Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1)[CH2:22][CH2:23][OH:24]
Reactant: OCCNCCO
Reactant: NS(=O)(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 99.1 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzenesulfonamide (VIII) [Herbert, R. B. and Hollman, R. G. Tetrahedron, 1965, 21, 663-675] (1.55 g, 5.5 mmol) and diethanolamine (1.16 g, 11 mmol) in dioxan (100 mL) was held at 60° C. for 1.5 h, then adsorbed directly onto silica gel. Excess solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with EtOAc/MeOH (19:1), to give 5-[N,N-bis(2-hydroxyethyl)amino]-2,4-dinitrobenzenesulfonamide (IX) (1.91 g, 99%), mp (EtOAc/petroleum ether) 138°-139° C. 1H NMR ((CD3)2SO) δ 8.53 (s, 1 H, H-3), 7.97 (s, 1 H, H-6), 7.93 (br s, 2 H, SO2NH2), 4.88 (t, J=5.1 Hz, 2 H, OH), 3.65 (dt, J=5.2, 5.1 Hz, 4 H, CH2OH), 3.49 (t, J=5.1 Hz, 4 H, NCH2). 13C NMR δ 146.84 (C-5), 140.53 (C-1), 136.84, 134.39 (C-2,4), 125.70 (C-3), 54.27 (NCH2). Anal. (C10H14N4O8S) C,H,N.
Reaction SMILES: C([N:3](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:54]=[CH:55][C:56]=1[N+:57]([O-:59])=[O:58])[C:40]([C:42]1[N:46]2[CH:47]=[C:48]([C:51](O)=[O:52])[CH:49]=[CH:50][C:45]2=[CH:44][N:43]=1)=[O:41].N>CN(C)C=O.O1CCCC1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:54]=[CH:55][C:56]=1[N+:57]([O-:59])=[O:58])[C:40]([C:42]1[N:46]2[CH:47]=[C:48]([C:51]([NH2:3])=[O:52])[CH:49]=[CH:50][C:45]2=[CH:44][N:43]=1)=[O:41]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ncc3ccc(C(N)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.16 ml (1.12 mmol) of triethylamine and then 0.49 g (1.12 mmol) of BOP are added to 0.346 g (1.01 mmol) of 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-6-carboxylic acid obtained in example 182 in 10 ml of N,N-dimethylformamide. The reaction medium is stirred at ambient temperature for 30 minutes, then 1.35 ml of a 1N solution of ammonia in tetrahydrofuran are added and the mixture is stirred at ambient temperature for 18 hours. The precipitate formed is filtered off and then washed with water. 0.25 g of a yellow solid is collected. Melting point: 289° C.; 1H NMR (d6-DMSO): 4.02 (3H, s), 7.82 (1H, d), 7.98 (1H, s), 8.06-8.10 (3H, m), 8.15 (1H, s), 10.21 (1H, s)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)Cl
Reactant: COc1cccc(C)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of 2,3-dimethylanisole (197.0 g) and propionyl chloride (147.0 g) in carbon disulfide (700 ml) is added anhydrous aluminum chloride (232.0 g) at 5°-10° C. over a period of 1.5 hours. Stirring is continued for 2 hours under cooling and additional 3 hours at room temperature. The reaction mixture is poured onto crushed ice--concentrated hydrochloric acid with stirring. The mixture is extracted with chloroform and the chloroform solution is washed successively with water, dilute sodium bicarbonate solution and water and then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue is distilled at 121°-126° C. (1-2 mmHg) to give the title compound (255.0 g), which is crystallized from n-hexane, m.p. 39°-40° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][CH2:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B5OC(C)(C)C(C)(C)O5)[CH:26]=4)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:20]=3)[N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:14]=2[CH:13]=[CH:12][CH:11]=1.Br[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][C:59]=1[CH3:60].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][CH2:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][C:59]=5[CH3:60])[CH:26]=4)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[N:20]=3)[N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:52])[CH3:50])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(B4OC(C)(C)C(C)(C)O4)cc13)n2COCC[Si](C)(C)C
Reactant: Cc1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(-c4cnccc4C)cc13)n2COCC[Si](C)(C)C
Temperature: 90 °C

Procedure:
An aqueous 2M sodium carbonate solution (0.11 mL, 0.23 mmol) was added to a solution of 3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 12c (60 mg, 0.09 mmol), 3-bromo-4-methyl-pyridine Compound 13a (10 μl, 0.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.01 mmol) in dioxane (1 mL) in a reaction tube. The reaction tube was sealed and heated to 90° C. overnight. After cooling to room temperature, the crude mixture was poured into water (30 mL) and was extract with DCM (2×25 mL). The combined organic layer was dried over sodium sulfate and concentrated. Silica gel chromatography (10% to 50% ethyl acetate/hexanes) gave 3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-5-(4-methyl-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 13b (54 mg, 95%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 9.17 (d, 1H, J=1.5 Hz), 8.92 (d, 1H, J=1.5 Hz), 8.71 (m, 2H), 7.87 (m, 2H), 7.61 (m, 2H), 6.50 (s, 2H), 6.23 (s, 2H), 5.17 (s, 2H), 4.04 (t, 2H, J=6 Hz), 3.86 (t, 2H, J=6 Hz), 3.66 (s, 3H), 2.62 (s, 3H), 1.18 (t, 2H, J=6 Hz); 1.05 (t, 2H, J=6 Hz), 0.18 (s, 9H), 0.05 (s, 9H); MS (ESI) m/z: 631 (M+H+).
Reaction SMILES: Br.S([O-])(O)=O.[Na+].[CH2:7]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][N:13]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10]>O.C(O)(=O)C>[CH2:7]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][N:13]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[C:12]1=[O:38])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1c(=O)cnn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCn1c(=O)cnn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reaction time: 5 h
Yield: 50.2 %

Procedure:
To a stirred mixture of 300 parts of a hydrobromic acid solution 48% in water, 100 parts of a hydrobromic acid solution in acetic acid and 2 parts of sodium hydrogen sulfite were added 18.9 parts of 4-butyl-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione. Stirring was continued for 5 hours at reflux temperature. After cooling, the precipitated product was filtered off and dissolved in a mixture of water and methanol. The mixture was neutralized with a saturated sodium hydrogen carbonate solution. The precipitated product was filtered off and crystallized twice; first from 4-methyl-2-pentanone and then from 1-propanol. The product was filtered off and dried in vacuo at 75° C., yielding 9.1 parts (50.2%) of 4-butyl-2-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 202.3° C. (compound 10.05).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-])=O)=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][C:15]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2F)CC1
Yield: 109.7 %

Procedure:
1.4 g of 4-(5-amino-2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester in solution in 20 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 139 mg of palladium-on-charcoal at 22° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 1.4 g of 4-(4,5-diamino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester are isolated in the form of a brown resin. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.41 (s, 9H); 2.73 (m, 4H); 3.40 (m, 4H); 4.23 (broad s, 2H); 4.37 (broad s, 2H); 6.27 (d, J=8.5 Hz, 1H); 6.31 (d, J=13.5 Hz, 1H). EI mass spectrum: m/z=310 M+. (base peak), m/z=254 (M-C4H)+, m/z=57 C4H+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][CH:19]([CH3:42])[CH:20]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[N:32]=1)=[O:27])[C:21]([O:23][CH3:24])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:31]3[N:32]=[C:28]([C:26]([NH:25][CH:20]([CH:19]([CH3:42])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])=[O:27])[S:29][CH:30]=3)=[CH:34][CH:35]=2)=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3Oc3ccccc3)cc2)cs1)C(C)C
Yield: 61 %

Procedure:
The title compound was synthesized analogous to Example 23, using 4-chloro-1-isocyanato-2-phenoxybenzene and intermediate 3. Yield: 61%; 1H NMR (DMSO-d6, 300 MHz): δ 9.54 (s, 1H), 8.81 (d, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.06 (d, 2H), 7.57 (d, 2H), 7.44 (d, 2H), 7.22 (t, 1H), 7.11 (d, 2H), 7.02 (d, 1H), 6.86 (d, 1H), 4.39 (t, 1H), 3.69 (s, 3H), 2.31 (m, 1H), 0.99 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.C(N(CC)CC)C.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cnc2ccc(O)cc2c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1
Temperature: 25 °C

Procedure:
To a mixture of methyl 6-hydroxyquinoline-3-carboxylate (0.142 g, 0.699 mmol) in methylene chloride (7 mL) and triethylamine (0.974 mL, 6.99 mmol) were added phenylboronic acid (197 mg, 1.62 mmol), copper(II) acetate (294 mg, 1.62 mmol) and 4 Å molecular sieves (approx 200 mg). The mixture was stirred at room temperature over night. Solids were removed from the reaction mixture by filtration and the filter pad was washed thoroughly with ethyl acetate. The filtrate was washed twice with ammonium hydroxide solution and then brine. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes to 50/50 hexanes/ethyl acetate gradient) to afford Int-17 (0.143 g, 73%). LC-MS: (FA) ES+280; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.22 (d, J=2.1 Hz, 1H), 8.95 (d, J=1.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.70-7.66 (m, 2H), 7.49-7.43 (m, 2H), 7.23 (tt, J=7.5, 7.5, 1.1, 1.1 Hz, 1H), 7.17-7.13 (m, 2H), 3.93 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CC=C(c3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(N2CCC(c3ccccc3)CC2)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene (6.4 g) in ethyl alcohol (192 ml) and tetrahydrofuran (192 ml) was added 10% palladium on carbon (0.64 g), and hydrogen gas at atmosphere pressure for 6 hours. The reaction mixture was filtered through celite and evaporated under reduced pressure to give 1-(4-aminophenyl)-4-phenylpiperidine (5.66 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6]O)[CH3:2].[NH2:10][C:11]([NH2:13])=[S:12].[BrH:14]>>[BrH:14].[BrH:14].[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][S:12][C:11](=[NH:10])[NH2:13])[CH3:2]
Reactant: NC(N)=S
Reactant: CCN(CC)CCCO
Agent: Br
Product: CCN(CC)CCCSC(=N)N

Procedure:
A mixture of 3-(diethylamino)propyl alcohol (65.5 g), thiourea (38.0 g) and aqueous hydrobromic acid (48%, 25 ml) was boiled under reflux for 17 hours, and evaporated to dryness. The residue was triturated with ethanol and recrystallised from ethanol/methanol to give the title product, m.p. 125°-127° which was further recrystallised from absolute ethanol to give a 10.0 g sample with m.p. 144°-145°.
Reaction SMILES: [OH:1][C@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([Br:18])=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][CH2:30]Cl)[CH3:28]>CN(C)C=O>[OH:1][C@H:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:30][O:29][CH2:27][CH3:28])[C:13]([Br:18])=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9]
Reactant: CCOCCl
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a stirring suspension of (R)-1-(5-hydroxyhexyl)-8-bromo-3-methylxanthine (2.9 g, 8.4 mmol) and potassium carbonate (1.50 g, 10.5 mmol) in dimethylformamide (70 ml) was added chloromethyl ethyl ether (0.83 g), 8.8 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (200 ml) and was stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml) and dried under vacuum to provide (R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (2.5 g, 74% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:20](OCC)(OCC)OCC>>[N:12]1([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:20]1
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Reaction time: 3 h

Procedure:
The method described in Part A of Example 10 was used to treat ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (10.0 g, 38.6 mmol, prepared in Part A of Example 18) with triethyl orthoformate (8.98 mL, 54.0 mmol). The reaction was complete in three hours. The reaction mixture was filtered to remove a precipitate and then subjected to the work-up procedure to provide 9.7 g of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>CN1CCCC1=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:5]2[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]3[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=3[N:6]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of 7-allyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (1.0 g), piperazine-1-carboxylic acid tert-butyl ester (1.1 g), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.59 ml), and 1-methylpyrrolidin-2-one (2 ml) were stirred under nitrogen atmosphere in an oil bath at 140° C. for 2 hours. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water followed by saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 10–20% (20% 2-propanol/ethyl acetate)/hexane to give 1.5 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14](=[O:16])[CH3:15])[CH3:2].[Br-:17].[Br-:18].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:17][CH:15]([Br:18])[C:14]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[O:3][CH2:1][CH3:2])=[O:16]
Reactant: CCOc1ccc2ccccc2c1C(C)=O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1C(=O)C(Br)Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 1-(2-ethoxy-naphthalen-1-yl)-ethanone (26 g) in tetrahydrofuran (200 mL) at 0° C. was added phenyl trimethylammonium tribromide (50 g). The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 4.5 hours. The mixture was washed with water (200 mL) and the aqueous phase was extracted with diethyl ether. The combined organics were washed with water (200 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford a dark green sticky solid. The sticky solid was triturated with diethyl ether (100 mL) and filtered to give 2,2-dibromo-1-(2-ethoxy-naphthalen-1-yl)-ethanone (12.6 g, 35%) as an off-white solid. The filtrate was evaporated to a dark green oil and purified by column chromatography, elution with 40% to 60% dichloromethane in cyclohexane, affording 2-bromo-1-(2-ethoxy-naphthalen-1-yl)-ethanone (15.8 g, 44%) as an off-white solid. 1H NMR (CDCl3): 1.45 (3H, m), 4.2 (2H, m), 4.5 (2H, m), 7.2 (1H, m), 7.4 (1H, m), 7.5 (1H, m), 7.8 (2H, m), 7.9 (1H, m).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:15]([O-:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>>[CH2:17]([O:16][P:15]([O:19][CH2:20][CH3:21])([C:2]([OH:1])([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:22])[CH3:18]
Reactant: CCOC(=O)C(=O)CCN1CCCC1
Reactant: CCOP([O-])OCC
Product: CCOC(=O)C(O)(CCN1CCCC1)P(=O)(OCC)OCC
Reaction time: 108 h

Procedure:
A mixture of 9.96 g (0.05 mole) of ethyl 2-oxo-4-(1-pyrrolidinyl)butanoate in 31 g (0.225 mole) of diethyl phosphite is stirred at 20°-30° for 3-6 days. The excess diethyl phosphite is removed on a rotary evaporator under high vacuum at a bath temperature of 50°-70° to yield the crude product as a viscous oil. This is purified by chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=2)[S:8][CH:9]=1)([CH3:3])[CH3:2].Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]([O:36][CH2:37]C)=[O:35])[CH:28]=[CH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]([O:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]4)=[C:12]([O:17][CH3:18])[CH:11]=2)[S:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(-c2nc(OC(C)C)cs2)ccc1O
Reactant: CCOC(=O)Cn1ccc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OCCCOc3ccc(-c4nc(OC(C)C)cs4)cc3OC)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a mixture of 4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxy-phenol (Example 37, 269 mg, 1.01 mmol) and ethyl [5-(3-bromopropoxy)-1H-indol-1-yl]acetate (Example 47, 331 mg, 1.01 mmol) in 8 mL DMF (containing 1 v/v % of water), was added cesium carbonate (661 mg, 2.03 mmol). After stirring the reaction mixture for 16 h at rt, DMF was evaporated under reduced pressure. The residue was suspended in ethyl acetate and filtered through a silica gel plug to give 204 mg (39%) of a white solid, which was used in the next step with no further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@H:38]1[CH2:43][CH2:42][C@H:41]([NH2:44])[CH2:40][CH2:39]1>>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][CH2:16][C@@H:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:40][CH2:39]1
Reactant: N[C@H]1CC[C@H](c2c[nH]c3ccc(F)cc32)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@H]1CC[C@H](c2c[nH]c4ccc(F)cc42)CC1)O3

Procedure:
This compound was prepared in a manner similar to Example 1, using toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.5 g, 1.29 mmol) and trans-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.4 g, 1.72 mmol) to give 0.09 g (18%) product as the fumarate salt: MS (ESI) m/z 446 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:33])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])=[O:24]>C(N(C(C)C)C(C)C)C>[CH3:21][N:22]([CH3:33])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:24])=[O:25]
Reactant: CN(C)S(=O)(=O)CCCCCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 92 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-dimethyl-6-chlorohexanesulfonamide (455.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-dimethyl-6-[4-[(4-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide (880.0 mg) as a pale brown oil (yield: 92.1%).