Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35](O)=[O:36])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1.CCN=C=NCCCN(C)C.[CH3:51][C:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([NH:58][S:55]([C:52]5([CH3:51])[CH2:54][CH2:53]5)(=[O:57])=[O:56])=[O:36])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Reactant: CC1(S(N)(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Compound 7e (100 mg, 0.187 mmol) was dissolved in DCM (5 ml), and EDAC (43 mg, 0.224 mmol) was added. The reaction mixture was stirred at RT for 1 h. Methylcyclopropanesulfonic amide (28 mg, 0.206 mmol) and DBU (59 μl, 0.393 mmol) were added and the reaction mixture was stirred at RT over night. Citric acid was added and the organic layer was separated, washed with brine, dried, filtered and evaporated. Purification of the residue by preparative HPLC provided the pure title compound (110 mg, 90%), MS (M+H)+652.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][C@H:38]([CH3:41])[CH2:39][OH:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][C@H:38]([CH3:41])[CH2:39][OH:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.74 Hz, 3 H), 1.48-1.59 (m, 4 H), 1.59-1.75 (m, 4 H), 2.35-2.47 (m, 2 H), 3.33-3.42 (m, 4 H), 3.48 (t, J=5.05 Hz, 2 H), 3.99-4.12 (m, 1 H), 4.14-4.23 (m, 4 H), 4.97-5.02 (m, 1 H), 7.14 (ddd, J=8.95, 6.63, 2.11 Hz, 2 H), 7.24-7.54 (m, 2 H), 7.98 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.37 (d, J=8.00 Hz, 1 H), 17.24 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.Br[C:16]1[CH:17]=[C:18]([CH2:23][S:24]([CH2:27][C@@H:28]([CH3:32])[C:29]([OH:31])=[O:30])(=[O:26])=[O:25])[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(O)CC.CCOC(C)=O>[CH3:32][C@H:28]([CH2:27][S:24]([CH2:23][C:18]1[CH:19]=[C:20]([CH:21]=[CH2:16])[CH:22]=[C:1]([CH3:2])[CH:17]=1)(=[O:25])=[O:26])[C:29]([OH:31])=[O:30]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1cc(Br)cc(CS(=O)(=O)C[C@@H](C)C(=O)O)c1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCO
Product: C=Cc1cc(C)cc(CS(=O)(=O)C[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Potassium vinyltrifluoroborate (247 mg, 1.8 mmol), triethylamine (0.21 ml, 1.5 mmol) and [1,1′-bis(diphenylphosphino-κP)ferrocene]dichloro-palladium (24 mg) are added to (S)-3-(3-bromo-5-methyl-phenylmethanesulfonyl)-2-methyl-propionic acid (0.5 g, 1.5 mmol) in 25 ml propanol. The mixture is stirred under argon for 2.5 hrs at reflux. After cooling to rt the mixture is diluted with EtOAc, washed with 0.5 N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and the solvents are evaporated. The residue is purified by chromatography on silica gel (flashmaster, DCM to DCM/methanol 9/1) followed by crystallization from DCM/diethyl ether/hexane to give the title compound as off-white crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:38].[Na+].[Na+]>C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:19][CH:20]=4)[C:15](=[O:38])[C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCN4CCCCC4)cc3c(=O)c2c1
Reaction time: 2 h

Procedure:
To a solution of 9.8 g (0.025 mole) of 2,7-bis(4-piperidinobutyryl)xanthene in 300 ml. of glacial acetic acid was added 9.8 g (0.033 mole) of sodium dichromate over 1/2 hour. The mixture was stirred for 11/2 hours, refluxed for 1 hour, then evaporated to near dryness, cooled, diluted with water and made alkaline with 28% NH4OH solution. The resulting solid was extracted with methylene chloride, chromatographed on alumina using methylene chloride as the eluant, recrystallized from heptane and dried under vacuum at 60°C. to give the desired product. M.P. 93°-95°C.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[CH:28]=5)[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CC[O:52][CH2:51]C1.C(OCC)(=O)C>O>[CH3:48][C:25]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3[N:11]2[CH2:10][CH2:9][N:8]([C:6]([N:1]3[CH2:5][CH2:4][O:52][CH2:51][CH2:2]3)=[O:7])[CH2:13][CH2:12]2)=[CH:28][N:27]([C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:26]=1
Reactant: C1COCCN1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)n4ccnc4)CC3)c2c1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)N4CCOCC4)CC3)c2c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg 1H-1-imidazolyl{4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]piperazin-1-yl}methanone obtained in Example 195 and 1 mL morpholine was stirred overnight at 140° C. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 96 mg of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:5]([S:9]([OH:12])(=[O:11])=[O:10])[C:3]=1[OH:4])[OH:2].[OH-].[Ca+2:14].[OH-]>>[C:1]1([CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O-:12])(=[O:11])=[O:10])[C:3]=1[OH:4])[OH:2].[Ca+2:14].[C:1]1([CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O-:12])(=[O:11])=[O:10])[C:3]=1[OH:4])[OH:2]
Reactant: O=S(=O)(O)c1cccc(O)c1O
Agent: [Ca+2]
Agent: [OH-]
Product: O=S(=O)([O-])c1cccc(O)c1O

Procedure:
To 1000 g of 10% catechol sulfonic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium catecholsulfonate aqueous solution.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[CH2:31][CH2:30][CH:29]([CH3:32])[NH:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:28]1[CH:29]([CH3:32])[CH2:30][CH2:31][CH:27]1[CH3:26])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CC1CCC(C)N1
Product: CC1CCC(C)N1c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(2,5-Dimethyl-pyrrolidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamant-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2,5-dimethylpyrrolidine. Mass spectrum (ES) MH+=419.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)[S:27]([CH3:26])(=[O:29])=[O:28])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(Br)cc1CNc1ccc(Oc2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-2-methoxy-pyridin-3-ylmethyl)-(4-p-tolyloxy-phenyl)-amine (0.73 g, 1.82 mmol) from Step A in CH2Cl2/pyridine (6 mL/3 mL) was dropwise added methylsulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction was then diluted with CH2Cl2 and washed with aqueous HCl (3N) to remove pyridine. The organic layer was then brought to the usual work-up. The crude product was purified by chromatography (silica gel, 30% EtOAc/hexanes). MS (EI) 477, 479 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([NH2:27])=[O:26])[CH:23]=3)[N:18](C3CCCCO3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1>Cl.O1CCOCC1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([NH2:27])=[O:26])[CH:23]=3)[NH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(OCCC3CCCCN3)c1)nn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(OCCC4CCCCN4)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.7 %

Procedure:
3-[3-(2-Piperidylethoxy)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.61 g, 1.4 mmol) was suspended in 10 mL of 4 M HCl in dioxane and the suspension was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated and purification of the residue by preparative HPLC (20–80% acetonitrile in water) furnished 65 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 7.94 (dd, 1H), 7.62 (m, 2H), 7.5 (m, 1H), 7.45 (t, 1H), 7.32 (br s, 1H), 7.05 (dd, 1H), 4.18 (t, 2H), 2.7 (m, 2H), 2.5 (m, 4H), 1.5 (m, 4H), 1.4 (m, 2H); ES-MS (m/z) 365 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=[C:8]([F:27])[C:7]=1[C:28]([NH2:30])=[O:29].O>C(Cl)Cl>[F:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=[C:8]([F:27])[C:7]=1[C:28]([NH2:30])=[O:29]
Reactant: COc1ccc(-c2noc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(O)cc3)no2)c1F
Yield: 65 %

Procedure:
(Method L) Boron tribromide solution (1.0 M in CH2Cl2, 1.5 ml, 1.5 mmol, 2 equiv.) was added slowly, dropwise to stirred suspension of 2,6-difluoro-3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methoxybenzenecarboxamide (272 mg, 0.75 mmol, 1 equiv.) in CH2Cl2 (5 ml), at r.t., under N2. The reaction mixture was stirred at r.t. for 4 h and poured into water (20 ml). CH2Cl2 (10 ml) was added and the biphasic mixture was stirred for 30 min. at r.t. The white un-dissolved solid was filtered, washed with water and Et2O, to give 170 mg (65% yield), mp 209-210° C., HPLC-MS (method 1): m/z 348 [M+H]+, Rt=3.00 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.CC(C)([O-])C.[Na+].[CH2:62]([O:64][C:65]([CH:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)=[O:66])[CH3:63]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:70]2[CH2:71][CH2:72][CH:67]([C:65]([O:64][CH2:62][CH3:63])=[O:66])[CH2:68][CH2:69]2)[CH:21]=[CH:20][C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Br)ccc2F)nc2cc(Cl)ccc21
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(F)c(-c3nc4cc(Cl)ccc4n3C(=O)OC(C)(C)C)c2)CC1
Temperature: 85 °C
Yield: 23.9 %

Procedure:
Method 10—Step a 2-(5-Bromo-2-fluoro-phenyl)-5-chloro-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 7, step c) (1.06 g, 2.50 mmol), Pd2(dba)3 (0.36 g, 0.50 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (t-BuXphos) (0.32 g, 0.75 mmol) and sodium tert-butoxide (0.48 g, 5.00 mmol) were placed into a dried vial and few cycles of vacuum/nitrogen were performed. Then dry toluene (5 mL) and piperidine-4-carboxylic acid ethyl ester (0.50 mL, 3.25 mmol) were added, the reaction mixture was heated at 85° C. overnight, and washed with saturated Na2CO3 solution (3×5 mL) and water (3×3 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, and the crude was purified by flash chromatography (eluent: gradient from EtOAc:cyclohexane/1:5 to 1:2) to obtain 0.30 g of the title compound (24%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].Cl>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CC(C)=CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
In 750 ml of tetrahydrofuran was dissolved 149.9 g of 2',4'-dihydroxyacetophenone, and 409.2 g of anhydrous potassium carbonate and 150 ml of 1-chloro-3-methyl-2-butene were added to the solution and the mixture was stirred at room temperature in a nitrogen current for 5 days. After the reaction, the reaction mixture was made acidic by addition of hydrochloric acid and extracted with diethyl ether. The solvent was removed from the ether extract by distillation. Then, 800 ml of hexane was added to the obtained residue and the hexanesoluble substance was removed by decantation to obtain 2',4'-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a colorless solid. Then, 19.0 g of the so-obtained solid was dissolved in 160 ml of acetone, and 14.2 g of anhydrous potassium carbonate and 6.2 ml of methyl iodide were added to the solution and the mixture was stirred at room temperature overnight in a nitrogen current. After the reaction, the solvent was removed by distillation and the obtained residue was extracted with diethyl ether. The solvent was removed from the extract by distillation to obtain 20.0 g (yield =99.1%) of 2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)acetophenone.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:14]([O:16]CC)=[O:15])[NH:8]2)=[CH:4][CH:3]=1.[C:19]([C:25](OC)=[O:26])#[C:20][C:21]([O:23]C)=[O:22].[OH-].[Na+].Cl>C(O)C.O>[O:26]=[C:25]1[C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([CH2:11][CH2:12][CH3:13])[C:2]=2[O:1][C:20]([C:21]([OH:23])=[O:22])=[CH:19]1)[NH:8][C:7]([C:14]([OH:16])=[O:15])=[CH:6]3
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCCc1c(O)ccc2cc(C(=O)OCC)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c2[nH]c(C(=O)O)cc2cc2c(=O)cc(C(=O)O)oc12
Reaction time: 1 h

Procedure:
The product of step (c) (0.6 g, 0.0024 M), dimethyl acetylene dicarboxylate (0.33 ml, 0.0027 M) and "Triton B" (2 drops) were heated under reflux for 6 hours in dry ethanol (10 ml). The reaction mixture was cooled, NaOH (0.6 g, 14.6 mmol) in water (6 ml) was added and refluxing continued for 1 hour. The whole was cooled, poured into dil. HCl, extracted into ethyl acetate and washed with brine before drying over MgSO4 and evaporating to dryness to yield the sub-title compound as a pale yellow solid, 0.7 g, (86%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].C([O-])(=O)C.[K+].[CH3:14][CH:15]([CH3:19])[CH2:16][CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:8])[CH3:7]
Reactant: CC(C)CC=O
Reactant: COC(=O)C(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](C)NCCC(C)C
Temperature: 25 °C
Yield: 72 %

Procedure:
A suspension of DL-alanine methyl ester hydrochloride (41.8 g, 300 mmol) in dry dichloromethane (650 mL) was treated with potassium acetate (30.0 g, 306 mmol) and the reaction mixture stirred for ten minutes at rt. Reaction flask was then cooled to 10° C. and treated with 3-methylbutanal (25.8 g, 300 mmol). This was followed by the addition of sodium triacetoxyborohydride (82.5 g, 390 mmol) in portions over a period of ten minutes. Reaction mixture was stirred at room temperature for 16 h. Then saturated aqueous sodium bicarbonate solution was added to the reaction and the resulting mixture was stirred for another 30 minutes. The reaction mixture was then further basified with aqueous sodium carbonate to pH=˜10. Dichloromethane layer was separated and the aqueous layer extracted with dichloromethane (3×100 mL). Organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated to give titled product as a colorless oil (yield: 72%). 1HNMR (300 MHz, CDCl3): δ 0.92-0.98 (m, 6H), 1.28-1.41 (m, 5H), 2.48-2.68 (m, 3H), 3.30-3.40 (m, 1H), 3.74 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22][C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:29][C:26]3[CH:25]=[N:24][C:23]([S:22][CH3:21])=[N:28][CH:27]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Reactant: CSc1ncc(O)cn1
Product: CSc1ncc(OCc2csc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cn1

Procedure:
Example 208 was prepared from 4-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1) and 2-Methylsulfanyl-pyrimidin-5-ol in a manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.35 (2H, s), 7.23 (1H, s), 5.19 (2H, s), 4.22 (2H, m), 3.16 (1H, m), 2.87 (2H, m), 2.55 (3H, s), 2.10 (2H, m), 1.71 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH2:1]([Zn]CC)[CH3:2].FC(F)(F)C(O)=O.ICI.[F:16][C:17]([F:35])([F:34])[C:18]([N:20]1[CH2:26][C:25](=[CH2:27])[C:24]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:23]=2[CH2:22][CH2:21]1)=[O:19]>ClCCl>[F:35][C:17]([F:16])([F:34])[C:18]([N:20]1[CH2:26][CH:25]([CH:27]2[CH2:2][CH2:1]2)[C:24]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:23]=2[CH2:22][CH2:21]1)=[O:19]
Reactant: CC[Zn]CC
Reactant: C=C1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C1CC1
Reaction time: 0.25 h

Procedure:
A solution of diethyl zinc (1 mL, 1 M in hexanes) in dichloromethane (1 mL) at 0 C. was treated with trifluoroacetic acid in dichloromethane (0.5 mL) and the mixture stirred for 15 min. Diiodomethane (0.280 g, 1.0 mmol) in dichloromethane (0.5 mL) was then added and stirred for 15 minutes. N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.26 mmol) in dichloromethane (1 mL) was added and the mixture stirred for 30 minutes at 0 C. and then for 2 hours at 20 C. The product mixture was quenched with aqueous saturated NH4Cl (5 mL), extracted to twice with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 (10 mL), washed with H2O (10 mL), and concentrated. Flash chromatography (7% EtOAc in hexanes, silica) resulted in 0.050 g of a white solid. MS calculated for C15H16F3NO2+H: 300, observed: 300.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C[Al](C)C.[CH2:9]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:10][CH3:11]>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[C:12]1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reaction time: 0.05 h

Procedure:
A solution of n-propylamine (3.0 mL, 36 mmol) in dichloromethane (75 mL) was cooled to 0° C.; trimethylaluminum (available as a 2 M solution in toluene, 18 mL, 36 mmol) was added dropwise with stirring over a period of three minutes. The reaction was stirred for one hour at 0° C. and 30 minutes at ambient temperature. A solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (5.80 g, 17.8 mmol, prepared as described in Parts A-D of Example 1) in dichloromethane (30 mL) was added, and the reaction was then heated at reflux for three days. The work-up procedure described in Part E of Example 1 was followed to provide N-propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a brown oil.