Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(N)cc35)CCC4)CC2)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(NC(=O)c6ccccc6)cc35)CCC4)CC2)c1
Yield: 23.7 %

Procedure:
2 g of 8-amino-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]-ethyl}-4H-pyrrolo-[3,2,1-ij]quinoline (preparation see Example 20) were dissolved in 25 ml of chloroform. 1.45 ml of triethylamine and then, dropwise, 1.075 g of benzoyl chloride were added to the solution without exceeding a temperature of 20° C. in this process. The reaction mixture was allowed to react at room temperature for hour. To work up the reaction mixture, it was washed with 20 ml of 10% aqueous sodium hydroxide solution until neutral, dried and evaporated. The crude product obtained was purified by chromatography on a small silica gel column using toluene/ethanol 95:5 as the eluent. After recrystallization from ethanol, 0.6 g of 8-benzoylamino-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-ethyl}-4H-pyrrolo[3,2,1-ij]quinoline was obtained as a cream-colored powder. This was converted into the corresponding 0.5-hydrochloride having a melting point of 218° C. as described in Example 3H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.C(O)(=O)C.Cl>O>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnoc1C1CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnoc1C1CC1
Yield: 82.1 %

Procedure:
Ethyl 5-cyclopropylisoxazole-4-carboxylate (203.0 g, 1.12 mole) [prepared in Step B] was added to a solution of 405 ml of glacial acetic acid plus 505 ml of 6N HCl and the mixture was heated in an oil bath at 105°-110° C. for 3 h. After 18 h at ambient temperature the thick mixture was diluted with water, cooled in an ice bath and filtered to give 140.8 g (82%) of the title acid. Recrystallization of an aliquot from acetonitrile gave an analytical sample, mp 163°-165° C.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:52]2[N:56]([CH2:57][CH:58]=[C:59]([CH3:61])[CH3:60])[C:55]([C:62]([NH:64][CH2:65][C:66]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH:69]=[CH:68][CH:67]=3)=[O:63])=[N:54][N:53]=2)[CH2:47]1>O1CCCC1>[NH2:5][CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:52]2[N:56]([CH2:57][CH:58]=[C:59]([CH3:61])[CH3:60])[C:55]([C:62]([NH:64][CH2:65][C:66]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH:69]=[CH:68][CH:67]=3)=[O:63])=[N:54][N:53]=2)[CH2:47]1
Reactant: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCCC(O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCCC(N)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
14 mg phthalimide, 65 mg triphenylphosphine and finally 50 μl of diisopropyl azodicarboxylate are added to a solution of 39 mg 3-(3-hydroxy-piperidin-1-yl)-4-(3-methyl-but-2-enyl)-5-(naphth-1-ylmethylaminocarbonyl)-4H-[1,2,4]triazole in 1 ml dry tetrahydrofuran. The solution is stirred for 14 h at ambient temperature and then evaporated to dryness. The residue is taken up in 2 ml of toluene and combined with 50 μl ethanolamine. After 4 h stirring at 80° C. the mixture is cooled to ambient temperature and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 95:5:1->80:20:1).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44](O)=[O:45])=[CH:40][C:39]=4C)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C1COCC1>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([C:38]4[CH:39]=[CH:40][C:41]([CH2:44][OH:45])=[CH:42][CH:43]=4)[CH:31]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CO)cc2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (2 g, 2.81 mmol) and THF (18.74 ml) were stirred at 0° C. (ice bath). To this mixture was added borane tetrahydrofuran complex (5.90 ml, 5.90 mmol) in 3 min. The resulting mixture was staged at 0° C. for 15 min. The ice bath was then removed. Reaction mixture was stirred at room temperature for additional 1 hr. TLC indicated completion of reaction. Reaction was quenched by water (ice bath). The crude mixture was worked up with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting dark mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted by a EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated affording the title compound. LCMS (ESI) calc.=697.19; found=680.29 (M−OH−)+. 1H NMR (CDCl3, 400 MHz, 1:1 mixture of atropisomers): δ 7.83 (d, J=4 Hz, 1H), 7.71 (s, 0.5H), 7.67 (s, 1H), 7.66-7.58 (m, 2.5H) 7.43 (d, J=8 Hz, 0.5H), 7.40 (d, J=8 Hz, 0.5H), 7.38-7.32 (m, 1H), 7.28-7.23 (m, 1H), 7.22-7.14 (m, 2H), 7.12 (s, 1H), 7.05 (d, J=5.6 Hz, 0.5H), 7.03 (d, J=5.6 Hz, 0.5H), 5.56 (d, J=8.4 Hz, 0.5H), 5.23 (d, J=8 Hz, 0.5H), 4.97 (d, J=10.8 Hz, 0.5H), 4.93 (d, J=10.8 Hz, 0.5H), 4.68 (s, 2H), 4.15 (d, J=15.6 Hz, 0.5H), 3.95 (d, J=15.6 Hz, 0.5H), 3.85 (s, 1.5H), 3.83 (s, 1.5H), 3.80-3.66 (m, 1H), 2.32 (s, 1.5H), 2.26 (s, 1.5H), 0.52 (d, J=6.8 Hz, 1.5H), 0.38 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: Cc1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 13 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 15 (13% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.41 (s, 3H), 2.67 and 3.18 (2d, 6H), 2.84 and 3.08 (2t, 2H), 3.59 and 4.21 (2t, 2H), 4.49 and 5.09 (2s, 2H), 6.33 and 6.82 (2d, 1H), 6.96 and 7.15 (2d, 1H), 7.33-7.37 (m, 2H), 7.55-8.15 (m, 5H), 8.51-8.56 (m, 2H); MS (ESI) m/z 439 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:9]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: ClCc1ccccc1
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=O)c(Cl)c1OCc1ccccc1

Procedure:
A mixture of 78 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, 60.7 g of benzyl chloride, 3.9 g of sodium jodide, 74.6 g of potassium carbonate in 0.5 l of 95% ethanol was refluxed for 2 hours. After cooling the mixture was poured in water, the separated product was filtered and then recrystallized from absolute ethanol. 2-chloro-3-benzyloxy-4-methoxybenzaldehyde was obtained, m.p. 86°-88° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl.CO>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19]([O:22][C:3](=[O:4])[NH2:5])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](OC(N)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of 4.52 g of trichloroacetyl isocyanate in 8 ml of methylene chloride was added to an ice-cooled solution of 3.75 g of (3R)-1-(t-butoxycarbonyl)-3-hydroxypyrrolidine in 40 ml of methylene chloride, and the mixture was stirred for 30 minutes with ice-cooling. After completion of the reaction, the solvent was stripped off from the reaction mixture and the residue was dissolved in 100 ml of methanol. The solution was stirred with 35 g of silica gel for 5 hours at 30° C., and then filtered. The filtrate was concentrated, giving 3.05 g of (3R)-1-(t-butoxycarbonyl)-3-carbamoyloxypyrrolidine.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:18][CH2:19][S:20]([F:23])(=[O:22])=[O:21]>C1C=CC=CC=1>[F:23][S:20]([CH2:19][CH2:18][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:22])=[O:21]
Reactant: CCNc1ccccc1
Reactant: O=S(=O)(F)CCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CCS(=O)(=O)F)c1ccccc1

Procedure:
N-Ethylaniline (48.4 g 0.4 m), triethylamine (40.4 g 0.4 m) and benzene (100 ml) are stirred together at room temperature and 2-chloroethanesulfonyl fluoride (58.6 g, 0.4 m) is added dropwise. The reaction mixture is heated at reflux for 1.5 hr. after the addition is completed. The reaction mixture is cooled and filtered to remove any insoluble salts, and the benzene is removed by distillation. The crude product is drowned into hexane (150 ml) and purified by filtration and washing with hexane. The product melts at 48°-50° C.
Reaction SMILES: [C:1](=[NH:20])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:21]([CH:23]([CH2:28][C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1)[C:24](OC)=O)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][C:23]2[C:21](=[O:22])[N:20]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:24]=2)[CH:30]=[N:31]1
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)n1
Temperature: 130 °C
Yield: 7.2 %

Procedure:
To the solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethyl imidocarbamate (200 mg, 0.737 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (174 mg, 0.885 mmol) in NMP (3 mL) was added K2CO3 (408 mg, 2.95 mmol). The mixture was heated with a microwave reactor at 130° C. for 0.5 h. Purification via MDAP then afforded the title compound (22 mg, 7.15% yield). LCMS: rt=2.38 min, [M+H+]=418
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](I)=[CH:14][C:13]=1[CH3:20]>>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cc1cncc(B(O)O)c1
Product: Cc1cncc(-c2cc(C)c(Br)c(C)c2)c1

Procedure:
The title compound is prepared from 5-methyl-pyridine-3-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.93 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[F:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([CH:20]2[CH2:23][NH:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)[CH2:21]2)=[O:19])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)C1CNC1
Reactant: BrCc1ccc2ccccc2c1
Product: O=C(c1ccc(F)cc1)C1CN(Cc2ccc3ccccc3c2)C1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 2-bromomethylnaphthalene and 3-(4-fluorobenzoyl)azetidine.
Reaction SMILES: [CH2:1]([C:5]1([CH2:40][CH3:41])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](O)=[O:37])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:39])[CH2:2][CH2:3][CH3:4].[NH2:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH:53]([C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[CH:52]([CH2:62][CH2:63][CH:64]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)[OH:65])[C:51]2=[O:73])=[CH:46][CH:45]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([C:5]1([CH2:40][CH3:41])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([N:50]4[C:51](=[O:73])[CH:52]([CH2:62][CH2:63][CH:64]([C:66]5[CH:67]=[CH:68][C:69]([F:72])=[CH:70][CH:71]=5)[OH:65])[CH:53]4[C:54]4[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=4)=[CH:46][CH:45]=3)=[O:37])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:39])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCC(=O)O)c2)C1O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCC(=O)NCc3ccc(N4C(=O)C(CCC(O)c5ccc(F)cc5)C4c4ccc(OC)cc4)cc3)c2)C1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At room temperature, 140 mg of (2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenylcarbamoyl]methoxy}-ethoxy)acetic acid (17) and 100 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one are dissolved in 5 ml of dimethylformamide, 35 mg of 1-hydroxybenzotriazole and 45 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added and the mixture is stirred at room temperature for 6 h. The reaction mixture is concentrated under reduced pressure. Dichloromethane is added to the residue, the mixture is extracted twice with water and once with sat. sodium chloride solution and the organic extract is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified chromatographically (RP18; dichloromethane/methanol 92/8, changed over 25 min to dichloromethane/methanol 96/4). This gives the product of melting point 116-125° C. Molecular weight 1007.24 (C56H67FN4O10S); MS (ESI): 1008.53 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 100 °C

Procedure:
0.202 g (1.0 mmol) of 1-bromo-4-nitrobenzene and 0.20 ml of piperidine (2.0 mmol) were dissolved in 3 ml of dimethylsulfoxide. 0.207 g (1.5 mmol) of potassium carbonate was added and the reaction mixture was heated to 100° C. After 2 h 100 ml of water was added, and the mixture was extracted a few times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to obtain crude 4-(piperidin-1-yl)-1-nitrobenzene. Following the procedure outlined in Step 2 of Example 1, but substituting 4-piperidin-1-yl-1-nitrobenzene for 1-methyl-4-(4-nitrophenyl)piperazine, afforded 4-piperidin-1-ylaniline, which was reacted with 9-chloroacridine (according to Step 4 in the procedure of Example 1) to obtain the title compound with 6% overall yield.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (20.18 g), 4-benzyloxyphenol (17.70 g), anhydrous potassium carbonate (12.22 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (29.03 g, 88%) of 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole. Recrystallization from ethyl acetate-hexane gave colorless leaflet crystals. melting point: 126-127° C. A mixture of the obtained 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole (22.6 g), 5% palladium carbon (10.0 g) and tetrahydrofuran (300 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give crystals (16.3 g, 95%) of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH:23]([CH3:25])[CH3:24])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH2:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH:23]([CH3:24])[CH3:25])[CH2:14][S:15][C@H:10]12
Reactant: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)c(=O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Yield: 58.3 %

Procedure:
A solution of diphenylmethyl 7-(t-butoxycarbonylamino)-3-(3,4-dioxo-2-(2-propoxy)-1-cyclobutenyl)-3-cephem-4-carboxylate (300 mg, 0.496 mmol) and p-toluenesulfonic acid monohydrate (189 mg, 0.992 mmol) in acetonitrile (1.5 mL) was stirred for 1 hr at 22° C. The solution was applied to the Michel-Miller HPLPLC column. The column was eluted with acetonitrile-H2O (45:55, v/v) to remove the toluene-sulfonic acid and then with acetonitrile-H2O (70:30, v/v) to elute the deblocked amine. The acetonitrile was removed on a rotary evaporator and the resulting mixture extracted twice with ethyl acetate. The combined extracts were washed (saturated NaCl), dried (Na2SO4), and concentrated to leave the title compound (146 mg, 58% yield) as a yellow powder.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=O)[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[NH2:30][OH:31]>N1C=CC=CC=1>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[N:30][OH:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: NO
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50 %

Procedure:
100 mg of 4,24-cholestadien-3-one (0.26 mmol) is solubilized in 5 ml of pyridine in a 10 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate are added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1
Reactant: COC(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.2 g (10 mMol) of methyl 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4.5-b]pyridine-6-carboxylate in 150 ml methanol was mixed with a solution of 1.5 g lithium hydroxide in 20 ml water and stirred for 24 hours at room temperature. Then the mixture was diluted with 50 ml of water, the alcohol was distilled off and the aqueous phase was washed with ethyl acetate. After acidification with dilute hydrochloric acid the mixture was extracted several times with dichloromethane/methanol (9:1), the organic phase was dried with sodium sulphate and the solvent was distilled off. Yield: 2.1 g beige solid (70% of theory), Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[C:11]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:3]([O:2][CH3:1])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c1
Yield: 78.8 %

Procedure:
According to example 183, 5.00 g of methyl-3-tert-butyl-4-hydroxybenzoate was silylated using 4.34 g of tert-butyldimethylsilyl chloride, 3.59 g of imidazole, and 70 mL of anhydrous DMF. The crude product was purified by flash chromatography on silica gel (9:1 hexane:EtOAc) to afford 6.1 g (79%) of methyl 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzoate as a clear liquid.