Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[C@@H:17]([CH3:28])[CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C1COCC1.ClCCl>[CH3:28][C@@H:17]1[N:18]([CH3:21])[CH2:19][CH2:20][N:15]([CH:13]2[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:14]2)[CH2:16]1
Reactant: C[C@H]1CN(C2CN(C(=O)OCc3ccccc3)C2)CCN1C(=O)OC(C)(C)C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2CN(C(=O)OCc3ccccc3)C2)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a mixed solution of tert-butyl(2S)-4-(1-((benzyloxy)carbonyl)azetidin-3-yl)-2-methylpiperazine-1-carboxylate (36.7 g, 94.2 mmol) described in Production Example 4-1 and dichloromethane (20 mL) was added TFA (30 mL) at room temperature. The resultant mixture was stirred at room temperature for 35 minutes. The reaction mixture was concentrated under a reduced pressure. An aqueous formaldehyde solution (70.1 mL, 942 mmol) was added to a mixed solution of the resultant residue and THF (100 mL) at room temperature and then stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (29.9 g, 141 mmol) was added to the reaction mixture at 0° C., and the resultant mixture was stirred at room temperature for 12 hours and 45 minutes. An aqueous formaldehyde solution (10.0 mL) and sodium triacetoxyborohydride (17.5 g, 82.6 mmol) were further added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 45 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture at 0° C., and the resultant solution was extracted with ethyl acetate and then with dichloromethane. A combined organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate:methanol=3:1) and then further purified by NH silica gel column chromatography (ethyl acetate) to give the title compound (28.6 g, yield: quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[N:13]\[CH3:14])/[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:10])([F:11])[F:12])=[N:6][CH:7]=1
Reactant: C/N=C(\c1ccc(Br)cn1)C(F)(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNC(c1ccc(Br)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a stirred solution of [1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-eth-(E)-ylidene]-methyl-amine (0.1 g, 0.375 mmol) in methanol (5 mL) is added sodium cyano borohydride (0.027 g, 0.449 mmol) at 0° C. then stirred room temperature for 2 h. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 10% ethyl acetate in hexane to give the crude title compound (0.075 g, crude). 1H-NMR (400 MHz, DMSO) δ: 2.21 (d, J=5.32 Hz, 3H), 3.04 (m, 1H), 4.46 (m, 1H), 7.74 (d, J=8.24 Hz, 1H), 8.87 (dd, J1=2.4 Hz, J2=8.28 Hz, 1H), 8.48 (d, J1=2.36 Hz, 1H). LC-MS (m/z): [M+H]=271.2.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]([CH3:12])[CH3:11]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH:10]([CH3:12])[CH3:11])[CH:6]=1
Reactant: CC(C)Br
Reactant: Brc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc(Br)c1
Temperature: 0 °C
Yield: 29.6 %

Procedure:
A mixture of 4-bromo-1H-imidazole (1.0 g, 6.80 mmol) in dimethylformamide (5 mL) was stirred at 0° C., to which was added sodium hydride, 60% suspension in oil, (326 mg, 8.20 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes, followed by dropwise addition of 2-bromopropane (0.70 mL, 7.48 mmol). The reaction mixture was stirred at room temperature for 15 hours under nitrogen, then quenched with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (20 mL) and extracted with 1M hydrochloric acid (3×20 mL). The combined acidic extracts were washed with ethyl acetate (20 mL), then basified with ammonium hydroxide (pH 12), and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Preparative HPLC, eluting with an ethyl acetate-isohexane gradient, gave the product as a pale brown oil (380 mg, 30%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:9](=[N:15]O)[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1>[Pd].CO>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH:9]([NH2:15])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: ON=C1CCCc2cc(OCC(F)(F)F)cnc21
Agent: [Pd]
Solvent: CO
Product: NC1CCCc2cc(OCC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one oxime (167 mg) and 10% palladium on carbon (100 mg) in methanol (7 mL) was stirred at room temperature for 24 h under hydrogen atmosphere (4 atm). Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on NH-gel eluting with hexane/ethyl acetate (1:1-0:1) to give 68 mg (43% yield) of the title compound as a pale brown oil:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:23])=O)[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]#[N:23])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCC(CC)n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(CC)n1cc(-c2csc(C#N)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxamide (13.0 mg) obtained in Example 8 in DMA (2 mL) was slowly added dropwise trifluoroacetic anhydride (8.36 μL) under nitrogen atmosphere at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate) to give the title compound (9.2 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(#N)C>[O:28]([CH2:27][CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1nccc2cc(OC3CCCNC3)ccc12
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1nccc2cc(OC3CCCN(CCOc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of 6-(piperidin-3-yloxy)isoquinolin-1-ylamine (30 mg, 123 μmol) in DMF (1 ml) was added potassium carbonate (18 mg, 129 μmol) followed by a solution of (2-bromoethoxy)benzene (26 mg, 129 μmol) in acetonitrile (0.5 ml). The mixture was stirred for 16 h at ambient temperature, then the solvent removed in vacuo and aqueous sodium hydrogen carbonate added. The mixture was extracted with chloroform/iso-propanol (3:1), dried (magnesium sulphate) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give 6-[1-(2-phenoxyethyl)piperidin-3-yloxy]-isoquinolin-1-ylamine (12.5 mg) El-MS: m/z=364.8 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]2[NH:34][C:33](=[O:35])[C:32]3[C:27](=[CH:28][C:29]([O:38][CH3:39])=[CH:30][C:31]=3[O:36][CH3:37])[N:26]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][N:15]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[NH:34][C:33](=[O:35])[C:32]4[C:27](=[CH:28][C:29]([O:38][CH3:39])=[CH:30][C:31]=4[O:36][CH3:37])[N:26]=3)=[CH:23][N:24]=2)[CH2:14][CH2:13]1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Cl)nc3)nc2c1
Reactant: CC(=O)N(Cc1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(Cc5ccccc5)C(C)=O)CC4)nc3)nc2c1
Yield: 30.4 %

Procedure:
To a solution of N-benzyl-N-(piperidin-4-yl)acetamide (1.5 g, 6.3 mmol) and 2-(6-chloropyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.0 g, 3.2 mmol) in DMF (15 mL) was added K2CO3 (0.875 g, 6.3 mmol) and the reaction was heated at reflux temperature overnight. The resulting mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, to afford the title compound (0.500 g, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.84 (s, 1H), 8.86 (s, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.33-7.37 (m, 1H), 7.14-7.27 (m, 4H), 6.88-6.96 (m, 1H), 6.66 (d, J=1.5 Hz, 1H), 6.46 (d, J=1.5 Hz, 1H), 4.44-4.58 (m, 4.5H), 4.10-4.20 (m, 0.5H), 3.87 (s, 3H), 3.83 (s, 3H), 2.86-2.98 (m, 2H), 2.25 (s, 1.5H), 1.95 (s, 1.5H), 1.45-1.77 (m, 4H). ESI/APCI MS m/z 514 [M+H]+.
Reaction SMILES: [Li]N1C(C)(C)CCCC1(C)C.CC1CCCN(C)C1(C)C.CN(CCN(C)C)C.[Li]CCCC.[NH:35]([C:42]1[N:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[CH:48][C:47]([F:53])=[C:46]([O:54][CH3:55])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br:62]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1.O>[NH:35]([C:42]1[N:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[C:48]([Br:62])[C:47]([F:53])=[C:46]([O:54][CH3:55])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: CC1CCCN(C)C1(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2c(c(Br)c1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (785.4 mg, 5.6 mmol), TMEDA (651 mg, 5.6 mmol) and n-BuLi (3.5 mL, 5.6 mmol)] in THF (10 mL) was added to a cooled (40° C.) stirred solution of 2-anilino-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one (507 mg, 104 mmol) in THF (20 mL). The reaction mixture was warmed to room temperature. After 1 h, the mixture was cooled to −30° C. and 1,2-dibromotetrachloroethane (457 mg, 1.4 mmol) was added. After 30 min, water (50 mL) was added slowly, and then the reaction was warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using EtOAc afforded 2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one (101 mg, 16%) as a light yellow solid: LCMS RT: 2.75 min, MH+: 440.3.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19]([F:22])[CH:20]=3)[N:15]3[CH:24]=[CH:25][CH:26]=[C:14]3[CH:13]2[CH3:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:42])(=O)=O)=CC=1>C(#N)C>[F:42][C:24]1[N:15]2[C:16]3[C:21]([N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[CH:13]([CH3:27])[C:14]2=[CH:26][CH:25]=1)=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)c(F)cc3-n3cccc3C2C)cc1
Solvent: CC#N
Product: CC1c2ccc(F)n2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 52.8 %

Procedure:
To a 250 ml round bottom flask equipped with condenser was added 3.2 g (7.2 mmol) of the product from Example 9, 3.5 g (10.8 mmol) of N-fluorobenzenesulfonimide and 100 ml of acetonitrile. The solution was heated to reflux for 4 hours. At the end of this time the solution was concentrated and the residue washed with saturated potassium carbonate solution and extracted with ethyl acetate (3×50 ml). The organic layers were combined dried (MgSO4) and concentrated and the resulting crude material chromatographed with 20% ethyl acetate:hexane to yield 1.5 g of material. The enantiomers can be separated (see below) or this material can be hydrolyzed by dissolving in 50 ml of MeOH and 2 ml of 2N NaOH added. After 0.5 hr the solution was concentrated and neutralized with 2N HCL then extracted with ethyl acetate (3×50 ml). The organic layers were combined dried (MgSO4) and concentrated and the solid once again chromatographed with 40% ethyl acetate:hexane. The solid so obtained was recrystallized from ethyl acetate:hexane to yield 0.45 g of product, mp 184-186° C.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26]Cl)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CNCC(F)(F)F)OC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
(R)-3-(7-chloro-4-(chloromethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (6.80 g, 16.7 mmol) in acetonitrile (70.0 ml, 1340 mmol) was added 2,2,2-trifluoroethylamine (8.27 g, 84 mmol). After 20 min, potassium carbonate (2.308 g, 16.70 mmol) was added and the reaction mixture was refluxed for 2 h. The solvent was evaporated and the crude product was dissolved in a mixture of dichloromethane and chloroform. A thick emulsion formed and addition of methanol provided a clear organic phase. The organic layer was dried (Na2SO4), the solvent was removed and the crude product was used as such for the next step. MS (ESI) 470 (M+H); Rf=1.56.
Reaction SMILES: [Li][CH2:2]CCC.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH:16]=1)[CH:14]=O)([O-:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(N(C)C)=O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH:14]=[CH2:2])[CH:16]=1)([O-:8])=[O:7]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: C=Cc1cc([N+](=O)[O-])ccc1OCc1ccccn1
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
Methyltriphenylphosphonium bromide (4.97 g, 13.9 mmol) was dissolved in dry THF (30 ml) and a solution of n-BuLi (1.6 M in hexane, 8.69 ml, 13.9 mmol) was added drop-wise. After 15 minutes, 5-nitro-2-(pyridin-2-ylmethoxy)benzaldehyde (3.0 g, 11.6 mmol) dissolved in dry DMA was added. After 1 hour, the reaction was quenched with saturated sodium bicarbonate and the mixture was extracted with ethyl acetate. After evaporation, the crude material was purified on silica gel (20% EtOAc/petroleum ether) to give 2-[(4-nitro-2-vinylphenoxy)methyl]pyridine (1.11 g, 37%); NMR Spectrum: 5.40 (s, 2H), 5.48 (d, 1H), 6.06 (d, 1H), 7.05 (dd, 1H), 7.34 (d, 1H), 7.38 (dd, 1H), 7.55 (d, 1H), 7.87 (t, 1H), 8.18 (dd, 1H), 8.37 (d, 1H), 8.60 (d, 1H); Mass Spectrum: 257 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:31]([NH:34][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3])[CH2:32][CH3:33]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Reactant: CCCN
Agent: O=C(Cl)C(=O)Cl
Product: CCCNC(=O)CCCCCn1c(CCC)nc2cnc3ccccc3c21

Procedure:
6-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (3.0 g, 9.2 mmol, prepared in Parts A through E of Example 6) was treated with oxalyl chloride (1.45 mL, 16.6 mmol) and n-propylamine (2.27 mL, 27.6 mmol) according to the method described in Part F of Example 6 to provide 3.4 g of N-propyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide. The acid chloride solution was cooled to 0° C. before the addition of n-propylamine.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>[OH-].[Na+].C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mmoles (16.51 grams) of (L)-phenylalanine were dissolved in 50 ml of 2N NaOH, cooled in an ice bath and treated dropwise with 106 mmoles (15.04 ml) of benzyl chloroformate. Stirring at room temperature was carried out for 30 minutes. If the product precipitates out already, sufficient water is added thereto until a clear solution is attained. 4N Hydrochloric acid is dropped in until acid reaction (pH4) and shaken three times with ethyl acetate. The organic phases were dried over sodium sulfate and freed from solvent in a vacuum. There was obtained a colorless, oily product. It was dissolved in 200 ml of chloroform, precipitated in the cold by addition of 400 ml of petroleum ether and filtered off with suction in a large suction filter. Colorless crystals.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:23][CH:24]([CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:1]([O:3][CH:4]([O:23][CH:24]([CH:32]1[CH2:33][CH2:34][C:35](=[O:38])[CH2:36][CH2:37]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:5])[CH3:2]
Reactant: C=COCC
Reactant: O=C1CCC(C(O)Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl vinyl ether (998 mg, 1.32 ml, 13.8 mmol) and pyridinium tosylate (44 mg, 0.17 mmol) were added to a solution of 4-(1-hydroxy-2-phenylethyl)cyclohexanone (2.52 g, 11.5 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred at room temperature overnight. Methylene chloride (20 ml) was added to the mixture and the mixture was washed with water, 5% sodium bicarbonate solution and sodium chloride solution (50 ml of each). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH2:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1COCC1>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C2CCC2)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a stirred mixture of 3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 4.69 mmol) and potassium carbonate (1.48 g, 10.68 mmol) in THF (50 mL) at −5° C., was added phenyl chloroformate (0.88 g, 5.62 mmol) dropwise. After stirring for a further 30 min at −5° C., the reaction mixture was warmed to rt and stirred for a further 15 h. The mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford an oil. Recrystallization from petroleum ether gave phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.30 g, 83%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 6.53-7.53 (m, 12H), 3.57 (m, 1H), 2.26-2.38 (m, 4H), 1.64-2.07 (m, 2H); LC-MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2.0 g (5.84 mmol) of methyl 5-fluoro-2-[2-(4-trifluoromethylphenyl)ethoxy]benzoate are introduced into 25 ml of THF. At 0° C., 4.38 ml (4.38 mmol) of a 1 M lithium aluminum hydride solution in THF are added dropwise, and the mixture is stirred at RT until reaction is complete. The mixture is added to ice-water, acidified with hydrochloric acid and extracted with ethyl acetate. All the volatile components are removed in vacuo, and the crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 1.7 g (82% yield) of the title compound are obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.CN(C)CCCCCCN(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.O>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CSCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)CCCCCCN(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A solution of 3-(methylthio)-1-propanol (5.30 g, 50.0 mmol), triethylamine (10.5 mL, 75.0 mmol) and N,N,N′,N′-tetramethyl-1,6-hexanediamine (0.861 g, 5.00 mmol) in toluene (50 mL) was ice-cooled, and a solution of p-toluenesulfonyl chloride (14.3 g, 75.0 mmol) in toluene (50 mL) was added dropwise under nitrogen atmosphere. After completion of the dropwise addition, the mixture was stirred for 3 hr, during which the mixture was allowed to warm to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (12.2 g, yield 94%) as a colorless oil.