Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K].O>CN(C=O)C>[O:35]=[C:33]1[C:32]2[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](=[O:40])[N:34]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (13.4 g, 30.98 mmol, 1.00 equiv) in anhydrous DMF (100 mL) followed by potassium phthalimide (7.5 g, 40.49 mmol, 1.31 equiv). The resulting solution was heated to 100° C. and stirred for 3 h. The reaction progress was monitored by LCMS. The DMF was removed under vacuum to afford a brown oil residue. To the residue was added 200 mL water and the mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of solvent. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:3). The solvent was removed from fractions containing phthalimide and the residue was washed with 20% ethyl acetate/petroleum ether to yield 10.1 g (78%) of tert-butyl 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoate as pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:8]2[N:9]([CH:12]3[CH2:14][CH2:13]3)[C:10]3[C:5]([C:6](=[O:18])[C:7]=2[C:15]([OH:17])=[O:16])=[CH:4][C:3]([F:19])=[CH:2][N:11]=3)[CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NC1CCN(c2c(C(=O)O)c(=O)c3cc(F)cnc3n2C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 mL of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 mL of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiberglass pad to clarify, the filtrate was acidified to 6.6 with 6M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether, and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[N:18][CH:19]=1>CN(C=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[N:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])=[CH:15][CH:16]=1
Reactant: Oc1ccccn1
Reactant: Fc1ccccc1-c1ccc(CCCBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccccn1CCCc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.2 mg (0.18 mmol) of sodium hydride (55% suspension in mineral oil) were added to 17.8 mg (0.19 mmol) of 2-hydroxypyridine in 5 ml of DMF, and the mixture was stirred at room temperature for 30 min. Subsequently, 50 mg (0.17 mmol) of 5-(3-bromopropyl)-2-(2-fluorophenyl)pyridine were added. The reaction mixture was stirred for 4 h, concentrated, admixed with water and extracted with methylene chloride. The organic phase was separated and concentrated, and the residue was purified by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA) Yield: 11 mg (22%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:31])[CH3:17])=[CH:30][CH:29]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OCCCN(C)C)cc3)nc(=O)c1-2
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.03 g, 9.14 mmol), 4-[3-(dimethylamino)propoxy]benzaldehyde (2.76 ml), and xylenes was heated at 120° C. for 1 hour, then at 160° C. for 6 hours. p-Toluenesulfonic acid (300 mg) was added and the mixture was heated at 160° C. until the reaction was complete. The reaction mixture was cooled to room temperature, and a creamy white solid formed, which was collected by filtration, washed with methanol and recrystallized from ethyl acetate to afford 1-cyclopentyl-3-ethyl-6-[4-[3-(dimethylamino)propoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 175-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[CH2:34][NH:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:11]=[C:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-1-(4-nitro-phenyl)-4-(4-methanesulfonyl-phenyl)-1H-imidazole (2.6 g, 5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[2-(4-bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
Under an argon atmosphere, p-dibromobenzene (9.99 g), 4-methoxyphenylboronic acid (2.03 g) and tetrakistriphenylphosphine palladium (497 mg) were dissolved in dimethoxyethane (20 ml). A 2M aqueous sodium carbonate solution (20 ml) was added and the mixture was heated under reflux for 14 h. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and insoluble materials were filtered off. The solvent was evaporated and the obtained solid was washed with hexane to give the title compound (2.09 g) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]([OH:15])([C:11]([NH:13][NH2:14])=[O:12])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH3:19])=O>>[CH3:16][C:17](=[N:14][NH:13][C:11](=[O:12])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:15])[C:8]([NH2:10])=[O:9])[CH3:19]
Reactant: NNC(=O)C(O)(C(N)=O)c1ccccc1
Reactant: CC(C)=O
Product: CC(C)=NNC(=O)C(O)(C(N)=O)c1ccccc1

Procedure:
20 g of phenylhydroxymalonic acid amide hydrazide in 100 ml of acetone were heated under reflux for 3 hours. The crystals were filtered off under suction and recrystallized from ethanol. 15 g of phenylhydroxymalonic acid amide (2-propylidene)-hydrazide (m.p. 199°-201° C.) were obtained.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)C=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:7][C:8]1[CH:15]=[C:14]([CH:4]=[CH:3][C:1]#[N:2])[CH:13]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#CCC(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC=Cc1cccc(F)c1
Yield: 80.2 %

Procedure:
A mixture of 35.0 g (411 mmol) of cyanoacetic acid (CAS 372-09-8) and 56.2 g (453 mmol) of 3-fluorobenzaldehyde (CAS 456-48-4) in a mixture of 400 ml of toluene and 220 ml of pyridine is refluxed for 22 hours using Dean-Stark apparatus to remove the water formed during the reaction. The solvent is then removed under reduced pressure and the residue is co-evaporated 3 times with toluene. The residue is then taken up in ethyl acetate and the organic phase is washed successively with aqueous 1N sodium hydroxide solution, aqueous 1N hydrochloric acid solution and then with saturated sodium chloride solution. The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of silica gel, eluting with toluene, to give 48.5 g a mixture of (E) and (Z) 3-(3-fluorophenyl)-2-propenenitrile in a ratio of (7/3)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[NH:6][CH2:5]2.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:31]1([CH:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:6]3[CH2:5][C:4]4[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=4)[C:7]3=[O:12])=[CH:18][CH:19]=2)[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=C1NCc2cc(F)c(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3cc(F)c(F)cc3C2=O)cc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
At 0° C., 60 mg (0.355 mmol) of 5,6-difluoro-2,3-dihydro-1H-isoindol-1-one were added to 21.3 mg (0.53 mmol, 60% pure) of sodium hydride in 1 ml of DMF. The mixture was stirred for 30 min, and 125.3 mg (0.35 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. The reaction mixture was stirred for a further 2 h, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 2:1). This gave 30.0 mg (19.2% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CC(N(C)C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Agent: [K]
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 12 h

Procedure:
A solution of 3,5-dinitrobenzyl chloride (2.2 g, 10 mmol) in DMA (40 mL) was treated with potassium phthalimide (1.9 g, 10 mmol) and the mixture stirred 12 h. The mixture was then concentrated and the solid residue washed with ethyl acetate, dried, washed with water and dried to give 2.5 g (76%) of essentially pure adduct as a white solid: 1H NMR 400 MHz (DMSO) δ5.06 (s, 2H); 7.82-7.97 (m, 4H); 8.62 (s, 2H); 8.74 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[H][H].C(Cl)(Cl)Cl>C(O)C.[Pd]=O>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: COc1ccc(CCNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(CCNS(=O)(=O)c2ccc(N)cc2)cc1
Yield: 92.7 %

Procedure:
A solution of the product of stage (i) (4.5 g) in ethanol (150 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on charcoal (50% aq. paste, 0.5 g) for 2 h until hydrogen uptake ceased (1000 ml). Chloroform (150 ml) was added, and the mixture stirred until the product dissolved. The catalyst was filtered off, washed with ethanol, and the filtrate evaporated in vacuo to give a solid (3.8 g). A sample (0.2 g) was purified by flash chormatography eluted with chloroform:methanol (50:1) to give the title compound as a solid (0.11 g). m.p. 144°-146°.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[C:31]([S:32](Cl)(=[O:34])=[O:33])=[C:30]([CH3:36])[O:29][N:28]=1>>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([S:32]([C:31]5[C:27]([CH3:26])=[N:28][O:29][C:30]=5[CH3:36])(=[O:34])=[O:33])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: Cl
Product: Cc1noc(C)c1S(=O)(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and 3,5-dimethylisoxazole-4-sulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.41 (1H, d), 8.00 (1H, d), 7.94 (1H, s), 7.86 (1H, dd), 5.34 (2H, s), 4.65 (1H, m), 3.68 (2H, m), 2.86 (2H, m), 2.61 (3H, s), 2.33 (3H, s), 2.24 (2H, m), 2.00 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Reactant: Fc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-fluorobenzyl bromide (0.48 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (Na2SO4), evaporation in vacuo afforded 1.38 g (97%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ 7.4-7.2 (m, 5H), 7.0 (m, 1H), 6.75 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 334, 366.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13][C:14]1[N:15]=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24].[Cl-].[NH4+]>C1COCC1>[CH3:12][S:13][C:14]1[N:15]=[CH:16][N:17]2[CH:21]=[C:20]([Si:23]([CH3:25])([CH3:24])[CH3:22])[S:19][C:18]=12
Reactant: CSc1ncn2ccsc12
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ncn2cc([Si](C)(C)C)sc12
Temperature: -30 °C
Reaction time: 0.42 h

Procedure:
A 1.59 N n-butyllithium/n-hexane solution (9.91 ml) was added dropwise in an argon atmosphere at −50° C. to a solution of 2.55 g of 7-methylthioimidazo[5,1-b]thiazole in 100 ml of THF. The mixture was stirred at the same temperature for 25 min. Trimethylsilyl chloride (2.08 ml) was added thereto, and the mixture was stirred for 30 min. The temperature of the system was raised to −30° C. A 1.59 N n-butyllithium/n-hexane solution (5.72 ml) was added dropwise thereto, and the mixture was stirred at the same temperature for 30 min. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.58 g of 7-methylthio-2-trimethylsilylimidazo[5,1-b]-thiazole.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C=O)C>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH:4][S:15]([CH3:14])(=[O:17])=[O:16])=[C:2]([Br:1])[CH:8]=1)([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Commercially available 2-bromo4-nitroaniline (10.0 g, 46.07 mmol) was dissolved in DMF (250 mL) and NaH (60% in oil dispersion; 3.7 g, 92.15 mmol) added portion wise at 0° C. After 15 minutes, methanesulfonyl chloride (10.7 mL, 138.23 mmol) was added and the reaction was stirred overnight at ambient temperature. The reaction was quenched with 1M citric acid (100 mL) and extracted with ethyl acetate (3×). The combined extracts were washed with brine (2×), dried (MgSO4), filtered and concentrated in vacuo to yield a red oil that was purified by flash chromatography (silica gel; 20% EtOAc/Hexane) to afford the title compound as a yellow solid which was recrystallyzed from ether/hexanes. mp 148°-151° C; 1H NMR (300 MHz, DMSO-d6) δ3.24 (s, 3H), 7.70 (d; J=9 Hz; 1H), 8.23 (dd; J=9, 3 Hz; 1H), 8.49 (d; J=3 Hz; 1H), 9.85 (br. s., 1H). MS (DCI-NH3) m/z 312 (M+NH4)+.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=C([CH:23]=[CH:24][CH:25]=3)C=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C-:26]#N.[Na+].[CH3:29][C:30]([OH:32])=[O:31]>C(Cl)Cl.CO.O=[Mn]=O>[CH3:26][O:31][C:30](=[O:32])[C:29]1[CH:23]=[CH:24][CH:25]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:19]=1
Reactant: CC(=O)O
Reactant: [C-]#N
Reactant: CC(C)(c1cc(-c2cccc(C=O)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=[Mn]=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1
Reaction time: 12 h

Procedure:
To a solution of 3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzaldehyde (1.0 eq.) (see WO-0146151) in CH2Cl2:MeOH (1:1; 0.1M) was added NaCN (1.8 eq.), MnO2 (8.0 eq.) and AcOH (0.05 eq.). The mixture was stirred for 12 h, filtered on celite, and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the title compound as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, light yellow solid (98 mg, 80%), MS (ISP) m/z=489.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH2:18][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: Clc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OCc2cc(Cl)ccc2Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of 3-methoxyphenol (0.84 mL, 7.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (2 g, 7 mmol) in DMF (70 mL) was added potassium carbonate (1.94 g, 14 mmol). The reaction mixture was stirred at room temperature for 16 hours, then poured into water (500 mL) extracted into ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield 1-bromo-4-chloro-2-((3-methoxyphenoxy)methyl)benzene (2 g, 87%)
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:22]([CH2:24][NH:25][C:26](=[O:33])[C@@H:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])#[N:23].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:5]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[O:32][C@@H:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([NH:25][CH2:24][C:22]#[N:23])=[O:33])=[CH:13][CH:14]=1
Reactant: N=C(OC(c1ccc(Br)cc1)C1CCCCC1)C(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)C1CCCCC1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4-bromophenyl)(cyclohexyl)methyl 2,2,2-trichloroethanimidoate of step 2 (4.18 mmol, 1.73 g) in CH2Cl2 (15 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from Step 1, Example 67 (4.18 mmol, 0.71 g) and then PPTS (0.42 mmol, 0.105 g). The mixture was stirred at r.t. for 72 h. A red solution resulted. The mixture was diluted with EtOAc and washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) and concentrated under reduced pressure to give an oil. Chromatography gave the less polar diastereomer and the more polar isomer.