Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[S:8][C:7]=2[CH:33]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCOC(C)=O)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CC(=O)OCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 29 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(Acetoxymethoxy)phenyl]methanone (1.7 g, 2.5 mmol) was converted to the title compound by the procedure of Example 3 using 500 mg (7.5 mmol) of ethanethiol and 1.0 g (7.5 mmol) of aluminum chloride except that the total reaction time was 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[OH:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.2 %

Procedure:
A suspension of (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g, 6.1 mmol) and MnO2 (6.0 g, 69 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 2 days. The mixture was filtered through Celite and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 7:3) to afford (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1.0 g, 48%): 1H NMR (CDCl3) δ 7.90 (d, J=8 Hz, 1H), 7.50 (d, J=0 Hz, 1H), 7.37 (d, J=6 Hz, 1H), 7.05 (s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.88 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[S:18]([C:21]1[CH:22]=[C:23]([C:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=3)[N:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>ClCCl>[CH3:37][C:36]1([CH3:38])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)[CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: CN1CCC(N)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)=N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a stirred solution of 1-methylpyrrolidin-3-amine (52 mg, 0.52 mmol) and N,N-diisopropylethylamine (112 mg, 0.86 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.43 mmol) portionwise. The resultant yellow solution was stirred for 3 h at room temperature. The mixture was purified on preparative Thin layer chromatography to afford 152 mg of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(F)(F)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:33][CH2:34]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:34][O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCOCc1ccccc1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCOCc2ccccc2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and benzyloxymethyl chloride (0.1 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (90 mg, yield 47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 83 %

Procedure:
The title compound was prepared in 83% yield from 2-(3′-fluoro-5-hydroxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example B) and 3,5-difluorobenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[NH2:5][C:6]1[CH:11]=[N:10][C:9](Br)=[CH:8][N:7]=1>CN(C)C=O.O.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>[NH2:5][C:6]1[N:7]=[CH:8][C:9]([S:4][CH2:3][CH2:2][OH:1])=[N:10][CH:11]=1
Reactant: OCCS
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cnc(SCCO)cn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
According to the method described in WO2004/052869, 2-hydroxy-1-ethanethiol (0.93 mL) and tetrakis(triphenylphosphine)palladium (3.39 g) were added to a solution of 2-amino-5-bromopyrazine (1.00 g, 5.75 mmol) in N,N-dimethylformamide (15.1 mL), and the mixture was heated and stirred at 120° C. in a sealed tube for about 3 hours. After cooling, the reaction mixture was diluted with water and extracted with a mixed solution (dichloromethane:ethanol=5:1) (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then filtrated, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, and then ethyl acetate:methanol=10:1) and was recrystallized (using chloroform) to give the title compound as yellow needle crystals (470 mg, yield: 44%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[C:20](OCC)(=O)[CH:21]=[O:22].O.Cl>[Na].CO>[NH2:17][C:15]1[C:14]2[N:18]=[CH:20][C:21](=[O:22])[NH:19][C:13]=2[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Reactant: CCOC(=O)C=O
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product of example 2, step (c) (100 mg) was dissolved in a solution of sodium (0.05 g) in methanol (5 ml). This was left to stir for 15 min at room temperature, then ethyl glyoxalate (134 μl) was added to the mixture which was left to stir for 12 hr at room temperature. Water (5 ml) was added, then concentrated hydrochloric acid was slowly .5 added to acidify the solution to ˜pH5 whereupon a solid precipitated which was isolated by filtration and dried over P2O5 at 50° C. to yield a pale yellow solid (44.5 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:17]([C:16]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:20])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[C:6]=12
Reactant: Cc1cccc(-c2csc(N)c2C#N)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2scc(-c3cccc(C)c3)c2c1N
Temperature: 25 °C
Yield: 19.4 %

Procedure:
To a stirred solution of 2-amino-4-(3-methylphenyl)-3-thiophenecarbonitrile (Description 56) (2.98 g, 13.91 mmol) in toluene (75 mL) at RT was added ethyl acetoacetate (1.76 mL, 13.91 mmol) and SnCl4 (3.26 mL, 27.8 mmol). The reaction mixture was refluxed under a nitrogen atmosphere for ca. 4 h and was then cooled to RT and concentrated in vacuo. The residue was re-partitioned between ethyl acetate and water (ca. 80 mL each) and the aqueous layer separated and re-extracted with ethyl acetate (ca. 50 mL×2). The combined organic layer was then passed though a phase separator and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (880 mg). LCMS (A) m/z: 327 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH2:22])[CH3:14])=[CH:8][CH:7]=1
Reactant: CC(=O)Cc1ccc(OCCCCl)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)Cc1ccc(OCCCCl)cc1
Reaction time: 5 h

Procedure:
A 1.36 g sample of 4-(3-chloropropoxy)phenylacetone, prepared above, was dissolved in 200 mL of methanol. To this was added 7.71 g of ammonium acetate followed by 0.76 g sodium cyanoborohydride with stirring. After 5 hours, the solvent was evaporated in vacuo, the residue was dissolved in 150 mL diethylether and 200 ml of 1 N hydrochloric acid solution. The aqueous phase was separated and washed with a second portion of diethylether, basified to a pH of 10-12 with 6 N sodium hydroxide, and extracted with three, 100 mL portions of diethylether. The basic ether extracts were
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:18][CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(C(N)=O)c(Cl)c4)ccc3=O)ccnc2c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(OCCn3nc(-c4ccc(C#N)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
See example 75 for a general synthesis. To a solution of 2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzamide (120 mg, 266 μmol) in pyridine (10763 μL, 133075 μmol) was added thionyl chloride (194 μL, 2661 μmol). The reaction was then stirred overnight at 23° C. for 18 hours. The reaction was then chilled to 0° C., and quenched with sat. NH4Cl. The organic contents were extracted with DCM (30 mL), separated, dried over MgSO4, then concentrated to a solid under reduced pressure. The product was then purified on silica (12 g) eluting with 3>5% of NH3 in MeOH/DCM and isolated as an off white solid. MS (ESI pos. ion) m/z: (MH+); calc'd for C23H17ClN4O3: 432. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.92 (s, 3 H) 4.67 (t, J=5.02 Hz, 2 H) 4.81 (t, J=5.27 Hz, 2 H) 6.65 (d, J=5.52 Hz, 1 H) 6.99 (dd, J=9.29, 2.26 Hz, 1 H) 7.09 (d, J=9.54 Hz, 1 H) 7.30 (s, 1 H) 7.65 (d, J=9.54 Hz, 2 H) 7.68-7.74 (m, 1 H) 7.87 (s, 1 H) 7.95 (d, J=9.54 Hz, 1 H) 8.64 (d, J=5.02 Hz, 1 H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[C:13](=[C:14]([CH2:18][NH:19][C:25](=[O:27])[CH3:26])[CH:15]=[CH:16][CH:17]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC(C)=O)c1C(=O)OC
Temperature: 4 °C
Yield: 77.8 %

Procedure:
Triethylamine (1.87 g, 18 mmol) was added slowly to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The resulting mixture was cooled in an ice bath to 4° C. Acetyl chloride (0.73 g, 9 mmol) was added dropwise at a rate such that the temperature stayed between 4-7° C. After addition was complete, the mixture was stirred in the ice bath for an additional 30 minutes and then allowed to warm to room temperature and maintained for 2 hours. The reaction mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the product was purified by chromatography (dichloromethane/ethyl acetate 6 to 4) to afford 1.65 g (80%) of the product as an oil: 1H NMR (CDCl3) δ 7.86 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz); 7.46 (t, J=7.7 Hz); 6.29 (b, 1H), 4.39 (d, J=6.1 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@@H:7]1[CH:13]=[O:14]>>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@@H:7]1[C:13]([OH:2])=[O:14]
Reactant: C[C@@H]1CCCC(C)(C)[C@H]1C=O
Reactant: O=[N+]([O-])O
Product: C[C@@H]1CCCC(C)(C)[C@H]1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 38 g of nitric acid (aqueous 60% solution) and heated to 55° C. Then, 90 g of (1S,6R)-2,2,6-trimethylcyclohexanecarbaldehyde (14) [composition: 91% of the (1S,6R)-form, 9% of the (1R,6R)-form] synthesized in Synthesis Example 5-A) was added dropwise thereto with stirring over a period of 2 hours. After carrying out the reaction for 3 hours at the same temperature, the reaction mixture was washed with water with 90 g of toluene and 100 g of water at room temperature, followed by separating an organic layer formed from an aqueous layer. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, followed by separating the organic layer from an aqueous layer. The toluene was distilled off from an organic layer by an evaporator under reduced pressure to provide 98 g of crude (1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid (15) [composition: 91% of the (1S,6R)-form, 9% of the (1R,6R)-form]. The product was recrystallized from methylene chloride as a solvent to provide 46 g of pure (1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid (15) [melting point: 67° C. to 68° C.; optical rotation; [α]D25 =-14.40°].
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1>>[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:2]([CH3:3])[CH3:1])=[O:10])=[CH:7][N:6]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CN(C)C(=O)c1ccc(Cl)nc1

Procedure:
The title compound (D36) was prepared from dimethylamine and 6-chloronicotinic acid according to the procedure described for Description 35. MS electrospray (+ve ion) 185 (MH+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([C:15]2[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:19]1[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Yield: 105.8 %

Procedure:
Benzyl bromide (696 mg, 4.01 mmol) was added to ethyl 5-phenyl-1H-pyrazole-3-carboxylate (880 mg, 4.1 mmol) and potassium carbonate (562 mg, 4.01) in DMF (8 mL). The reaction was stirred for several h and then diluted with water. The mixture was washed several times with ethyl acetate and the combine extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified on ISCO using 0-100% ethyl acetate/hexane gradient to give ethyl 1-benzyl-5-phenyl-1H-pyrazole-3-carboxylate (1.3 g, quantitative). MS (ESI) m/z: Calculated for C19H18N2O2: 306.14. found: 307.1 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[N+:19]([O-:21])=[O:20])(=O)C>Cl.CCO>[N+:19]([C:6]1[C:7]([C:15]([F:16])([F:17])[F:18])=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]=1[NH2:4])([O-:21])=[O:20]
Reactant: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Yield: 71.2 %

Procedure:
A mixture of 1-acetamido-2-nitro-3,5-bis(trifluoromethyl)benzene (200 mg, 0.63 mmol) in concentrated HCl (3 mL) and EtOH (3 mL) was refluxed overnight, then it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 2-nitro-3,5-bis(trifluoromethyl)aniline 123 mg (71%). 1H NMR (DMSO-d6): δ6.392 (s, 2H), 7.131 (s, 1H), 7.375 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([NH:14][C:15]([C:17]1[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[C:28]([F:31])([F:30])[F:29])=O)[CH2:7][CH2:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1[S:41][C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])=[N:14][C:8]=1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 140 °C
Yield: 108.8 %

Procedure:
A mixture of N-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (Preparation 56A, 337 mg, 0.783 mmol) and Lawesson's reagent (2,4-Bis-[4-methoxyphenyl]-1,3-dithia-2,4-diphosphetane 2,4-disulfide) (475 mg, 1.175 mmol) in THF (4.0 ml) was heated for 33 min at 140° C. on a microwave which resulted in an incomplete reaction. The reaction mixture was then microwaved for 15 min more at 140° C. The crude reaction mixture was loaded onto a 40 g silica gel Redisep® cartridge which was presaturated with 10% EtOAc-hexanes and eluted with the same. The 5-(7-methoxy-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (0.365 g, 0.852 mmol, quant. yield) was isolated as a yellow solid. The product had an LC ret. time=2.62 min. (condition: Start % B=0; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=220; Solvent Pair=MeOH/H2O/TFA; Solvent A=0.1% TFA in MeOH: H2O (10:90); Solvent B=0.1% TFA in; MeOH: H2O (10:90); Column 1=Waters Sunfire C18 5 um 4.6×30 mm); LC/MS M+1=429.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([NH:16]C(=O)OCC2C=CC=CC=2)[CH3:15])[CH:6]=[CH:7][C:8]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].C(N)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([NH2:16])[CH3:15])[CH:6]=[CH:7][C:8]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: COc1cc(C(C)NC(=O)OCc2ccccc2)ccc1NS(C)(=O)=O
Agent: CCN
Product: COc1cc(C(C)N)ccc1NS(C)(=O)=O

Procedure:
Through similar procedure to that in Example 1-2 excepting using Benzyl N-{1-[3-methoxy-4-(methylsulfonylamino)phenyl]ethyl}carbamate (14-1) as a starting material, □1□3-Methoxy-4-(methylsulfonylamino)phenyl]ethyl amine (14-3, CHK-570) having following physicochemical properties was synthesized:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reaction time: 16 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in methylene chloride (1 ml). Cinnamoyl chloride (34.5 mg, 0.207 mol) was added to the methylene chloride mixture. The pH of the stirred mixture was adjusted to ~9 with 50 μl of triethylamine. After stirring for 16 hours the mixture was filtered. The product in the filtrate was purified by prep TLC. The product band was collected by washing the silica containing the product, with 80:20:2 CMW. The solvent was evaporated and the residue was dissolved in methanol, placed in a small vial and evaporated. Yield 16.6 mg.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:36]([O:38][CH2:39][CH2:40][CH3:41])=[O:37]>ClCCl>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([CH3:25])([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:24])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])[C:18]=2[N:19]=1)[CH3:34]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: CCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(COCC)n2CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Triethylamine (2.67 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (1.5 g, 1 eq) in dichloromethane (150 mL). A solution of propyl chloroformate (1.55 g, 3.3 eq) in dichloromethane (5 mL) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 24 hours. The reaction mixture was washed sequentially with water (150 mL), 4% sodium carbonate (150 mL), water (150 mL), and brine (150 mL). The organic layer was concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-20% CMA in chloroform, 1500 mL) followed by recrystallization from diethyl ether to provide 1.23 g of propyl 2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white powder, mp 177-179° C. Anal calcd for C22H31N5O5S: C, 55.33; H, 6.54; N, 14.66. Found: C, 55.41; H, 6.47; N, 14.45.