Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Yield: 52.3 %

Procedure:
N-Bromosuccinimide (1.1 g. 6.2 mmole) was added portionwise to a solution of 2-methyl-5-nitrobenzofuran (1.0 g, 5.6 mmole) and benzoyl peroxide (50 mg) in carbon tetrachloride (50 ml) and the reaction mixture was heated at reflux temperature for 6 hours in the presence of bright light. The reaction mixture was then cooled, filtered and the filtrate evaporated to dryness. The residue was recrystallised from petroleum ether to give the title compound yield 0.75 g, m.p. 96°-98°.
Reaction SMILES: CO.[CH3:3][NH2:4].C(O[C:8]([C:10]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:33]4[CH:32]=[CH:31][S:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[N:12]([CH2:34][CH:35]=[CH2:36])[N:11]=1)=[O:9])C>CO>[CH3:3][NH:4][C:8]([C:10]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:25]3[C:33]4[CH:32]=[CH:31][S:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)[N:12]([CH2:34][CH:35]=[CH2:36])[N:11]=1)=[O:9]
Reactant: C=CCn1nc(C(=O)OCC)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: CN
Solvent: CO
Product: C=CCn1nc(C(=O)NC)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
40% methylamine methanol solution (5 ml) was added to a methanol solution (5 ml) of 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 1.1 mmol) and the mixture was stirred at room temperature for 3 days. The solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid methylamide (0.32 g, 67% yield) as white powder.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][CH:28]=[C:27]2[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][CH:28]=[C:27]2[S:35]([N:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:3]([CH2:2][OH:1])[CH2:8]1)(=[O:37])=[O:36]
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
To a solution of tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (0.479 g) and triethylamine (0.618 mL) in THF (6 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 0.715 g) in THF (10 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure before adding water and extracting into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with ethyl acetate gave the subtitle compound (0.855 g).
Reaction SMILES: CS(OC[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=O)=O.CS(Cl)(=O)=O.O(CC1C=CC(CO)=CC=1)C1C=CC=CC=1.[Na].[C:35]1([C:41]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C=O)C>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:42]=[C:41]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)OCc1cnccn1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: OCc1ccc(COc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cnccn1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 2-(methanesulfonyloxymethyl)pyrazine (5 mmole), (prepared from 2′-(pyrazin-2-yl)styrene according to the procedure in EP 02257, followed by treatment with methanesulfonyl chloride, according to a procedure in Can. J. Chem. 1999, 77 (4) 463 in 20 ml THF was added dropwise to the sodium salt of ethyl N-(diphenylmethylene)glycinate (5 mmole) in 20 ml DMF cooled in an ice bath. The mixture was allowed to warm to room temperature during 4 hrs. The reaction mixture was partitioned between ether and water. The aqueous layer was separated and reextracted with ether (75 ml). The combined ethereal extracts were washed with brine and dried over MgSO4. Evaporation of the solvent afforded a residue which was chromatographed on silica and eluted with acetone:hexane (1:3) to afford 1.27 g (78%) of ethyl 2-(pyrazin-2-yl)-N-(diphenylmethylene)glycinate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: Cc1cccc2nc(CCl)n(-c3ccccc3Cl)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2nc(CSc3ncnc4[nH]cnc34)n(-c3ccccc3Cl)c(=O)c12
Yield: 79.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2g (300 mg, 0.940 mmol), 6-mercaptopurine monohydrate (176 mg, 1.03 mmol), K2CO3 (142 mg, 1.03 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 324 mg of a white crystalline solid (79%), mp 227.8-230.1° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.57 (br s, 1H); 8.49 (s, 1H); 8.47 (s, 1H); 7.69-7.78 (m, 2H); 7.66 (d, J=7.3 Hz, 1H); 7.55 (d, J=7.9 Hz, 1H); 7.39-7.52 (m, 2H); 7.36 (d, J=6.9 Hz, 1H); 4.38-4.50 (m, 2H); 2.74 (s, 3H). 13C NMR (DMSO-d6) ppm: 161.2, 156.3, 152.4, 151.5, 148.6, 143.9, 141.0, 134.6, 134.5, 132.3, 131.7, 131.4, 130.4, 130.2, 128.7, 125.7, 119.0, 32.0, 22.8. MS (ES): m/z 435.0 (M+). Anal. calcd. for C21H15ClN6OS.0.65C2H6O.0.1H2O: C, 57.40; H, 4.13; Cl, 7.60; N, 18.01; S, 6.87. Found: C, 57.11; H, 3.96; Cl, 7.45; N, 17.79; S, 6.90.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[N+:18]([C:17]1[C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 2-chloro-3-nitropyridine (0.476 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in absolute ethanol. The reaction was heated at room temperature under nitrogen for 72 hours. The resulting reaction mixture was filtered to afford the title compound (69%) as a dark red solid. Mp, 162.0°-163.5° C.; Rf =0.6 in diethyl ether; 13C NMR (DMSO-d6) δ155.6, 150.5, 135.5, 133.5, 129.7, 127.9, 127.6, 125.9, 118.5, 115.0, 113.4, 111.2, 101.2. Analytical calculated for C13H10N4O2 : C, 61.41; H, 3.96; N, 22.04. Found: 61.22; H, 3.80; N, 22.08.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.30 g, 1.1 mmol), benzyl bromide (0.61 g, 3.5 mmol) and potassium carbonate (0.32 g, 2.3 mmol) and DMF (10 ml) was stirred at room temperature for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.39 g, 95%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]3[C:24]=2[C:25]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=2)=[N:26][CH:27]=[N:28]3)[CH2:10]1)(C(C)(C)C)(C)C.C(#N)C>FC(F)(F)C(O)=O>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[F:42])[NH:35][C:25]1[C:24]2[C:29](=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:23]=2[O:22][CH2:21][C@H:11]2[NH:12][CH2:13][C@H:9]([OH:8])[CH2:10]2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc(OC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (860 mg) was dissolved in trifluoroacetic acid (40 ml) and stirred at room temperature for 24 hours. The reaction mixture was then concentrated in vacuo, and excess water was added, followed by the careful addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with 3% methanol in DCM and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a light brown foam. Trituration with cold acetonitrile gave (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]-pyrrolidin-3-ol as an off-white solid (394 mg, 69%); NMR spectrum (DMSO-d6) 10.50-10.00 (br, 1H), 8.49 (s, 1H), 8.25 (dd, 1H), 7.90-7.84 (m, 1H), 7.44 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 4.92 (br s, 1H), 4.38 (dd, 1H), 4.32 (br s, 1H), 3.92-3.86 (m, 4H), 3.77-3.23 (br s, 1H), 3.09 (dd, 1H), 2.83 (d, 1H), 1.88 (dd, 1H), 1.74-1.65 (m, 1H); Mass spectrum MH+ 419.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.O>CN(C)C=O>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (91 mg, 0.20 mmol) produced in Example A18(iv) and 2-chloro-2-oxoethyl acetate (137 mg, 1.00 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with acetone to give the title compound (22 mg, 21%) as a pale-yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(F)c2)CC1
Temperature: 20 °C
Yield: 37.6 %

Procedure:
The experiment is carried out as in Example 1, starting with 2(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide(8.4 g), triethylamine (4.2 cc) and 4-(3-fluorophenyl)piperazine (5.3 g) in toluene (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and ethyl acetate (5-50 vol) as eluant, and recrystallization from boiling acetonitrile (20 cc), 2-(3-[4-(3-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (4.7 g) is obtained, m.p. 103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[C:10]1[C:15](N)=[CH:14][CH:13]=[C:12](C)[C:11]=1[OH:18].Cl>[OH-].[Na+]>[CH:7]1[C:2](=[N:1][C:14]2[CH:13]=[CH:12][C:11]([OH:18])=[CH:10][CH:15]=2)[CH:3]=[CH:4][C:5](=[O:8])[CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1ccc(N)c(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=CC(=Nc2ccc(O)cc2)C=C1
Yield: 106.4 %

Procedure:
A first solution is prepared by dissolving 0.02 mole (2.18 g) of paraaminophenol in 200 cm3 of a 0.1 N NaOH solution. A second solution is prepared by dissolving 0.01 mole (1.37 g) of 2,6-dimethyl-3-amino phenol also in 100 cm3 of 0.1 N NaOH solution. The two solutions are mixed and air is bubbles for 2 hours in the resulting mixture at ambient temperature. The pH of the reaction mass in then brought to 5 by addition of an aqueous hydrochloric acid solution. The reaction mass is then filtered off to produce 2.12 g of said indophenol which, after recrystallization in a dimethylformamide-water mixture, melts at 248°C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) were dissolved in glacial acetic acid (50 ml) and the solution added with a solution of sodium chlorite (8.2 g, 75 mmol) in water (15 ml). The reaction mixture was stirred at room temperature for 1 hr then water (300 ml) was added so obtaining the precipitation of a solid that was filtered and dried at 40° C. under vacuum (12 g, 48 mmol, 97% yield).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[NH4+].[Cl-]>O1CCCC1.O>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
First, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After a stirring period of one hour, 6.3 ml (0.05 mol) of chlorotrimethylsilane, dissolved in 25 ml of tetrahydrofuran was added to this solution over 3 hours. The reaction mixture was stirred for an additional 3 hours. Then, 50 ml of an aqueous NH4Cl solution was added to the dark yellow solution. The solution was treated with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The product 9-(trimethylsilyl)fluorene was crystallized at 4° C. A yield of 8.33 g was obtained.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([C:26]2[C:35]([C:36](O)=[O:37])=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[N:31][CH:32]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[C:35]([C:36]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:37])=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[N:31][CH:32]=3)[N:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc2cnccc2nc1-c1ccccc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1cc2cnccc2nc1-c1ccccc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Phenyl-[1,6]naphthyridine-3-carboxylic acid. LC-MS (basic): tR=1.20 min; [M+H]+=509.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]([NH:51][C:52]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][C:53]=1[C:54](O)=[O:55])(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[C:58]([Br:61])[CH:59]=[CH:60][C:52]=3[NH:51][C:48](=[O:50])[CH3:49])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(=O)Nc1ccc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-acetamido-5-bromobenzoic acid (6.0 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=2[O:2]1.[N+:11]([O-])(O)=O.O>C(O)(=O)C>[CH2:1]1[O:2][C:3]2[CH:4]=[C:5]([CH3:10])[C:6]([NH2:11])=[CH:7][C:8]=2[O:9]1
Reactant: Cc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1N)OCO2
Reaction time: 0.75 h
Yield: 87 %

Procedure:
To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20 ml) cooled with a cold water bath was added, dropwise, nitric acid (70%, 5 ml). The mixture was stirred for 45 min. To work up, water (100 ml) was added and the resulting yellow precipitate was filtered and washed with water until the aqueous filtrate was colorless. The yellow solid was dissolved in EtOAc (250 ml) and dried (MgSO4), and the solid was filtered off. The filtrate was subjected to catalytic hydrogenation (10% Pd/C, 1 atm) for 12 hours. The reaction mixture was then filtered off the catalyst and the filtrate was concentrated on a rotavap to give (3,4-methylenedioxy)-6-methylaniline as a brownish grey solid (5.49g, 87% yield).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@@H:27]3[CH2:31][CH2:30][N:29]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@@H]3CCNC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@@H]3CCN(S(C)(=O)=O)C3)c12

Procedure:
3-(3-Chloro-phenyl)-1-((R)-1-methanesulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (29 mg) was prepared according to general procedure H from (R)-3-(3-chloro-phenyl)-7-methoxy-1-pyrrolidin-3-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (42 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 501 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:6])=[CH:3][C:2]=1[O:1][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCBr
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(OC)c(OCCCCC)c1
Temperature: 90 °C
Yield: 198 %

Procedure:
3-Hydroxy-4-methoxybenzoic acid (9.6 g, 0.057 mol) was dissolved in DMF (90 ml), and to this solution were successively added 1-bromopentane (25.9 g, 0.17 mol, 3.0 eq) and anhydrous potassium carbonate (47.4 g, 0.34 mol, 6.0 eq). The mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and anhydrous potassium carbonate was filtered off. Water (200 ml) was added to the filtrate, and the mixture was extracted twice with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=15/1-10/1) to give pentyl 4-methoxy-3-pentyloxybenzoate (17.4 g, 98.8%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].O1CC1C[C:15]1[C:16]([O:34][CH3:35])=[C:17]([O:21][C:22]2C=CC=[C:24](CC3OC3)[C:23]=2[O:32]C)[CH:18]=[CH:19][CH:20]=1.CO>C1(C)C=CC=CC=1>[CH3:35][O:34][C:16]1[CH:15]=[CH:20][CH:19]=[CH:18][C:17]=1[O:21][CH2:22][CH:23]([OH:32])[CH2:24][N:8]1[CH2:7][CH2:6][C:5]2([O:1][C:2](=[O:11])[NH:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: COc1c(CC2CO2)cccc1Oc1cccc(CC2CO2)c1OC
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccccc1OCC(O)CN1CCC2(CC1)CNC(=O)O2
Yield: 86.7 %

Procedure:
A mixture of 3.12 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 5.4 g 2,3-epoxypropyl-o-methoxyphenyl ether, 5 ml methanol and 10 ml toluene is heated at reflux for 24 hours. The solvent is evaporated and the residue filtered through 20 g silica gel with 10% methanol/methylene chloride. Evaporation of solvent and crystallization from diethyl ether affords 4.6 g 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 124°-125°.