Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(CC=O)cc1
Yield: 1058.3 %

Procedure:
To a solution of ethyl 4-methylphenylacetate (0.89 g, 5.0 mmol) in dry methylene chloride (5 ml) cooled to −78° C. under nitrogen was added drop-wise 1.1 M di-isobutyl-aluminum hydride in toluene (4.5 ml, 5 mmol), keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched by drop-wise addition of methanol (5 ml), saturated potassium sodium tartrate solution (5 ml), and water (5 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (40 ml), and the filtrate layers were separated. The aqueous layer was extracted with ethyl acetate (40 ml). The combined ethyl acetate layers were washed with water (20 ml), and brine (20 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give 7.1 g of 4-methylphenylacetaldehyde as a volatile liquid: 1H NMR (CDCl3) 9.73 (1H, t, J 2.5 Hz), 7.17 (2H, m), 7.12 (2H, m), 3.64 (2H, d, J 2.5 Hz), 2.35 (3H, s). To a stirred mixture of benzyl (trans-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)carbamate (524 mg, 1.5 mmol), triethylsilane (0.36 ml, 260 mg, 2.25 mmol), and bismuth tribromide (45 mg, 0.10 mmol), in anhydrous acetonitrile (7.5 ml), was added the freshly prepared 4-methylphenylacetaldehyde (460 mg, approx. 2.2 mmol) slowly, keeping the temperature at or below 25° C. After stirring for 4 h, the reaction was quenched with half-saturated sodium bicarbonate (30 ml) and ethyl acetate (25 ml). The mixture was filtered through filter aid, the pad was washed with ethyl acetate (3×8 ml), and the filtrate layers were separated. The organic layer was washed with one-fifth saturated brine (8 ml) and water (8 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a heterogeneous oil (1.19 g). The oil was chromatographed on silica gel, eluting with ethyl acetate:hexane (5:95 increasing to 25:75) to give a white solid. The solid was triturated with ethyl acetate:hexane (20:80), filtered off and dried to give benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 55%) as a white solid. A second crop was obtained from the mother liquor (34 mg, 6%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:23][CH2:22]2)[N:3]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N3CCCC3)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (64 mg, 0.16 mmol, Example 120) and sodium carbonate (0.49 mmol, 52 mg) in ethanol (3 mL), 1,4-dibromobutane (22 uL, 0.16 mmol, Aldrich) was added and the mixture was stirred at reflux for 3 days. The solvent was removed under reduced pressure and the residue was purified by reversed phase HPLC to give a white solid. 30 mg, 43%. MS (ES) MH+=432.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)#[N:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: N#Cc1ccccc1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1ccccc1C=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 2-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (22.2 mg, yield: 94%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:31]1[N:32]=[N:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1>C(#N)C>[C:37]([C:34]1[N:33]=[N:32][C:31]([N:12]2[CH2:11][CH2:10][N:9]([C:8]3[CH:7]=[CH:6][C:5]([N:15]4[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]4=[O:22])=[CH:4][C:3]=3[F:2])[CH2:14][CH2:13]2)=[CH:36][CH:35]=1)#[N:38]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: N#Cc1ccc(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nn1
Yield: 79.1 %

Procedure:
3-(3-Fluoro4-(piperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one hydrochloride (6.63 g, 20 mmol) was suspended by stirring in acetonitrile (200 ml) under nitrogen, and triethylamine (4.44 g, 44 mmol) added. The mixture was stirred for 10 minutes 3-chloro-6-cyanopyridazine (2.79 g, 20 mmol) added, and the mixture heated under reflux for 18 hours. After cooling, solid was filtered, washed with water (3×150 ml) and diethyl ether (2×150 ml) to give the title product (6.3 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C@H:28]1[CH2:30][C@H:29]1C(=C)C(OC)=O)#[N:8].[O:37]1CCC[CH2:38]1>>[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C@H:28]1[CH2:30][C@H:29]1[CH2:38][OH:37])#[N:8]
Reactant: C=C(C(=O)OC)[C@@H]1C[C@@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CO)c3cc(C#N)ccc32)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
Powdered lithium aluminum hydride (120 mg, 3.16 mmol) was carefully added to a stirred solution of methyl [cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-acrylate (185 mg, 0.47 mmol) in anhydrous tetrahydrofuran (10 ml) at −30° C. The resulting mixture was stirred at −20° C. for 1.5 h. The reaction was quenched with ethyl acetate (5 ml) and allowed to warmed to room temperature. After 10 min, water (120 μL) was added and after 5 min followed by a solution of aqueous sodium hydroxide (1N, 360 μL). After a further 5 min water (120 ml) was added and the solution was stirred 20 min. The aluminum salts were removed by vacuum filtration. The salts were rinsed with ethyl acetate (100 ml) and the combined filtrates were concentrated in vacuo. The crude material was purified by silica gel column chromatography with 45% ethyl acetate in hexanes to afford 131 mg (76% yield) of cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanemethanol as a white solid: 1H NMR (400 MHz, CDCl3): δ 8.04 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=1.0 Hz), 7.74 (2H, d, J=6.8 Hz), 7.57 (1H, dd, J=8.6, 1.6 Hz), 7.44 (1H, d, J=1.3 Hz), 7.26 (2H, d, J=8.2 Hz), 3.50 (1H, m), 3.16 (1H, m), 2.36 (3H, s), 2.05 (1H, m), 1.60 (1H, m), 1.19 (1H, m), 0.99 (1H, t, J=5.5 Hz), 0.72 (1H, q, J=5.6 Hz); MS m/e 349 (M−OH)−.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[F:8][C:7]1[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[N:5][CH:4]=[N:3][C:2]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCC#CCOc1ncnc(F)c1F
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CCC#CCOc1ncnc(N2CCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
0.1 g of 4,5-difluoro-6-(2-pentynyloxy)pyrimidine and 0.04 g of pyrrolidine were added to 0.2 ml of toluene, then the reaction mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.11 g of 5-fluoro-4-(2-pentynyloxy)-6-pyrrolidinopyrimidine (referred as the present compound (5) hereinafter).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)#[N:2]
Reactant: CCOC(=O)C1CC(CC#N)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC(CC#N)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 19.9 g (67.2 mmol) of ethyl 4-cyanomethyl-N-t-butoxycarbonyl-2-piperidinecarboxylate (prepared in Example 3F) in 100 ml of dichloromethane was added 50 ml of trifluoroacetic acid (CO2 evolution). The mixture was stirred for 3 hr at room temperature and then was concentrated under vacuum. To the residue was added 100 ml of dichloromethane, and the solution was again concentrated under vacuum. The residue was dissolved in 200 ml of dichloromethane, 200 ml of saturated aqueous sodium bicarbonate was added, and the mixture was stirred for 15 minutes at room temperature. The organic layer was separated and washed with 100 ml of saturated aqueous sodium bicarbonate, and the combined aqueous washes were extracted twice with 100 ml each of dichloromethane and once with 50 ml of diethyl ether. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 12.7 g (96%) of ethyl 4-cyanomethyl-2-piperidinecarboxylate. GC analysis showed an 85:15 mixture of cis:trans isomers. To a solution of 11.6 g (59.1 mmol) of the product in 60 ml of dimethylsulfoxide was added 9.9 g (118.2 mmol) of sodium bicarbonate and 5.7 ml (7.9 g, 65.0 mmol) of allyl bromide. After 1 hr at room temperature, another 1.1 ml portion of allyl bromide was added, and after another 2 hours at room temperature, the mixture was poured into 100 ml of water and 100 ml of brine and was extracted 5 times with 50 ml each of dichloromethane and once with 50 ml of diethyl ether. The combined organics were washed with 100 ml of water, then dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to afford 8.6 g (62%) of ethyl cis-(±)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate and 1.2 g (9%) of ethyl trans-(±)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate, both of which were >99.9% one isomer by GC.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([CH3:22])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CI
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(C)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.15 g, 0.6 mmol) in DMF (2 mL) was added sodium hydride (60%, 28 mg, 0.7 mmol) at 0° C. and a solution of MeI (38 μL, 0.7 mmol). The mixture was stirred for 30 min at 0° C. Water was added to the reaction mixture, which was then extracted by DCM. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (5:95) and then further purified by preparative HPLC to afford the title compound (86 mg); 1H-NMR (CDCl3): δ 10.50 (1H, s), 8.26 (1H, m), 7.77 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.05 (2H, m), 5.35 (1H, s), 4.28 (2H, q), 3.54 (2H, t), 3.26 (3H, s), 3.14 (2H, m), 1.36 (3H, t). MS (ES): 271 (MH+).
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([NH:11][C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][C:21]2([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]2)[CH2:20][CH2:19]3)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O)Nc1cccc2ccccc12

Procedure:
A mixture of 1-naphthyl isocyanate (9.5 mg, 0.056 mmol), (±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione hydrochloride (described in Intermediate 2) (15 mg, 0.056 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.056 mmol) was stirred in THF (0.5 mL) at ambient temperature for 18 h. The crude mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=401 (M+1). HRMS: m/z=401.1638; calculated m/z=401.1608 for C23H21N4O3.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[CH2:7]([SH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C1CCN2C(=NCCC2)CC1>[CH2:7]([S:13][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCS
Reactant: C#CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCSC=CC(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (5°) solution of methyl propiolate (1.96 g, 23.0 mmol) is added 2 drops of DBU. 1-Hexanethiol (2.5 g, 21.0 mmol) is then added over a period of 3 minutes. The ice bath is removed, and the reaction mixture is stirred at RT for 1.5 hours. It is then purified by prep. TLC (preparative thin layer chromatography) to give methyl 3-hexylthio-2-propenoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: NCc1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-hydroxy-naphthalene-2-carboxylic acid (2.0 g, 10.6 mmol, Aldrich) and benzylamine (1.7 g, 15.9 mmol, Aldrich) in DMF (40 mL, Aldrich) at 0° C. was added EDC (3.05 g, 15.9 mmol, Aldrich). The reaction was warmed to RT and stirred for 16 h. The volatile portion was removed in vacuo. The residue was diluted with 100 mL of EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in EtOAc and passed through a short silica gel column and the filtrate was concentrated in vacuo. Recrystallization with 50% EtOAc/hexane provided the title compound as a white solid.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[O:27]1[CH2:28][CH2:29][N:24]([C:21]([C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[O:23])[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylic acid, the product of Example 54 (40 mg, 0.121 mmol), morpholine (12 μL, 0.133 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (51 mg, 0.133 mmol) were combined in dichloromethane (2 mL). Triethyl amine (52 μL, 0.374 mmol) was added and mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane and washed with a 1 N aqueous sodium hydroxide solution. The organic layer was absorbed on silica gel and the mixture was purified by column chromatography eluting with a gradient of methanol and dichloromethane (2-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.41-1.54 (m, 2 H) 1.59-1.70 (m, 4 H) 1.94-2.12 (m, 1 H) 2.24-2.38 (m, 1 H) 2.39-2.60 (m, 4 H) 2.95-3.11 (m, 1 H) 3.37-3.48 (m, 1 H) 3.49-3.61 (m, 1 H) 3.61-3.80 (m, 9 H) 3.81-3.93 (m, 1 H) 7.33 (dd, J=8.31, 1.87 Hz, 1 H) 7.55 (d, J=8.14 Hz, 1 H) 7.73 (d, J=1.70 Hz, 1 H); MS (ESI+) m/z 401.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:8][CH2:14][C:12](=[O:13])[CH:10]=[CH:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(C)=O
Reactant: O=CCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C=CC(c2ccccc2)CC1

Procedure:
A mixture of 19.5 cm3 of phenylacetaldehyde, 16.7 cm3 of methyl vinyl ketone, 0.17 cm3 of 36% sulphuric acid and 85 cm3 of toluene is heated for 1 hour at a temperature in the region of the reflux temperature. After cooling to a temperature in the region of 20° C., 50 cm3 of ethyl acetate are added to the reaction mixture. The resulting mixture is washed with 100 cm3 of saturated aqueous sodium bicarbonate solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (90/10)] to give 4.7 g of 4-phenylcyclohex-2-enone in the form of a yellow oil, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]([C:15]1[CH:16]2[C:21](=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]([CH:20]=1)[CH:18]1[C:35]([N:37]([CH2:40][CH2:41]OC(=O)C=CC3C=CC(C(C)C)=CC=3)[C:38](=[O:39])[CH:17]21)=[O:36])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:56]([NH:59][C:60]1[CH:70]=[CH:69][C:63]([CH:64]=[CH:65][C:66]([OH:68])=[O:67])=[CH:62][CH:61]=1)(=[O:58])[CH3:57].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:56]([NH:59][C:60]1[CH:70]=[CH:69][C:63]([CH:64]=[CH:65][C:66]([O:68][CH2:41][CH2:40][N:37]2[C:38](=[O:39])[CH:17]3[CH:18]([CH:19]4[C:21](=[C:22]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:16]3[C:15]([C:2]([OH:1])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:20]4)[C:35]2=[O:36])=[O:67])=[CH:62][CH:61]=1)(=[O:58])[CH3:57]
Reactant: CC(C)c1ccc(C=CC(=O)OCCN2C(=O)C3C4C=C(C(O)(c5ccccc5)c5ccccn5)C(C4=C(c4ccccc4)c4ccccn4)C3C2=O)cc1
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C=CC(=O)OCCN2C(=O)C3C4C=C(C(O)(c5ccccc5)c5ccccn5)C(C4=C(c4ccccc4)c4ccccn4)C3C2=O)cc1
Reaction time: 72 h
Yield: 99 %

Procedure:
A similar procedure (Schwartz, E. et al. Macromolecules 2011, 44, 4735-4741) to that previously described for the preparation of 347 was followed using 2 (1.50 g, 2.70 mmol), 4-acetamidocinnamic acid (0.50 g, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.04 g, 5.60 mmol), triethylamine (1.24 mL, 8.91 mmol) and dimethylaminopyridine (60 mg, 0.49 mmol) in dichloromethane (25 mL), at room temperature for 72 h. Purification by flash chromatography (hexane/ethyl acetate 1:4) afforded 337 as a white solid (2.0 g, 2.69 mmol, 99%). mp 125-130° C.; 1H NMR (300 MHz, CDCl3) δ 2.17 (3H, s, NHAc), 3.35-3.90 (4.16H, m, NCH2CH2O, H-2, H-3, W/H-4), 3.83-3.95 (0.84H, m, U/H-1, V/H-1, Y/H-4), 4.14 (0.14H, m, U/H-4), 4.28-4.38 (2.32H, m, NCH2CH2O, V/H-4), 4.43-4.47 (0.54H, m, W/H-1, Y/H-1), 5.53 (0.32H, dd, J=3.4 and 1.2 Hz, V/H-6), 5.55 (0.38H, dd, J=3.4 and 1.2 Hz, Y/H-6), 5.59 (s, OH), 5.60 (s, OH), 5.63 (s, OH), 5.69 (s, OH), 6.06 (0.14H, dd, J=3.4 and 1.2 Hz, U/H-6), 6.06 (0.16H, dd, J=3.4 and 1.2 Hz, W/H-6), 6.17 (0.30H, d, J=15.8 Hz, COCH═CH), 6.26 (0.70H, d, J=15.8 Hz, COCH═CH), 6.74-7.61 (21H, m, Ar and COCH═CH), 8.40-8.63 (2H, m, αPyr); m/z (ESI, 70 eV) 765 (MNa+, 100%); (Found MNa+ 765.2684, C46H38N4NaO6 requires 765.2687).
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13](Br)[CH2:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2].[OH-].[K+]>CN1CCN(C)C1=O.O>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13]=[CH:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(=O)N1c2cccc3c2C(CC=C3)C1c1ccccc1
Temperature: 110 °C
Yield: 85.5 %

Procedure:
A portion (5.60 g) of the compound obtained in Example 161 was dissolved in dimethylimidazolidone (DMI; 100 ml) and to the solution was added potassium hydroxide powder (1.46 g). The mixture was heated for 1 hour at 110° C. and allowed to cool. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 3.70 g (86%) of the titled compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=[O:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1c(C=Cc2ccccc2)ccc2c1ncn2C1CCCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C=O)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A 1 L three-necked round bottom flask fitted with an overhead stirrer was dried and cooled under a stream of nitrogen then charged with 4-methoxy-5-styryl-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (25 g, 0.074 mol, 1.0 equiv.) in dioxane (250 mL) and water (80 mL). To this solution was added sodium periodate (36.77 g, 0.17 mol, 2.3 equiv.) and osmium tetroxide (15 mL, 4% aq. soln.) at 0° C., and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with ice cold water (1 L) and extracted with EtOAc (2×750 mL). The organic layers were combined, washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (40-50% EtOAc) to afford 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (15 g, 77%) as a pale yellow solid.