Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]1[O:31][N:32]=[C:33]2[CH:38]=[C:37]([C:39](Cl)=[O:40])[CH:36]=[CH:35][C:34]=12>C(Cl)Cl>[N:30]1[O:31][N:32]=[C:33]2[CH:38]=[C:37]([C:39]([N:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[C@H:9]3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=3)=[O:40])[CH:36]=[CH:35][C:34]=12
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc2nonc2c1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (50 mg, 180 μmol) and diea (31 μL, 180 μmol) in DCM (1 mL) was added benzo[c][1,2,5]oxadiazole-5-carbonyl chloride (43 mg, 234 μmol). The resulting mixture was then stirred at RT for overnight. Then, the mixture was concentrated and the residue was dissolved in MeOH (1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was then dissolved in MeOH (1 mL). The solution was then washed through PL-HCO3 resin and the resin was then washed with MeOH (1 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a white solid. MS (ESI, positive ion) m/z: 424 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=4)[N:22]([CH3:35])[C:21]=3[CH:36]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S:37]1[CH2:41][C:40](=[O:42])[NH:39][C:38]1=[O:43].N1CCCCC1>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=[C:41]5[S:37][C:38](=[O:43])[NH:39][C:40]5=[O:42])=[CH:29][CH:28]=4)[N:22]([CH3:35])[C:21]=3[CH:36]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1c(COc2ccc(C=O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c(COc2ccc(C=C3SC(=O)NC3=O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Yield: 86 %

Procedure:
A mixture of 4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzaldehyde (502 mg), thiazolidine-2,4-dione (234 mg), piperidine (170 mg ) and ethanol (60 ml) was heated at reflux for 19 hours. The reaction mixture was evaporated to dryness and to the residue was added water and insoluble product was isolated by filtration and washed with water and diisopropyl ether to give the title compound (517 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: C#Cc1cccnc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3cccnc3)c21

Procedure:
Using Method D above, 3-ethynyl pyridine (60.6 mg, 0.59 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (75 mg, 0.23 mmol) (Starting Material 1) using (Ph3P)4Pd (13.3 mg) (Aldrich) and CuI (3 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 100° C. for 18 h, to yield (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 52 mg, 66%).
Reaction SMILES: C(S[C:9](=[O:46])[CH:10]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:11]([OH:38])[CH:12]=[CH:13][CH:14]([OH:37])[CH2:15][CH:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:19]=1)C1C=CC=CC=1.[Li+].[OH-:48].OO.Cl>C1COCC1>[CH2:39]([CH:10]([CH:11]([OH:38])[CH:12]=[CH:13][CH:14]([OH:37])[CH2:15][CH:16]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:20][CH:19]=1)[C:9]([OH:46])=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)CC(O)C=CC(O)C(Cc1ccccc1)C(=O)SCc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)CC(O)C=CC(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16 stereoisomers of 50 were synthesized by the following procedure: To a solution of 49 (1.0 equiv) in THF (60 mL/mmol) was added 0.2 N LiOH (aq) (2.0 equiv) and 30% H2O2 (aq) (equal volume to LiOH (aq)). The solution was stirred for 3 h at room temperature, then acidified with 1 N HCl (aq) to pH=1 and extracted with CH2Cl2. The organic solution was dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography to afford 50 in 64–84% yield on 0.020 to 0.030 mmol scale.
Reaction SMILES: [S:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[C:2]#N.[BH4-].[Na+].Cl[CH2:17][Si:18](C)([CH3:20])[CH3:19]>CC#N>[CH3:17][Si:18]([CH2:2][S:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)([CH3:20])[CH3:19]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(C)CSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1.95 g of 4-thiocyanato-2-nitroaniline in 40 ml of CH3CN blanketed by nitrogen there is added in portions 0.5 g of NaBH4. The stirring is continued for one hour. At this time the color of the reaction mixture changes from yellow to dark purple. 1.4 ml of chloromethyltrimethylsilane is added with a syringe and the mixture is refluxed overnight. The solvent is evaporated and the residue is exhaustively extracted with petroleum ether. Evaporation of the solvent yields 1.9 g of the title A compound as a red solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=1
Reactant: Fc1ccccc1CNc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccccc2F)nc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 93.7 %

Procedure:
In a round bottom flask, (5-bromo-pyridin-2-yl)-(2-fluoro-benzyl)-amine (40, 3.90 g, 13.9 mmol) was combined with 60.0 mL of tetrahydrofuran at −78° C. under nitrogen and tert-butyllithium (5.57 mL, 2.50 M in hexane) was added over 5 minutes. After 30 minutes additional tert-butyllithium (17.1 mL, 1.7 M in hexane) was added over 5 minutes. After 25 minutes, N,N-dimethylformamide (2.6 mL, 34 mmol) was added and the mixture was stirred for 70 minutes at −78° C., then allowed to warm up to room temperature for 1 hour. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was dried with sodium sulfate, filtered and filtrate concentrated under vacuum to provide the desired compound (41, 3.0 g), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([C:24](OCC)=[O:25])[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].B.CSC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][OH:25])[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:29]([F:30])([F:32])[F:31]
Reactant: CCOC(=O)c1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of ethyl 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-4-oxo-1,4-dihydro-5-pyrimidinecarboxylate (2.36 g, 4.87 mmol) in dry THF (20 mL) was added borane-methyl sulfide complex (2.0M in toluene) (7.30 mL, 14.60 mmol) dropwise under argon at 0° C. The mixture was stirred at 0° C. for 0.5 h, and warmed to room temperature for 1 h, then quenched with acetone. Purification via reverse phase flash chromatography then afforded the title compound (921 mg, 2.080 mmol, 42.7% yield). LCMS: rt=3.28 min, [M+H]=443
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[O:17]([CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: Nc1nc2ccccc2c2c1ncn2CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1ncn2CCOc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (25 mg, 0.108 mmol) and N,N-dimethylformamide (1 mL) were combined. Phenol (12 mg, 0.130 mmol) and triphenylphosphine (34 mg, 0.130 mmol) were added and the resulting slurry was sonicated for about 1 minute. Diethyl azodicarboxylate (23 mg, 0.130 mmol) was added and the reaction mixture was shaken at ambient temperature for 24 hours. Analysis by LC-MS showed that a major amount of starting material remained. An additional equivalent each of phenol, triphenylphosphine and diethyl azodicarboxylate were added. The reaction mixture was sonicated for 30 minutes. After 1 hour analysis by LC-MS showed product. The solvent was removed and the residue was purified by semi-preparative HPLC using Method A: Mass Measurement: TM=304, NM[M+H]+1=305.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([OH:23])=O.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[NH:33][NH2:34].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([NH:34][NH:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)O)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
3.1 500 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoic acid, 144 mg of tert-butyl carbazate and 250 mg of DAPECl are dissolved in 1 ml of DMF and stirred at RT for 16 h. The reaction mixture is poured into water, the precipitate formed is filtered off and dried. Purification by column chromatography (ethyl acetate/methanol) gives 120 mg (19%) of tert-butyl N′-{2-[3-(2,6-dichlorophenylamino)-imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=574.2; Rf (polar method): 1.80 min.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:28][C:22]2=[C:23]([CH3:27])[S:24][C:25]([CH3:26])=[C:21]2[CH2:20]1)=[O:18])[CH3:15].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>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:20][C:21]2=[C:25]([CH3:26])[S:24][C:23]([CH3:27])=[C:22]2[CH2:28]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (500 mg, 2.84 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (816 mg, 3.41 mmol), HATU (1.62 g, 4.26 mmol) in anhydrous DMF (15 mL) is added DIPEA (704 μL, 4.26 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (74) as white solid (1.10 g, 97%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[F:12][C:13]([C:16]([CH2:18][CH3:19])=[O:17])([F:15])[F:14].[Cl-].[NH4+]>C1COCC1>[F:12][C:13]([F:15])([F:14])[C:16]([OH:17])([CH2:18][CH3:19])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(C#C[Si](C)(C)C)C(F)(F)F
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of trimethylsilylacetylene (6.0 g, 61.1 mmol) in THF (80 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (38 mL, 61.1 mmol) was added dropwise. The solution was then stirred 1 hour, before a solution trifluoromethylethylketone (10 g, 79.4 mmol) in 25 mL of THF was added slowly. The reaction was stirred at −78° C. for 4 hours. The reaction was then poured into a saturated ammonium chloride solution and the aqueous layer was extracted (4×) with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 5.83 (s, 1H), 1.80 (q, 2H), 1.14 (t, 3H), 0.18 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][C:47]=2[CH3:49])[NH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:52]([C:54]1[CH:61]=[CH:60][C:57]([CH2:58]Br)=[CH:56][CH:55]=1)[CH3:53].Cl>CN(C)C=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][C:47]=2[CH3:49])[N:42]([CH2:58][C:57]2[CH:60]=[CH:61][C:54]([CH2:52][CH3:53])=[CH:55][CH:56]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2[nH]cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c12
Reactant: CCc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(C)cccc32)cc1
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-methyl-1H-indole (150 mg) in N,N-dimethylformamide (2 mL) was added 55% sodium hydride (12 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-ethylbenzyl bromide (55 mg) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with a mixed solvent of n-hexane and diethyl ether (10/1), and dried under reduced pressure to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-ethyl-benzyl)-4-methyl-1H-indole (139 mg). This material (125 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetra hydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give the title compound (58 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:29]([CH2:28][CH2:27][O:26][CH3:25])[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COCCC(=O)Cl
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Product: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(6-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152–156. 3-Methoxypropionyl chloride was used in Part C. The crude product obtained in Part D was recrystallized from acetonitrile. The crystals were washed with cold acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8]1)[CH3:4].C(N(CC)CC)C.[C:30](OCC)(=[O:36])[C:31](OCC)=[O:32]>C(Cl)(Cl)Cl>[CH2:3]([N:5]1[C:31](=[O:32])[C:30](=[O:36])[N:8]2[CH2:9][C@@H:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[C:16]([C@@H:7]2[CH2:6]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4]
Reactant: CCNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Yield: 60.8 %

Procedure:
To a stirred solution of cis-1,2,3,4-tetrahydro-1-(ethylamino)methyl-4-phenyl-isoquinoline dihydrochloride (19.5 g, 0.057 m) in chloroform (250 ml) maintained under nitrogen at ambient temperature was added triethylamine (26.0 g, 0.25 m) and then in one portion diethyl oxalate (36.4 g, 0.23 m) and the mixture heated to reflux for 5 hours. The mixture was cooled and washed with 10% HCl (3×150 ml) and water (200 ml) and dried over MgSO4. The solvent was evaporated to a yellow oil, which was dissolved in 200 ml ethanol, decolorized with Norite. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 11.2 g of cis-1,3,4,6,7,11b-hexahydro-2-ethyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH:15]1([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (5 g, 24.97 mmol) in DCE (70 ml) at 20 to 25° C. was added cyclobutanone (1.75 g, 24.97 mmol) followed by acetic acid (1.5 g, 24.97 mmol) dropwise. The resulting mixture was stirred at 20 to 25° C. for ca. 2 h. Sodium triacetoxyborohydride (7.94 g, 37.46 mmol) was added in 9 portions, keeping the temperature in the range of 20 to 25° C. The resulting suspension was stirred at 20 to 25° C. overnight. Saturated NaHCO3 (80 ml) was added in four portions and the biphasic mixture stirred at 20 to 25° C. for ca. ½ h. The organic layer was separated, washed with water (20 ml) and the aqueous phase back extracted at pH 9 with DCM (20 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound as yellow oil (6.1 g, 96%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[C:10]([I:15])[C:9]=1[OH:16].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[I:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[C:10]([I:15])[C:9]=1[O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1c(I)cc(I)cc1I
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(I)c(OC2CCCC2)c(I)c1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 107.9 %

Procedure:
Milled, anhydrous potassium carbonate (14.2 g, 103 mmol, 1.2 eq) was added in portions to a stirred solution of 2,4,6-triiodophenol (40.5 g, 85.8 mmol) in 50 ml of dry (4A sieves) dimethylformamide at room temperature. After stirring for 20 minutes, cyclopentyl bromide (12 ml, 112 mmol, 1.3 eq) in dimethylformamide (20 ml) was added and the viscous mixture was gradually heated to 130° C. under argon for approximately 45 minutes. After cooling, the mixture was filtered and the collected solid was washed with chloroform. The filtrate was concentrated in vacuo to give 50 g of an amber oil The crude oily product was partitioned between ethyl acetate (300 ml) and water (500 ml); the organic layer was dried over magnesium sulfate and passed through a short pad of silica gel. The filtrate was treated with decolorizing carbon, filtered, and stripped to give an amber oil. The oil was dried at 60° C. under high vacuum to give 40.4 g (87%) of product.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][CH:8]([NH:18][CH2:19][CH:20]([OH:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27]CC1C=CC=CC=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1>[C].[Pd].C(O)C>[CH3:7][CH:8]([NH:18][CH2:19][CH:20]([OH:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COc1ccc(CC(C)NCC(O)c2ccccc2O)cc1
Yield: 81 %

Procedure:
A mixture of 1.5 g of α-[(α-methyl-4-methoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol oxalate [the diastereoisomer of M.p. 138°-139° C. (decomp.)], 0.3 g of 10% palladium-carbon and 30 ml of 90% aqueous ethanol is treated in the same manner as described in Example 1-(4-a). The crude product is recrystallized from ethanol in the presence of 300 mg of oxalic acid, and crystalline precipitates are collected by filtration. 0.76 g of α-[(α-methyl-4-methoxyphenethylamino)methyl]-2-hydroxybenzylalcohol 3/2 oxalate [the diastereoisomer of M.p. 175°-176° C. (decomp.)] is thereby obtained.