Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>C(Cl)Cl>[Cl:21][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:22])[C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]2[C:42]3[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=3[C:36]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)=[N:35]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cncc2Cl)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3c(Cl)cncc3Cl)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of 103 mg (0.30 mmol) of 4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%) of a white solid. MS (electrospray): exact mass calculated for C28H30Cl2F3N5O3, 611.17; m/z found, 612.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d, J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz, 1H), 4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98 (m, 2H), 3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m, 0.8H), 2.85-2.75 (m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m, 1H), 2.22 (s, 1.5H), 2.17 (s, 1.5H), 2.03-1.90 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH:14]([OH:16])[CH3:15].CN(C)C=O>>[C:1]1(=[O:11])[N:5]([CH2:15][CH2:14][OH:16])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)Br
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCO
Temperature: 70 °C
Reaction time: 12 h
Yield: 44.12 %

Procedure:
Potassium phthalimide 2 (2.7 g, 14.6 mmol) was added to a solution of bromoethanol 1 in N,N-dimethylformamide (12 mL, 14.1 mmol). After stirring for 12 h at 70° C., the mixture was concentrated and then diluted with dichloromethane (100 mL). After removal of solids by filtration, the organic layer was washed with water, dried, and concentrated. The concentrate was purified by flash column chromatography (3:2 to 2:3 hexane-ethyl acetate) to give compound 3 as a white solid (1.19 g, 44.12%) having a RF of 0.22 (3:2 hexane-ethyl acetate). See FIG. 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCNC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.250 g, 0.928 mmol), triethylamine (0.30 g, 3.0 mmol), and 4-fluorobenzoyl chloride (0.18 g, 1.1 mmol) in dichloromethane (7 mL) was stirred for two hours and then concentrated under reduced pressure. The residue was dissolved in methanol, and 1 N hydrochloric acid was added. The reaction was stirred for three days at room temperature and then heated at reflux overnight. A precipitate was present and was isolated by filtration and stirred with 2 M aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane. The combined extracts were then concentrated under reduced pressure. The residue was purified by chromatography using an INTELLIFLASH system (eluting with 0% to 30% CMA in chloroform). The pure product was dried in a vacuum oven overnight at 90° C. to provide N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-4-fluorobenzamide as a white powder, mp 198-199° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#[N:17].[Cl-].[NH4+]>C(OCC)C>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[NH:17])=[C:3]([F:10])[CH:4]=1
Reactant: N#Cc1ccncc1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: N=C(c1ccncc1)c1cc(F)c(Br)cc1F
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
A stirred solution of 1,4-dibromo-2,5-difluorobenzene (2.72 g) in anhydrous diethylether (50 ml) under nitrogen was cooled to −78° C. in a dry-ice/acetone bath then treated with n-butyllithium (1.6M in hexanes, 7.2 ml). The reaction mixture was stirred for 20 min and a solution of 4-cyanopyridine (1.4 g) in diethylether (60 ml) was added dropwise. The resulting mixture was stirred for a further 20 min then treated with saturated aqueous ammonium chloride. The ether layer was separated, washed with brine, dried (sodium sulfate) and concentrated under vacuum. The crude product was purified on an SPE cartridge (silica) using a cyclohexane/ethyl acetate gradient as eluant to give the title compound as a colourless gum (1.50 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:33]4[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: CN(C)[C@H]1CCNC1
Solvent: COCCOC
Product: CN(C)[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)C1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
To a suspension of 52 (1.0 g, 2.41 mmol) in DME (˜20 ml) was added (S)—N,N-dimethylpyrrolidin-3-amine (413 mg, 3.62 mmol) and TEA (486 mg, 2 eq, 4.82 mmol) and the reaction mixture was heated to reflux for an hour. The reaction mixture was cooled to RT, filtered then concentrated. The mixture was partitioned between EtOAc/H2O and the biphasic system was filtered and the resultant yellow solid was collected was collected by filtration to afford title compound 60 (450 mg, 38% yield). The organic phase was separated from the biphasic system; it was then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (9:1 EtOAc:MeOH+1% cone NH4OH solution) to afford an additional amount of 60 (82 mg, 7% yield). MS (m/z): 493 (M+H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.28 min; [M+H]+=495.1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:14](=[O:15])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[Cl:18])=[CH:63][N:64]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(C(=O)NCCN4CCCC4)nc3)nc2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Intermediate 1 (Example 2) (0.076 g, 0.222 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.047 g, 0.266 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.05 mL, 0.443 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 23 (Example 31) (0.076 g, 0.233 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.081 g, 56%).
Reaction SMILES: C([O:5][C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@@H:14]([N:17]=[N+:18]=[N-:19])[C@@H:13]([OH:20])[CH2:12][O:11]1)[CH3:9])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@@H:14]([N:17]=[N+:18]=[N-:19])[C@@H:13]([OH:20])[CH2:12][O:11]1)[CH3:9])([OH:7])=[O:5]
Reactant: C[C@H](C(=O)OC(C)(C)C)N1OC[C@H](O)[C@H](N=[N+]=[N-])C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N=[N+]=[N-])C1=O
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a cooled (0˜−5° C.) stirred solution of the tert-butyl ester 11 (0.469 g, 1.64 mmol) in CH2Cl2 (8 ml), a precooled (ca. 0° C.) trifluoroacetic acid (6.5 mL) was added portionwise. The reaction mixture was kept for 1.5 hours at room temperature and was evaporated in vacuo to dryness. Traces of trifluoroacetic acid were removed by repeated addition and evaporation of dry ether (3×15 mL). After drying in vacuo, 0.373 g (99%) of the product 12 was obtained as a yellowish semisolid. 1H NMR (400 MHz) in CDCl3 (J, Hz): δ 1.58 (3H, d, 3J=7.4, α-MeCH), 4.10-4.06 (1H, m, 5-H), 4.13 (1H, dd, 2J=−11.7, 3J=4.1 , 6-HA), 4.31 (1H, dd, 2J=−11.7, 3J=5.9, 6-HB), 4.43 (1H, d, 3J=7.4, 4-H), H), 5.12 (1H, q, 3J=7.4, α-CH), 6.51 (2H, br. s, OH, COOH). 13C (100 MHz) in CD3CN: δ 13.51, 54.74, 65.75, 71.38, 78.21, 167.55, 170.91. IR (film), cm−1: 3456, 2959, 2125, 1746, 1654, 1284. MS (CI, isobutane), m/Z: 231 (M++1). The compound was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:24])[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:24])[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(Cc2ccc(NS(C)(=O)=O)cc2F)n(C)c1C(=O)c1ccccc1
Temperature: -5 °C
Yield: 62.4 %

Procedure:
3-Fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (1.0 g, 3.1 mmol) [prepared as described in Example 1] was dissolved in pyridine (10 ml) and the solution was cooled to -5° C. Methanesulfonyl chloride (0.39 g, 3.4 mmol) was added and after 1 h the reaction mixture was poured into 1M HCl/ice/water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness. The residue was crystallized from methylene chloride-methanol to give N-{3-fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-methanesulfonamide (775 mg, 62%) as a solid, mp 165-167° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2.[CH:30]([B-](F)(F)F)=[CH2:31].[K+]>CCO.OS([O-])(=O)=O.[K+]>[CH:30]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1)=[O:12])[CH2:6]2)=[CH2:31]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Br)c3C2)CN1C(=O)OC(C)(C)C
Reactant: C=C[B-](F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Temperature: 25 °C

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (10.0 g, 21.3 mmol) in EtOH (200 mL) was added potassium vinyltrifluoroborate (4.28 g, 32 mmol) and Et3OH (4.5 mL, 32 mmol) followed by dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloromethane adduct (175 mg, 0.21 mmol). The reaction mixture was heated to reflux for 6 hours, cooled to RT, diluted with 10% aqueous KHSO4. The EtOH was removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc, and the organic phase washed with brine, dried over Na2SO4. The solvent was evaporated, and the crude product was purified by chromatography on silica eluting with 40-60% EtOAc/hexane to give, after evaporation, the title compound (8.18 g). LRMS (ESI) m/z 417.2 [(M+H)+; calcd for C22H29N2O6: 417.2].
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([OH:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][C:25]([O:24][CH3:23])=[O:26])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cc(Br)c(O)c2ncccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1c(Br)cc(C(C)=O)c2cccnc12

Procedure:
26.6 g of 5-acetyl-7-bromo-8-hydroxyquinoline are dissolved in 200 ml of tetrahydrofurane, 11 g of triethylamine are added and 9.5 g of chloroformic acid methyl ester, diluted in 50 ml of tetrahydrofurane, are added dropwise, whilst stirring and cooling. When the exothermic reaction has ended, the triethylamine hydrochloride which has separated out is removed by filtration and the clear filtrate is evaporated.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: OC1(c2ccccn2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 66 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and 2-bromopyridine, the title compound was formed in 66% yield as a white solid, mp 194°-196° C. free base: 1H NMR (CDCl3, 250 HHz) 8.53 (d, J=5.0 Hz, 1H), 7.70 (ddd, J=1.5, 7.7, 7.7 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.22 (m, 5H), 6.94 (m, 4H), 5.23 (s, 1H), 4.30 (s, 1H), 3.52 (s, 2H), 2.99 (m, 2H), 2.81 (dt, J=2.0, 12.0 Hz, 2H), 2.65 (d, J=2.0 Hz, 2H), 2.07 (dt, J=5.0, 13.0 Hz, 2H), 1.60 (m, 2H) MS (CI, CH4) m/z 383 (M+1,100), 411 (M+29,20), 365 (18), 364 (17) hydrochloride salt: Analysis for C26H26N2 O.2HCl.0.1H2O: Calculated: C, 68.30; H, 6.22; N, 6.13 Found: C, 68.17; H, 6.21; N, 6.09
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.O[N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:2]([C:7]([O:9][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Boc-Leu-OH.H2O (49.9 g, 0.2 M) and HOSu (23.0 g, 0.2 M) were dissolved in THF (300 ml) in a 1 lit. round flask. DCC (41.3 g, 0.2 M) in THF (200 ml) solution was added dropwise at -10° C. for about 10 minutes and the mixture was stirred at room temperature overnight. Precipitated DCU was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 ml), washed with 1 N-HCl, NaCl solution and a small amount of water and dried with anhydrous sodium sulfate. After removal of the drying agent, the solution was concentrated, and n-hexane was added thereto to obtain Boc-Leu-OSu as a colorless powder (m.p. 106°-110° C., 59.11 g, yield: 90%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:7]=1
Reactant: OCCO
Reactant: O=Cc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1cccc(C2OCCO2)n1
Yield: 99.2 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (3 g, 16.22 mmol) in toluene (60 mL) was added ethylene glycol (4.97 g, 80.2 mmol) and p-toluenesulphonic acid (0.152 g, 0.8 mmol). The reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure to afford the crude which was dissolved in ethyl acetate and washed with water. The organic layers were washed with a brine solution, and dried over sodium sulfate. The solvent was removed under reduced pressure to afford 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (3.7 g). The material was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[H-].[Na+].[CH3:13]I>CN(C=O)C>[CH3:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6]
Reactant: CI
Reactant: Cc1ccc(C#N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1C
Temperature: 0 °C
Yield: 91.4 %

Procedure:
15 g (0.11 mol) of 3-hydroxy-4-methylbenzonitrile dissolved in 30 ml of DMF were added dropwise to a suspension of 0.11 mol of NaH and 30 ml of DMF, and the mixture was stirred until no further H2 evolution was observed. Then 10.6 ml (0.17 mol) of methyl iodide were added dropwise, and the mixture was stirred at RT for 1 h. The solution was poured into ice-water, and the product was extracted with ether/ethyl acetate 7:1. After the solvent had been stripped off, the product began slowly to crystallize. 14.8 g (89%) of the product were obtained. 1H-NMR (CDCl3; δ in ppm): 7.2 (m, 2H); 7.02 (s, 1H); 3.85 (s, 3H); 2.25 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:33][N:34]([CH3:38])[C:35]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(OC(=O)N(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 100 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 25 mg, 0.058 mmol) was dissolved in pyridine (1 mL), N,N-dimethylcarbamoyl chloride (6.9 μL, 0.075 mmol) was added thereto, and then the mixture was stirred at 100° C. for 3 hours. N,N-Dimethylcarbamoyl chloride (3.0 μL, 0.033 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL). The mixture was washed with 0.2 N aqueous HCl solution (75 mL), water (50 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (1st time: hexane-ethyl acetate, 2nd time: toluene-ethyl acetate) to give the titled compound (8.5 mg) as a colorless amorphous product. (Yield 29%)