=[CH:34]\[C:35]1[O:39][CH:38]=[N:37][CH:36]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[O:39]1[C:35](/[CH:34]=[C:10]2\[CH2:11][N:12]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH:9]\2[OH:8])=[CH:36][N:37]=[CH:38]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cnco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cnco1
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.7 %

Procedure:
To a solution of (E)-4-(t-butyldimethylsilyloxy)-3-[(1,3-oxazol-5-yl)methylidene]-1-(triphenylmethyl)piperidine (499 mg) in tetrahydrofuran (8 ml) was added tetrabutylammonium fluoride (483 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (254 mg, yield: 65%) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH2:22][CH3:23])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
2,2-Diphenylacetic acid (50 g) was dissolved in ethanol (350 mL). Concentrated sulfuric acid (3 mL) was added, and the mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated and diluted with diethyl ether. The organic solvent solution was then extracted with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was then dried with magnesium sulfate, filtered, and concentrated to obtain the title compound. MS (DCI+) m/z 241 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][N:12]3[C:16](=[O:17])[CH2:15][CH2:14][C:13]3=[O:18])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][N:12]3[C:16](=[O:17])[CH2:15][CH2:14][C:13]3=[O:18])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(=O)N1Cc1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (459 mg, 1.72 mmol) (obtained as described in Reference Example 69(2)) in methylene chloride (50 ml) were added methanesulfonyl chloride (0.16 ml, 2.06 mmol) and triethylamine (0.29 ml, 2.06 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (515 mg, yield 87%) as a pale yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.C[N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=CC=1.P(Cl)(Cl)([Cl:23])=O>C1C=CC=CC=1>[Cl:23][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[C:10]([C:17]2[CH:20]=[N:13][CH:14]=[CH:19][CH:18]=2)[N:9]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1ccccc1
Solvent: c1ccccc1
Product: Clc1nc(-c2cccnc2)nc2ccccc12
Temperature: 25 °C

Procedure:
A solution of the quinazolinone compound (6.7 g, prepared in Reference example 7) and 5.7 mL of N,N-dimethylaniline in 200 mL of benzene was heated to reflux, under nitrogen atmosphere, for one-half hour with the removal of 15 mL of distillate. After cooling to room temperature, phosphorus oxychloride (4.5 g) was added and the resulting solution heated to reflux for six hours. After cooling to room temperature, the solution was washed with ice water and dilute sodium hydroxide solution. The organic extract was dried over sodium sulfate and concentrated under reduced pressure. The concentrate was triturated in ether and collected to give the title compound (3.0 g) having the following physical data.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:19])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:19][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1cc(O)c(-c2ccccn2)nc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ccccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 7 h
Yield: 20.7 %

Procedure:
Dimethyl sulfoxide (1.5 ml) was added to 5,6-dimethyl-[2,2′]-bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (101 mg), and cesium carbonate (147 mg), and the mixture was stirred at 130° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (12 mg, yield 20%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28](O)[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH3:29])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: CC(O)c1ccccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(C)(C)O2)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.28 mmol) and 1-pyridin-2-yl-ethanol (81a) (48 mg, 0.39 mmol) in 4 mL of THF was added PPh3 (110 mg, 0.42 mmol) at 0° C., followed by DIAD (0.082 mL, 0.42 mmol) drop-wise. The mixture was stirred at room temperature overnight, concentrated, and purified by reverse phase HPLC to give a white solid (30 mg, 27% yield). 1H NMR (400 MHz, CDCl3) δ 9.61 (br. s., 1 H) 8.79 (d, J=4.55 Hz, 1 H) 7.94-8.06 (m, 1 H) 7.69 (d, J=8.08 Hz, 1 H) 7.45-7.53 (m, 1 H) 7.27-7.31 (m, 1 H) 6.94-7.00 (m, 2 H) 6.81-6.86 (m, 1 H) 5.84 (q, J=6.40 Hz, 1 H) 3.80 (s, 3 H) 3.09 (s, 2 H) 1.70-1.77 (m, 3 H) 1.48 (d, J=4.80 Hz, 6 H); LCMS for C22H24N4O3 m/z 393.20 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:12]1[O:16][C:15](=[O:17])[C@H:14]([CH3:18])[CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:11][S:27]([CH3:26])(=[O:29])=[O:28])[C@@H:12]1[CH2:13][C@@H:14]([CH3:18])[C:15](=[O:17])[O:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A solution of 7.80 g of (3R,5S)-5-[(R)-2-benzyloxy-1-hydroxyethyl]-3-methyldihydrofuran-2-one obtained in Example (76c) (31.2 mmol) in methylene chloride (200 ml) was cooled in an ice bath. Then, 9.45 g of triethylamine (93.6 mmol) and 5.36 g of methanesulfonyl chloride (47.0 mmol) were added thereto, and the mixture was stirred at the same temperature for three hours. 500 ml of water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=4/1-1/1) to obtain 9.90 g of the title compound (yield: 97%).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([O:23]CC)=[O:22].CO.O>C1COCC1>[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
Lithium hydroxide (0.032 g, 1.344 mmol) was added to a solution of ethyl 3-chloro-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.059, 0.17 mmol) in THF:methanol:water/3:1:1 (3 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.054 g, ˜75% pure).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24].[NH4+:25].[OH-]>C1COCC1>[NH2:25][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24]
Reactant: [NH4+]
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCBr)c4ccccc43)c12
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCN)c4ccccc43)c12
Temperature: 65 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
1-(2-Bromo-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (55 mg, 0.14 mmol) is dissolved in THF (1.5 mL) and NH4OH (1.5 mL, 27% aqueous) is added into it at room temperature. The mixture is then stirred for 16 hr at 65° C. and another one week at room temperature. Then the solvents are removed under vacuum and the residue is washed with THF. The solid formed is filtered and rinsed with more THF to give 28 mg (61%) of 1-(2-Amino-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]2([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[O:14][C@H:13]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][O:11]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:15][CH:13]1[CH2:12][O:11][C:10]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:14]1)=[N+:34]=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](CCc3ccc(Cl)cc3)(Cn3ccnc3)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)O1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of QC-16 (201 mg, 0.42 mmol) in N,N-dimethylformamide (3 mL) was added sodium azide (546 mg, 8.40 mmol, 20 equiv). The mixture was heated at 110° C. with stirring for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, extracted with EtOAc (3×), and the combined organic extracts were washed sequentially with a saturated aqueous solution of Na2CO3, and H2O, and then dried (Na2SO4). The solution was concentrated and the golden oily residue purified by flash column chromatography on silica gel (EtOAc) to give the free base as an oil (Rf=0.29, EtOAc). High-vacuum drying left 121 mg (0.35 mmol, 83%) of QC-112 as a colorless oil: [α]D24=+6.6° (c=0.7, CDCl3); 1H NMR (400 MHz, CDCl3): δ 1.90-2.05 (m, 2H), 2.66-2.81 (m, 2H), 3.20 (dd, J=13.2, 5.2 Hz, 1H), 3.39 (dd, J=13.2, 4.0 Hz, 1H), 3.44-3.51 (m, 1H), 3.64 (t, J=8.0 Hz, 1H), 3.78 (dd, J=8.0, 6.4 Hz, 1H), 4.02 (s, 2H), 6.98 (br s, 1H), 7.05 (br s, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.49 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.0, 38.7, 51.8, 53.0, 67.9, 76.1, 109.9, 120.9, 128.8, 129.3, 129.8, 132.1, 138.7, 139.6; HRMS (EI) [M+H]+ Calcd. for C16H19ClN5O2: 348.1227. Found: 348.1234.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>C(Cl)Cl>[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COCCC(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCC(=O)N1CCC(N)CC1
Reaction time: 4.5 h
Yield: 36.2 %

Procedure:
3-Methoxypropanoic acid (225 μL, 2.40 mmol) was added to a solution of 4-(N-Boc-amino)-piperidine (400 mg, 2.00 mmol) in methylene chloride (25 mL) at room temperature. N,N-diisopropylethylamine (1.30 mL, 7.49 mmol) and propylphosphonic anhydride (1.78 mL, 50 wt. % in ethyl acetate, 3.00 mmol) was added, and the solution was stirred for 4.5 h. The reaction mixture was concentrated and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic portion was washed with 0.2M HCl (2 mL), sat. Sodium bicarbonate (5 mL) and brine (5 mL). The solution was then dried over sodium sulfate and concentrated to a white solid. This solid was taken up in methylene chloride (6 mL), and trifluoroacetic acid (3 mL) was added at room temperature. After 1 h the solution was concentrated. The resulting solid was dissolved in methylene chloride (2 mL) and 1M sodium hydroxide (1 mL). This mixture was extracted with methylene chloride (4×2 mL) and ethyl acetate (4×2 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give 135 mg of the title compound, 1-(4-aminopiperidin-1-yl)-3-methoxypropan-1-one (36% over two steps). 1H NMR (300 MHz, CD3OD) δ 4.51-4.41 (m, 1H), 4.03-3.93 (m, 1H), 3.64 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 3.17-3.05 (m, 1H), 2.96-2.83 (m, 1H), 2.75-2.55 (m, 3H), 1.99-1.80 (m, 2H), 1.40-1.14 (m, 2H).