Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH:12]=[N:13][OH:14].[CH2:15]([C:17](=[CH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:16].Cl[O-].[Na+].O>ClCCl.C(N(CC)CC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]1[CH2:23][C:17]([CH2:15][CH3:16])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][N:13]=1
Reactant: Cc1c(C=NO)n(C)c2ccccc12
Reactant: C=C(CC)C(=O)OCC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1(CC)CC(c2c(C)c3ccccc3n2C)=NO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
1,3-Dimethyl-1H-indol-2-aldehyde oxime derivative (356 mg, 2.07 mmol) was dissolved in dichloromethane (20 ml), and the mixture was kept at 0□. Ethyl 2-ethylacrylate (345 mg, 1.3 Eq) and triethylamine (6 drops) were dissolved in dichloromethane (5 ml), thus obtained solution was slowly added to the above, and sodium hypochlorite solution (5.5 ml) was further added. The reaction solution was warmed to room temperature and stirred for 4 hours. Water (20 ml) was added, and the mixture was extracted with dichloromethane (40 ml×2), washed with aqueous sodium chloride solution (20 ml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (15% ethyl acetate-hexane) to give the title compound (230 mg, Yield 35%).
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[S:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]=2[CH3:22])O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:17]1[S:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]=1[CH3:22]
Reactant: Cc1c(C(O)c2cccc(Br)c2)sc2ccccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cc2cccc(Br)c2)sc2ccccc12
Temperature: -10 °C

Procedure:
A solution of 1.56 M hexane (23.7 ml) of n-butyl lithium was added dropwise to a solution of 3-methyl-1-benzothiophene (5.0 g) in tetrahydrofuran (50 ml) at −78° C. under an argon atmosphere, and the mixture was stirred for half an hour at the same temperature. Then, a solution of 3-bromobenzaldehyde (6.05 g) in tetrahydrofuran (6 ml) was added dropwise to the mixture, and the mixture was stirred for half an hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous solution of saturated ammonium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl)(3-methyl-1-benzothiene-2-yl) methanol (10.0 g) as achromatic oily matter. Borontrifluoride diethyl ether complex (4.42 ml) and triethylsilane (9.58 ml) were added to a solution of (3-bromophenyl)(3-methyl-1-benzothiene-2-yl) methanol in dichloromethane (100 ml) at −30° C., and the mixture was stirred for half an hours. After the reaction mixture was heated to −10° C. and stirred for 10 minutes, aqueous solution of saturated sodium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-(3-bromobenzyl)-3-methyl-1-benzothiophene (6.68 g).
Reaction SMILES: [C:1]([N:4]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[CH:21]=[CH:22][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:1]([N:4]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:25]([CH3:31])=[CH:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH:21]=[CH:22][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cccc3C)c2)C(C)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a solution of methyl 3-(4-{acetyl[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.644 g, 1.55 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (0.430 g, yield 69%) as colorless prism crystals.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:20])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)[CH2:4][CH2:5][CH2:6][NH:7]C=O.[Cl-].C[N+](C)([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)CCCN.[NH2:39]C1C=C(C)C=CC=1OC>>[Cl-:1].[CH3:20][N+:3]([CH3:2])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:19]=[N:39][C:34]2[CH:33]=[C:32]([O:35][CH3:36])[C:31]([NH2:37])=[CH:30][C:29]=2[CH3:28])[CH:12]=1)[CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COc1ccc(C[N+](C)(C)CCCNC=O)cc1N
Reactant: COc1ccc(C)cc1N
Reactant: COc1ccc(C[N+](C)(C)CCCN)cc1N
Agent: [Cl-]
Product: COc1cc(N=Nc2cc(C[N+](C)(C)CCCN)ccc2OC)c(C)cc1N

Procedure:
Proceeding in a manner similar to that described above in Example 3, N,N-dimethyl-N-(3-amino-4-methoxybenzyl)-N-3-formamidopropylammonium chloride was hydrolyzed and the resulting N,N-dimethyl-N-(3-amino-4-methoxybenzyl)-N-3-aminopropylammonium chloride was diazotized and coupled with 2-amino-4-methylanisole to obtain N,N-dimethyl-N-[3-(4-amino-5-methoxy-2-methylphenyl)azo-4-methoxybenzyl]-N-3-aminopropylammonium chloride in aqueous solution. This product was diazotized in situ and coupled with acetoacetanilide to obtain the brown, water-soluble dyestuff having the formula ##STR100##
Reaction SMILES: C([O:3][C:4](=[O:7])[CH2:5][SH:6])C.[H-].[Na+].[H][H].Cl[C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.BrC1OC(C2C=CC=CC=2)=C(C2C=CC=CC=2)N=1>CN(C=O)C>[C:18]1([C:16]2[N:17]=[C:13]([CH:5]([SH:6])[C:4]([OH:7])=[O:3])[O:14][C:15]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CS
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: [H][H]
Agent: Brc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(S)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 5 h

Procedure:
12 g. of thioglycolic acid ethyl ester is added to a suspension of 2.4 g. of NaH in 200 ml. of freshly distilled DMF, and the mixture is agitated until the evolution of hydrogen has ceased. Thereafter, 25.5 g. of 2-chloro-4,5-diphenyl-oxazole or 30 g. of 2-bromo-4,5-diphenyl-oxazole is added to the mixture. The latter is agitated for 5 hours at 80° and worked up as usual, thus obtaining the ethyl ester of 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid, b.p. 207°-210°/0.1 mm.; m.p. 54°-56° (hexane).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=[O:28])[O:23]C(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:22]([OH:28])=[O:23].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)cn1
Product: O=CO
Reaction time: 1.5 h
Yield: 83 %

Procedure:
A solution of 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(2-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 60) (126 mg, 0.250 mmol) in dichloromethane (DCM) (2 mL) was treated at room temperature with trifluoroacetic acid (TFA) (500 μl, 6.49 mmol) and the resulting mixture was stirred at this temperature for 1.5 h then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by MDAP (modifier: formic acid). The desired fractions were combined and the solvent was removed under vacuo to give (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-2-pyridinyl-1,2,3,4-tetrahydro-4-quinolinamine formate (93 mg, 0.206 mmol, 83% yield) as a cream solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 47.4 %

Procedure:
A solution of 4-pyridyl piperazine (9.78 g), 4-fluorobenzonitrile(7.26 g) and powdered potassium carbonate(10 g) was stirred and heated in DMSO(100 ml) at 100° C. for 18 hours. The solution was poured into water (500 ml) to give a precipitate which was filtered and washed with water. The crude solid was dried in a vacuum oven for 18 hours. The residue was dissolved in dichloromethane and purified by flash chromatography on alumina (ICN Alumina N 32-63) using an increasing concentration of ethyl acetate in dichloromethane (up to 100% ethyl acetate) as eluant to give a solid which was recrystallised from ethyl acetate/isohexane to give 1-(4-cyanophenyl)-4-(4-pyridyl)piperazine (7.5 g) as a solid. m.p. 157-158° C.; microanalysis. found: C, 72.7; H, 6.1; N, 21.0%; C16H16N4 requires: C, 72.7; H, 6.1; N, 21.2%. NMR (dmso-d6):3.45-3.55(8H,bs),6.8-6.9(2H,d);7.0-7.1(2H,d); 7.55-7.65(2H,d);8.1-8.2(2H,d); MS m/Z 265 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCOCC1>O>[CH3:1][N:2]1[CH2:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1
Reactant: CN1Cc2c([nH]c3ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CN1Cc2[nH]c3ccccc3c2C1
Reaction time: 5 h

Procedure:
2-Methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one, 1.7 g., and LiAlH4, 2.3 g., are heated in refluxing dioxane, 300 ml., for five hours. The mixture is cooled and carefully hydrolyzed with excess water. Solids are filtered away and washed with dioxane, after which the filtrate is concentrated to dryness giving 1.4 g. of a crude brown product, m.p. 110°-120° C. Since the crude product is sensitive to air oxidation (darkens rapidly on standing), it is not further purified before methiodide preparation.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([Si:17]([C:20]1C=CC=CC=1)(C)[CH3:18])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[F:26][B-](F)(F)F.[H+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([Si:17]([F:26])([CH3:20])[CH3:18])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(c1ccccc1)C1CC(=O)c2c(nc3ccccc3c2N)C1
Agent: O=C([O-])[O-]
Agent: [H+]
Agent: [K+]
Solvent: ClCCl
Product: C[Si](C)(F)C1CC(=O)c2c(nc3ccccc3c2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 9-amino-3,4-dihydro-3-(phenyldimethylsilyl)acridin-1(2H)-one (5.0 g), dichloromethane (80 ml) and tetrafluoroboric acid etherate (25 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into saturated potassium carbonate solution and extracted with ethyl acetate. The suspension was filtered through celite and the organic phase was separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to give 3.79 g (90%) of product, which is used in Example 8 without purification and without delay.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]=[C:11]([NH2:18])[CH:10]=1.[Cl:19][CH2:20][C:21](=O)[CH2:22]Cl>C(O)C>[Cl:19][CH2:20][C:21]1[N:18]=[C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]2[CH:22]=1
Reactant: O=C(CCl)CCl
Reactant: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Solvent: CCO
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CCl)cn12

Procedure:
3 g (9.99 mmol) of 6-(2,4-dichlorophenyl)-2-(ethylsulphanyl)pyrimidine-4-amine (Example 3A) are added to a solution of 1.395 g (10.99 mmol) of 1,3-dichloropropan-2-one in 33 ml of dry ethanol, and the mixture is then heated under reflux conditions for 20 h. The solvent is substantially removed and the residue is purified by preparative HPLC. 1.5 g (37% of theory) of the product are obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]([O:11][CH3:12])=O)[CH2:4]1.[CH3:13][O:14]CCl.C(NC(C)C)(C)C.[NH4+].[Cl-]>ClCCl.O>[CH3:13][O:14][CH2:12][O:11][CH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: COCCl
Reactant: COC(=O)[C@H]1CCC[C@@H](CO)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCOC[C@@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
1.70 g of methyl cis-3-hydroxymethylcyclohexanecarboxylate are dissolved in 20 ml of dichloromethane, 1.60 g of methoxymethyl chloride and 2.60 g of diisopropylamine are added and the mixture is stirred at room temperature for 15 h. 50 ml of saturated NH4Cl solution and 50 ml of water are added to the solution, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate and concentrated. This gives 2.0 g of methyl cis-3-methoxymethoxymethylcyclohexanecarboxylate as a yellow oil. This is dissolved in 50 ml of diethyl ether, 350 mg of LiAlH4 are added and the mixture is stirred at room temperature. After 2 h at 0° C., 5 ml of ethyl acetate, 40 ml of methyl tert-butyl ether and 3 g of MgSO4 are added. 15 ml of 10N KOH are then added dropwise. The suspension is stirred for 3 h and filtered through Celite and the filtrate is concentrated, which gives 1.65 g of (cis-3-methoxymethoxymethylcyclohexyl)methanol as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:51]=[C:52]([CH:58]=[CH:59][CH:60]=1)[O:53][CH2:54][CH2:55]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:55][CH2:54][O:53][C:52]2[CH:58]=[CH:59][CH:60]=[C:50]([F:49])[CH:51]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCCOc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 43.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (124 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-fluorophenoxy)-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 46%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccc2ccccc2n1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc3ccccc3n2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Quinoline-2-carboxylic acid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10](Cl)=[O:11].[CH3:18][C:19]1[NH:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>ClCCl.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:10]([C:21]2[NH:20][C:19]([CH3:18])=[CH:23][C:22]=2[CH3:24])=[O:11])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: Cc1c[nH]c(C)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2[nH]c(C)cc2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Aluminum chloride (1.7 g, 12.75 mmol) in dichloromethane (100 mL) was added to the 3,4-dimethoxybenzoyl chloride (2.0 g, 10 mmol) at room temperature, followed by a solution of 2,4-dimethylpyrrole (1.5 g, 15.8 mmol) in dichloromethane (5 mL). The mixture was then stirred at room temperature for overnight. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was chromatographed eluting with ethyl acetate and hexane to give 1 g (39%) of (3,4-dimethoxy-phenyl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
43 mL benzyloxycarbonyl chloride in 135 mL dichlormethane was added to 17.6 g 1-benzyl-2,5-dihydro-1H-pyrrole in 135 mL dichlormethane at 0° C. in 60 min. The mixture was stirred 3 h at RT and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried and evaporated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate: 5/1) to give 19.7 g of the desired product.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10][C:9]=3[C:8]=2[C:27]#[N:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:34]CC1>>[O:34]=[C:10]1[C:9]2[C:8]([C:27]#[N:28])=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3=O)cc1
Temperature: 2.5 °C

Procedure:
A solution of 2-(piperidin-1-yl)-4-p-tolyl-9H-fluorene-1-carbonitrile (364 mg) in THF was added sodium hydride (40 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; mp 230-232° C.; ESMS 379 (M++1); IR (KBr) 1703 cm−1 (CO), 2219 (CN); 1H NMR (300 MHz, CDCl3) δ 1.60-1.64 (m, 2H, CH2), 1.79-1.84 (m, 4H, 2CH2), 2.48 (s, 3H, CH3), 3.19-3.24 (m, 4H, 2CH2), 6.65-6.70 (m, 1H, ArH), 6.87 (s, 1H, ArH), 7.14-7.19 (m, 2H, ArH), 7.28-7.33 (m, 4H, ArH), 7.63-7.67 (m, 1H, ArH). HRMS calcd. for C26H22N2O 378.1732 found 378.1728.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][C:26]1([CH3:38])[CH2:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35](Cl)=[O:36])[C:28]=2[O:27]1.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:35]([C:34]2[C:28]3[O:27][C:26]([CH3:38])([CH3:25])[CH2:30][C:29]=3[CH:31]=[CH:32][CH:33]=2)=[O:36])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)Cc2cccc(C(=O)Cl)c2O1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OC(C)(C)C3)Cc2ccccc2C1
Yield: 77.9 %

Procedure:
A test tube (25×150 mm) containing a stirring bar and 2-amino-indane-2-carboxylic acid ethyl ester (0.5 g, 2.436 mmol) is charged with dry DCM (3 mL). Stirring is initiated. After dissolution, the DIPEA (1.50 mL, 8.6 mmol) and 4-dimethylaminopyridine (2 mg, 17 μmol) are added. A solution of 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride (0.73 g, 3.47 mmol) in dry DCM (4 mL) is added to the reaction tube. After stirring for 18 h, tlc analysis (silica, 10% CH3OH in DCM) indicates complete consumption of the starting amine. The reaction mixture is diluted with DCM (10 mL) and washed with 5% aqueous HCl (2×5 mL) and brine (5 mL), dried over MgSO4 filtered and evaporated by pumping to constant weight gives 0.72 g of a light brown gum. This material is purified by chromatography (silica, 0% to 20% EtOAc in DCM) on the ISCO Companion using a 40 g cartridge (silica). Fractions 17-22 are combined, evaporated and pumped to a constant weight to provide 0.62 g (67%) of a glassy solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Br:9]N1C(=O)CCC1=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:9]/[CH:6]=[C:5]1\[CH2:4][CH2:3][CH2:2][C:1](=[O:8])[O:7]\1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#CCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCC/C(=C\Br)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
This compound was prepared according to the procedure set forth in Kraft et al, J. Am. Chem. Soc., 103, 5459-5466 (1981). A mixture of the 5-hexynoic acid of Part A (1.1 g, 9.8 mmol), KHCO3 (1.5 g, 15 mmol), N-bromosuccinimide (2.6 g, 15 mmol) and 0.4M aqueous tetrabutylammonium hydroxide (2 mL, 0.8 mmol) in CH2Cl2 (90 mL) was stirred at room temperature for 3.5 h. The mixture was washed with 5% Na2S2O3 and saturated NaCl. The organic phase was dried (MgSO4) and the solvent was removed in vacuo to give a residue weighing 1.8 g. The residue was purified by flash chromatography (silica gel, Aldrich catalog #22,719-6, 230-400 mesh). The column was eluted with CH2Cl2 and fractions having a spot with Rf =0.32 (CH2Cl2, Bakerflex IBF-2 silica TLC plates) were combined. The solvent was removed in vacuo to give 1.0 g (58% yield) of product as a colorless oil.