Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1.[O:17]=[C:18]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.[Cl-].[Li+]>O.O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:6]1[N:7]=[CH:8][C:3]([CH2:2][CH:19]([C:18](=[O:17])[CH2:24][CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:5]=1)#[N:12]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Yield: 51 %

Procedure:
Process 1: Under argon atmosphere, tetrahydrofuran (900 mL) solution of 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile (31.9 g, 117 mmol), methyl 3-oxoheptanoate (27.8 g, 176 mmol), diisopropylethylamine (31.0 g, 240 mmol), and lithium chloride (8.2 g, 193 mmol) was refluxed under heating for 23 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (hexane/ethyl acetate=2:1) to give methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate (20.9 g, 51%) as brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:31]([O:30][C:27]1[CH:26]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:28]=1[F:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:17]=[C:18]([O:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:25])[CH2:10][CH2:9]1)[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 72a), N-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 257) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 525.2 (MH+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[NH:37]N>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=484.1 (M+H)+
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1>C(O)(=O)C.[Pt](=O)=O>[C:1]1(=[O:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][NH:2]1
Reactant: O=c1[nH]ccc2ccccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=c1[nH]ccc2c1CCCC2
Yield: 59.7 %

Procedure:
60 g (413 mmol) of 2H-isoquinolin-1-one (=isocarbostyril) are dissolved in 1 l of glacial acetic acid and, after addition of 2.3 g (10 mmol) of platinum(IV) oxide, hydrogenated under 3 bar at RT until conversion is complete. This entailed changing the catalyst after 3 days and a further 5 days. The suspension is filtered, concentrated and again concentrated after addition of toluene. The crude product is recrystallized from 1.6 l of water. Long needles are filtered off, and the mother liquor is concentrated and dried and separated on silica gel. 36.8 g (60%) of a colorless oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]([CH3:31])([CH3:30])[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:32](O)=[O:33])[CH:26]=5)[NH:21]4)[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]([CH3:30])([CH3:31])[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:32]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:33])[CH:26]=5)[NH:21]4)[CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Yield: 25.8 %

Procedure:
A mixture of 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60.5 mg, 0.32 mmol), 4-dimethylaminopyridine (39 mg, 0.32 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonyl)-methanesulfonamide (30 mg, 26%) as a light yellow solid: LC/MS m/e calcd for C29H33ClN4O3S M+: 553.13, observed: 553.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[C:12]([CH2:26][O:27][CH3:28])=[N:11][C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[C:48]([O:52][C:53](=[O:57])[C@@H:54]([CH3:56])[NH2:55])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl>[C:48]([O:52][C:53](=[O:57])[C@H:54]([NH:55][C:29]([C:10]1[N:11]=[C:12]([CH2:26][O:27][CH3:28])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[C:15]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:14]=2)=[O:30])[CH3:56])([CH3:51])([CH3:50])[CH3:49]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nc(C(=O)N[C@H](C)C(=O)OC(C)(C)C)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a mixture of 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (79 mg, 0.19 mmol), NEt3 (56 μl, 0.4 mmol), and CH2Cl2 (5 ml) cooled with an ice bath was added ClCO2iBu (26.5 μl, 0.2 mmol) with stirring. After stirring for 15 min (R)-alanine tert-butyl ester hydrochloride (36 mg, 0.2 mmol) was added and the mixture was allowed to warm up to ambient temperature overnight with stirring. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (2×15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography on silica gel using EtOAc as the eluent gave the title compound as a tan oil (88 mg); MS-(+)-ion: M+23=565.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][N:23]=[CH:24]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+]>CC(O)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][NH:23][CH2:24]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc2cnccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc2c1CCNC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-isoquinolin-5-ylmethyl-1H-pyridin-2-one (Example 84) (0.14 g, 0.34 mmol) in AcOH (1.3 mL) was added NaCNBH3 (0.09 g, 1.4 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0° C., and diluted with water (10 mL) and 40% aqueous NaOH (10 mL), and the aqueous layer was washed with EtOAc (3×50 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 98:1.8:0.2 to 88:10.8:1.2 CH2Cl2/MeOH/NH3) provided 3-chloro-4-(2,4-difluoro-benzyloxy)-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-1H-pyridin-2-one as a white solid (0.13 g, 92%): mp 180-184° C.; 1H NMR (300 MHz, MeOD) δ 7.65-7.55 (m, 2H), 7.16-7.00 (m, 4H), 6.90-6.80 (m, 1H), 6.60 (d, J=8 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 4.06 (s, 2H), 3.21 (t, J=6 Hz, 2H), 2.82 (t, J=6 Hz, 2H). ESHRMS m/z 417.1173 (M+H C22H20ClF2N2O2 requires 417.1176)
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][CH:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18]([NH2:20])=[O:19])=[C:5]([F:26])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[CH:17]([NH:16][C:6]1[C:5]([F:26])=[CH:4][C:3]([C:1]([NH2:2])=[O:33])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]([F:23])([F:25])[F:24]
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4,4,4-trifluorobutanamide (98 mg, 0.250 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (1 mL) was added. The mixture was purified by HPLC to give the titled compound (28 mg). MS 406.1 (M+H); UV 204.7, 287.8 nm.
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:21][C:18]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: N#CC1(C2(O)CCOCC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 mL) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. and the reaction solution was stirred at −78° C. for 40 minutes. A solution of dihydro-2H-pyran-4(3H)-one (550 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol) was added and the mixture was warmed up to room temperature, and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: EtOAc=20:1) to obtain the title compound as a corloless oil (0.40 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 3.97 (dd, J=11.4, 4.2 Hz, 1H), 3.60-3.50 (m, 2H), 3.40-3.33 (m, 1H), 2.66-2.57 (m, 2H), 2.30-2.16 (m, 3H), 1.99-1.87 (m, 2H), 1.72 (dd, J=8.8, 3.6 Hz, 2H), 1.63-1.58 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)=[CH:4][C:3]=1[O:39][CH3:40].Br[CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].[OH-].[K+]>C(OCC)(=O)C>[CH3:40][O:39][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:33][CH2:34][O:35][CH2:36][CH2:37]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2[C:47](=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46]1=[O:55]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of Example 474 (26.9 mg, 0.05 mmol) and N-(3-bromopropyl)phthalimide (16.1 mg, 0.06 mmol) was treated with KOH (3.4 mg, 0.06 mmol) and stirred at room temperature for 5 hours. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by silica gel column chromatography (0 to 60% ethyl acetate in dichloromethane) to give the title compound. MS (ESI) m/e 725 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.76 (s, 1H), 7.70-7.88 (m, 5H), 7.71 (d, J=8.1 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.10-7.16 (m, 3H), 7.00 (d, J=8.5 Hz, 1H), 6.80-6.95 (m, 7H), 3.99-4.08 (m, 4H), 3.78 (t, J=6.4 Hz, 2H), 3.69-3.73 (m, 4H), 3.62 (s, 3H), 2.95-2.98 (m, 4H), 2.86 (t, J=6.8 Hz, 2H), 2.06-2.12 (m, 2H).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:37])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:21]([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:20]=2)[CH:10]=1.CO.C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.CCOCC>[CH3:8][N:9]1[CH:14]=[CH:13][CH2:12][C:11]([C:15](=[O:37])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:21]([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:20]=2)=[CH:10]1
Reactant: CC(C)C(=O)Oc1ccc(CCNC(=O)c2ccc[n+](C)c2)cc1OC(=O)C(C)C
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Oc1ccc(CCNC(=O)C2=CN(C)C=CC2)cc1OC(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.55 g (1 mmol) of 1-methyl-3-{N-[[β-[3,4-bis(isobutyryloxy)phenyl]ethyl]]carbamoyl}pyridinium trifluoroacetate in 50 ml of deaerated water containing 10 ml of methanol was extracted three times with 30 ml portions of ether. To the resultant aqueous solution was added NaHCO3 (0.25 g, 3 mmol) and 50 ml of ethyl ether and the mixture was kept under nitrogen. To this ice-cold mixture was added sodium dithionite (0.52 g, 3 mmol) and the mixture was stirred vigorously for 30 minutes. The ether layer was separated and the aqueous layer was extracted twice with ether. The combined ether extracts were washed with water and dried over sodium sulfate. Ether was removed under vacuum, leaving an oily product. NMR analysis confirmed that the product has the structural formula: ##STR1577##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13](I)[CH3:14].CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: CCI
Reactant: COC(=O)c1ccc(CO)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4-(Hydroxymethyl)benzoic acid methyl ester (2.0 g) and ethyl iodide (3.8 g) were dissolved in N,N-dimethylformamide (60 mL), potassium tert-butoxide (2.8 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (2.0 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(O)ccc2-c2ccc(Br)cc21
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1cc(Br)ccc1-2

Procedure:
A mixture of 2-bromo-9,9-dioctyl-7-hydroxyfluorene (6.00 g, 0.0124 mol), 1-bromooctane (3.104 g, 0.0161 mol), potassium carbonate (3.41 g, 0.0247 mol) and butanone (100 cm3) was heated under reflux overnight. The cooled mixture was filtered and evaporated down under reduced pressure. The crude product was purified by column chromatography [silica gel, dichloromethane: hexane: 1:1] and then used without further purification (yield 5.04 g, 68.3%), GC: 99%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:20])([F:19])[CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:11][C:12](O)=[O:13].S([O-])([O-])(=O)=O>C(OCC)C>[F:7][C:8]([F:19])([F:20])[CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: CCCCC(CCC(=O)O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCC(CCCO)C(F)(F)F
Reaction time: 4 h
Yield: 71.7 %

Procedure:
In a flask replaced with nitrogen, 72 mg (1.9 mmol) of lithium aluminum hydride and 2 ml of dry diethyl ether were placed and cooled with ice, and a solution of 0.4 g (1.9 mmol) 4-trifluoromethyloctanoic acid in 1 ml of dry diethyl ether was added dropwise thereto. The mixture was stirred for 4 hours on an ice bath for reaction, and a saturated sulfate aqueous solution was added thereto, followed by decantation to recover the ether layer. The ether solution was dried on sodium sulfate, followed by distilling-off of the solvent and distillation for purification to obtain 0.27 g of 4-trifluoromethyloctanol. Yield: 71%, B.P.: 80-85° C./19 mmHg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:35]([CH2:34][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)#[N:36]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)NC(=O)CO3)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC#N)C(=O)CO3)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
A mixture of tert-butyl 4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate (70 mg, 0.162 mmol), 2-bromoacetonitrile (58.4 mg, 0.487 mmol) and potassium carbonate (67.3 mg, 0.487 mmol) in DMF (2 ml) was stirred at 40° C. for 16 h. The reaction mixture was cooled and diluted with water (10 ml) and extracted with DCM (8 mlX3). The combined organic phase was concentrated and the residue was purified by column (biotage, 10 g) eluted with Ethyl acetate/cyclohexane 0-30% to give product 12 mg. 1H NMR (500 MHz, CDCl3) 7.29 (s, 1H), 7.19-7.26 (m, 5H), 7.13 (m, 2H), 7.05 (d, 2H), 4.88 (s, 2H), 4.81 (s, 2H), 4.73 (br, 1H), 4.21 (d, 2H), 1.38 (br, 9H). LCMS (Method D): RT=1.35 min, M+H+=472.2.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35]>CN1C(=O)CCC1.O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Reactant: CCCCOC(=O)Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 27.4 %

Procedure:
Triethylamine (1.93 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in NMP (6.0 mL). n-Butyl chloroformate (1.13 g, 3 eq) was added dropwise. The reaction mixture was allowed to come to ambient temperature and stirred for 24 hours. The reaction mixture was diluted with cold water (25 mL) and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2000 mL) followed by recrystallization from acetonitrile to provide 0.35 g of butyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white solid, mp 164-166° C. Anal calcd for C22H31N5O4S: C, 57.25; H, 6.77; N, 15.17. Found: C, 57.13; H, 6.61; N, 15.20.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:18]4[CH:19]=[CH:20][S:16][CH:17]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])[CH:2]=1
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)cs1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Yield: 33.2 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(3-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 98.2 mg (33.3%) of the desired product as a solid.