Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:35]([O:37][C:38](=[O:57])[C@H:39]([CH3:56])[CH2:40][C@H:41]([NH2:55])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)[CH3:36].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:57])[C@H:39]([CH3:56])[CH2:40][C@H:41]([NH:55][C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:47][CH:48]=1)[CH3:36]
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][CH2:29][O:30][C:31]([C:33]1[CH:44]=[C:36]2[C:37]([C:41]([OH:43])=O)=[CH:38][CH:39]=[CH:40][N:35]2[N:34]=1)=[O:32].[C:45]12([CH2:55][NH2:56])[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH2:46]1)[CH2:52]2.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH2:29]([O:30][C:31]([C:33]1[CH:44]=[C:36]2[C:37]([C:41](=[O:43])[NH:56][CH2:55][C:45]34[CH2:54][CH:49]5[CH2:48][CH:47]([CH2:53][CH:51]([CH2:50]5)[CH2:52]3)[CH2:46]4)=[CH:38][CH:39]=[CH:40][N:35]2[N:34]=1)=[O:32])[CH3:28]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1cc2c(C(=O)O)cccn2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 15 h

Procedure:
BOP (11 g, 24 mmol) is added to a slurry of pyrazolo[1,5-a]pyridine-2,4-dicarboxylic acid 2-ethyl ester (5.6 g, 24 mmol), adamantan-1-ylmethylamine (4.4 g, 27 mmol), iPr2NEt (21 mL, 120 mmol), and DMF (240 mL) under N2. The reaction vessel is sealed and the mixture is left to stir for 15 h. EtOAc (200 mL) is added. The solution is washed with 50% sat. aq. NH4Cl (2×500 mL). The aqueous phases are extracted with EtOAc (3×200 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (2:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) affords the title compound as a tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.62 (d, 1H), 7.60 (d, 1H), 7.44 (s, 1H), 7.00 (t, 1H), 6.23 (bs, 1H), 4.48 (q, 2H), 3.23 (d, 2H), 1.98-2.07 (m, 3H), 1.57-1.78 (m, 12H), 1.45 (t, 3H). LC-MS m/z (M+H+): 382.2; RT=1.09 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@H:11]3[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][OH:20])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@H:11]3[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][O:20][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1nnc2c(N)ncnc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2nnc3c(N)ncnc32)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Mixed compound 27.3 (969 mg, 3.4 mmol) with pyridine and concentrated under reduced pressure. The resulting solid was suspended in pyridine 5 mL, treated with TBSCl (615 mg, 4.1 mmol) and the mixture was stirred at r.t. for overnight. The mixture was concentrated down under reduced pressure and water was added to give solid. The suspension was stirred for 30 min, filtered and the solid was dried under reduced pressure to give compound 27.4 (1.33 g, 98% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:19]([O-])=O)[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H][H]>CN(C=O)C.[Pd]>[NH2:19][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:2]2[OH:1]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(CN3CCOCC3)cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Yield: 89.8 %

Procedure:
A solution of ethyl 4-hydroxy-6-(4-morpholinylmethyl)-8-nitro-3-quinolinecarboxylate (Preparation 1, 1.36 g) in DMF (50 mL) is hydrogenated at 50 psi hydrogen pressure in the presence of 10% Pd/C (400 mg) for 15 min. The catalyst is filtered off and the filtrate is evaporated. The residual solid is triturated with methanol to afford 1.12 g of the title compound. Physical characteristics. 1H NMR (DMSO-d6) δ1.28, 2.35, 3.44, 3.57, 4.21, 5.59, 6.98, 7.33, 8.41.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:18][CH:17]([C:19](=O)[NH2:20])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1>C(OC(=O)C)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Solvent: CC(=O)OC(C)=O
Product: N#CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A solution of 0.57 g (1.5 mmoles) of 1-cyclopropyl-6,8-difluoro-7-(3-carbamoyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 6) in 12 ml of acetic anhydride is heated under reflux for 24 hours. Cooling, filtering and washing with water and ethanol yield 0.15 g (27%) of 1-cyclopropyl-6,8-difluoro-7-(3-cyano-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at >325° C.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].N(CCO)CCO>>[CH:2](=[C:18]1[NH:12][C:13](=[O:14])[NH:15][C:16]1=[O:17])[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)ccc1O
Solvent: OCCNCCO
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O

Procedure:
condensing vanillin and hydantoin by heating together in admixture with diethanolamine to produce 5-vanillylidenehydantoin, and
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:18]([N:28]1[CH2:32][CH2:31][CH:30](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[C:8]([C:7]([CH:31]1[CH2:30][CH2:29][N:28]([S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:32]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Diphenylacetonitrile (17.1 g) was added to a stirred suspension of sodium hydride (4 g of a 60% suspension in mineral oil) in anhydrous toluene (250 ml) and the mixture was heated under reflux for 2 hours. On cooling to room temperature, 1-tosyl-3-(R,S)-tosyloxypyrrolidine (28 g--see Preparation 5) was added in portions and the mixture heated under reflux for 3 hours. The mixture was diluted with toluene (150 ml), washed with 5% aqueous sodium hydroxide (2×100 ml) and brine (150 ml) then dried (MgSO4) and concentrated in vacuo to give a solid which was purified by trituration with methanol to give the title compound as a colourless microcrystalline powder, yield 18 g, m.p. 186°-187° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[NH2:21][OH:22]>C(O)C>[OH:22][N:21]=[CH:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1

Procedure:
To a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (10.0 g) in ethanol (110 ml) is added dropwise hydroxylamine (50% in water, 2.48 ml). The mixture is heated to reflux for 2 hours. Volatile substances are subsequently removed under reduced pressure. This gives tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (10.5 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH-].[Na+].Cl[O-].[Na+].Cl[O-].S(S([O-])=O)([O-])(=O)=[O:33].[Na+].[Na+]>C(O)(=O)C.CC(C)=O.O.C(#N)C>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:33])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
(2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]-thio]1H-benzimidazole (10 g) was suspended in 100 ml of a mixture of acetonitrile and water (7:3). A solution of sodium hydroxide was added to this suspension. 61 g of sodium hypochlorite solution (4.2%) was added over a period of 4 hours maintaining a temperature of 5° C.-10° C. Excess hypochlorite was decomposed using 3% aqueous sodium metabisulfite solution. Acetone (50 ml) was added and the pH was adjusted to between 7.5 to 8.5 using dilute acetic acid. The solids were filtered, washed with chilled water and dried in an oven to give 8 g of the title compound. The product was slurried in acetone followed by purification by dissolving in a mixture of acetone and aqueous sodium hydroxide solution. The pH of the clear solution was adjusted to about 7.0-8.0 using dilute acetic acid solution and the product was isolated by filtration, slurried in water and dried in an oven to give about 7 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[CH:12](OC)[O:13]C.O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: CCCc1c(F)ccc(C(OC)OC)c1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(F)ccc(C=O)c1Cl
Yield: 99.4 %

Procedure:
2-Chloro-1-(dimethoxymethyl)-4-fluoro-3-propylbenzene (1.20 g) was dissolved in a mixed solvent of tetrahydrofuran (16 mL)-1 mol/L hydrochloric acid (8 ml), and the mixture was heated under reflux for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate. The ethyl acetate solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=30:1→3:1) to give the title compound as a colorless oil (yield: 970 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Added BH3 (1M in THF, 40 mL) to a solution of 2-bromo-4-chlorobenzoic acid (3.14 g, 13.33 mmol) in THF (3 mL) drop wise at 0° C. The reaction mixture was stirred at room temperature overnight. Extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2SO4, concentrated to give the title compound (2.5 g, 85%). 1H NMR (300 MHz, CDCl3): δ 4.72 (2H, s), 7.32 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.43 (1H, d, J=8.1 Hz), 7.56 (1H, d, J=2.1 Hz).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.BrC1C=CC=[C:39]2[C:35]=1[C:36]1([C:52]3=CC4OCOC=4C=[C:51]3[O:50][CH2:49]1)C(=O)[N:38]2CCCCC.COC1N=CC(B(O)O)=CC=1.CN(C)C1N=CC(B(O)O)=CC=1>>[CH3:49][O:50][C:51]1[N:38]=[CH:39][C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:25]4=[CH:26][C:27]5[O:31][CH2:30][O:29][C:28]=5[CH:32]=[C:24]4[O:23][CH2:22]2)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[CH:36][CH:52]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCO5)C(=O)N3Cc2ccc(C(F)(F)F)o2)cn1

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (6-methoxypyridin-3-yl)boronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (51%) as a colorless solid: mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 1H), 7.69 (d, 1H), 7.34 (t, 1H), 7.03 (d, 1H), 6.89-6.86 (m, 2H), 6.65 (d, 1H), 6.61 (d, 1H), 6.56 (d, 1H), 6.17 (d, 2H), 5.87 (d, 2H), 4.99 (ABq, 2H), 4.56 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.7, 163.5, 158.4, 156.1, 151.8, 151.8, 149.2, 147.8, 146.1, 142.3, 141.6, 138.8, 136.9, 132.6, 130.0, 129.1, 127.8, 127.2, 126.2, 119.9, 112.7, 112.7, 110.9, 109.6, 109.5, 108.5, 102.3, 101.6, 93.6, 78.2, 58.5, 53.6, 37.0; MS (ES+) m/z 537.4 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[C:7]([CH2:8][CH2:9][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:4][CH2:3][C:2]#[N:1])#[N:10]
Reactant: C=CC#N
Reactant: NCCCCN
Solvent: CO
Product: N#CCCNCCCCNCCC#N
Reaction time: 18 h

Procedure:
To a solution of 1,4-diaminobutane 1 (n=4; 25.0 g, 0.28 mol) in methanol (50 mL) was added dropwise a solution of acrylonitrile (31.6 g, 0.60 mmol) in methanol (25 mL) at 0° C. After the addition the mixture was allowed to come to room temperature and then stirred for 18 h. Finally, the solvent was removed in vacuo, to give the diamine 2 as a pale yellow liquid, (57.0 g, quant.).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=12.[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=12
Reactant: COC(=O)CCc1c2n(c(=O)c3ccccc13)CCc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1c2n(c(=O)c3ccccc13)CCc1ccccc1-2

Procedure:
2.45 g (7.35 mmol) of methyl 8-oxo-5,8-dihydro-6H-dibenzo[a,g]quinolizine-13-propanoate dissolved in 40 ml of ethanol are introduced into a 100 ml round-bottomed flask, 2 ml of aqueous 30% sodium hydroxide are added and the mixture is heated at reflux for 3 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])=O)=[CH:5][CH:4]=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:31]([NH2:33])[CH3:32])[CH:27]=[CH:28][C:29]=1[F:30].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:23][C:24]1[CH:25]=[C:26]([CH:31]([NH:33][CH:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:32])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2OC)cc1
Reactant: CC(N)c1ccc(F)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2OC)cc1

Procedure:
Following a similar procedure to that described in Example (1a), 2.02 of 2-methoxy-5-nitrophenyl 4-methoxyphenyl ketone, 2.02 a of 1-(3,4-difluorophenyl)ethylamine hydrochloride, 4,37 ml of triethylamine, 0.69 ml of titanium tetrachloride, 1.46 g of sodium cyanoborohydride and 0.45 ml of acetic acid were reacted, to obtain 2.10 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: Clc1ccc(SCCCCBr)cc1Cl
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylmercapto)-butylbromide.
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([N:25]([CH3:27])[CH3:26])[N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:28]N1C(=O)CCC1=O>C(#N)C>[Br:28][C:22]1[C:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:18][C:19]([N:25]([CH3:26])[CH3:27])=[N:20][C:21]=1[O:23][CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Temperature: 23 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 1.56 g (4.13 mmol) of 4-hexadecyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 30 mL of acetonitrile were added 888 mg (4.99 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 23° C. and protected from light for 5 h. The reaction mixture was concentrated under diminished pressure and the residue was dissolved into 100 mL of ethyl acetate. The organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 9:1 hexanes-ethyl ether afforded the expected product as white solid: yield 1.80 g (95%); mp: 66-67° C.; silica gel TLC Rf 0.60 (9:1 hexanes-ethyl ether); 0.86 (t, 3H, J=6.8 Hz), 1.34-1.20 (br m, 26H), 1.65 (quint, 2H, J=7.2 Hz), 2.68 (dd, 2H, J=7.6, 7.6 Hz), 3.12 (s, 6H) and 3.93 (s, 3H); 13C NMR (CDCl3) δ14.10, 26.67, 27.62, 29.34, 39.37, 29.45, 29.57, 29.63, 29.65, 29.68, 29.68, 29.68, 29.68, 29.68, 31.90, 36.71, 36.95, 36.95, 53.98, 91.17, 160.08, 165.07 and 169.06.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[CH2:13][C:14](O)=[O:15].B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[CH2:13][CH2:14][OH:15]
Reactant: COc1ccc(Br)c2[nH]c(=O)cc(CC(=O)O)c12
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(Br)c2[nH]c(=O)cc(CCO)c12
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a well-stirred and cold solution of 2-(8-bromo-5-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acetic acid (5.5 g; 17.62 mmol) in dry THF (90 ml) was slowly added a borane solution (1M in THF) (38.8 ml; 38.8 mmol) under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction mixture was carefully quenched with a solution of sodium hydroxide 1N (40 ml), the organic volatiles were removed under reduced pressure and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to furnish 2.7 g (51%) of 8-bromo-4-(2-hydroxyethyl)-5-methoxyquinolin-2(1H)-one as a light brown solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:23]=[C:22]([O:24][CH3:25])[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[C:12]([O:26][CH3:27])[CH:11]=1.[C:28](O)(=[O:32])[C:29]([CH3:31])=[CH2:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([O:26][CH3:27])[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[C:22]([O:24][CH3:25])[CH:23]=1
Reactant: COc1cc(-c2nc3ccccc3s2)cc(OC)c1OCCCCCCO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCCCCCOc1c(OC)cc(-c2nc3ccccc3s2)cc1OC
Yield: 67 %

Procedure:
A solution of 6-(4-benzothiazol-2-yl-2,6-dimethoxy-phenoxy)hexan-1-ol (1.10 g, 0.0038 mol), methacrylic acid (1.30 g, 0.015 mol) of p-toluenesulfonic acid (0.10 g, 0.0005 mol), hydroquinone (0.10 g, 0.0009 mol) and toluene (50 cm3) was heated under reflux for 48 hours in a Dean and Stark apparatus to remove water continuously and then allowed to cool. The solvent was removed under reduced pressure and the residue dissolved into diethyl ether (100 cm3). The resultant solution was washed with water (20 cm3), dried (Na2SO4), filtered and then evaporated down under slightly reduced pressure. The residue was recrystallised from methanol to yield 1.16 g (67.1%) of the desired product. A small amount of 2,6-di-tert-butyl-4-methylphenol was added to act as an inhibitor to prevent spontaneous polymerisation.
Reaction SMILES: [SiH](CC)(CC)CC.O=[C:9]1[CH:17]2[CH2:18][C:13]3([NH:20][C:21](=[O:23])[CH3:22])[CH2:14][CH:15]([CH2:19][CH:11]([CH2:12]3)[O:10]1)[CH2:16]2>C(Cl)(Cl)Cl.O>[C:13]12([NH:20][C:21](=[O:23])[CH3:22])[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:19][CH:11]([O:10][CH2:9]3)[CH2:12]1)[CH2:14]2
Reactant: CC(=O)NC12CC3CC(C1)OC(=O)C(C3)C2
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC12CC3COC(CC(C3)C1)C2
Temperature: 60 °C
Yield: 70 %

Procedure:
InBr3 (0.056 mmol) and Et3SiH (12.6 mmol) were successively added to a solution of lactone 16A (0.54 mmol) in CHCl3 (5 mL) and the reaction mixture was heated at 60° C. for 1 h. The reaction mixture was allowed to cool to rt, was diluted with H2O (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (10/90 to 30/70 EtOAc/hexane) to provide ether 16B in 70% yield. Data: LC/MS (ESR) m/z 210 [M+1]+.