Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)c(O)c1
Reactant: COCCOCCOCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCCOCCOc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a stirred mixture of 2-(2-hydroxy-4-nitrophenyl)benzothiazole (0.15 g, 0.55 mmol), triphenylphosphine (0.216 g, 0.825 mmol) and triethylene glycol monomethyl ether (0.108 g, 0.66 mmol) in dry THF (10 ml) at 0° C. was added dropwise DIAD (0.167 g, 0.825 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, then left to rise to room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.176 g, 76%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:30](=[O:31])[CH:29]([CH3:33])[CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 2-methylpropanoyl chloride (21 mg, 150 μmol). Yield 18 mg (84%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:22]=[CH:21][CH:20]=[CH:19][C:13]=3[N:14]3[C:18]=2[CH2:17][CH2:16][CH2:15]3)=[CH:7][CH:6]=1.Cl.[OH-].[Na+]>C1COCC1>[N:22]1[C:12]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)=[C:18]3[N:14]([C:13]=2[CH:19]=[CH:20][CH:21]=1)[CH2:15][CH2:16][CH2:17]3
Reactant: COCOc1ccc(-c2c3n(c4cccnc24)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1ccc(-c2c3n(c4cccnc24)CCC3)cc1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
To a solution of 9-[4-(methoxymethoxy)phenyl]-7,8-dihydro-6H-pyrido[2,3-b]pyrrolizine (200 mg) in THF (4 mL) was added 1 M HCl aqueous solution (1 mL). The mixture was heated at 70° C. for 2 h. The mixture was neutralized with 1 M NaOH aqueous solution and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The precipitate was washed with 50% AcOEt in hexane and collected by filtration to give the title compound (154 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1.[H-].[Na+].Br[CH2:26][CH3:27].O>CN(C)C(=O)C>[CH2:26]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1)[CH3:27]
Reactant: CCBr
Reactant: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1c(COc2cc(F)c(C=O)cc2OC)nc2ccccc21
Yield: 89 %

Procedure:
To a solution of 4-(1H-benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzaldehyde (215, 4.0 g, 13 mmol) in N,N-dimethylacetamide (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.65 g, 16 mmol) portion wise. After the addition was complete, the reaction was stirred for 30 minutes after which bromoethane (1.2 mL, 16 mmol) was added and then allowed to stir for several hours. The reaction mixture was then poured into water (1 L) with stirring and the precipitated solid was filtered, washed with water and dried to give the desired compound (216, 3.8 g, 87% yield).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([S:3][C:4]1[N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2]
Reactant: CCSc1nc(C)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 29.6 %

Procedure:
To a solution of 2-ethylthio-6-methylpyrimidin-4(3H)-one (6.1 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (10.6 g) in acetonitrile (120 mL) was added potassium carbonate (5.9 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.83 g, 30%) as a colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:31])=[C:15]([N:19]5[CH2:24][CH2:23][N:22]([CH2:25][C:26]6[O:30][CH:29]=[CH:28][CH:27]=6)[CH2:21][CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:32])[C:6]([C:33]([O:35]CC)=[O:34])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[OH-].[K+]>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:31])=[C:15]([N:19]5[CH2:20][CH2:21][N:22]([CH2:25][C:26]6[O:30][CH:29]=[CH:28][CH:27]=6)[CH2:23][CH2:24]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:32])[C:6]([C:33]([OH:35])=[O:34])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(Cc5ccco5)CC4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(Cc5ccco5)CC4)c(F)cc3cc2c1=O
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
A suspension of 1.5 g of ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was heated, with stirring, at a temperature around 80° C. for approximately 1 hour 30 in 15 cm3 of ethanol and 14 cm3 of 1 N potassium hydroxide solution, 32 cm3 of 5% acetic acid were added at this same temperature and the suspension was stirred for 20 minutes. After recrystallizing from a mixture of 15 cm3 of dimethylformamide and 15 cm3 of ethanol, 0.7 g of 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was obtained in the form of a yellow solid melting at about 241° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[C:22]([O:23]COC)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:8]([C:12]1[CH:28]=[CH:27][C:15]([CH2:16][C:17]2[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1ccc(Cc2ncccc2OCOC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1ccc(Cc2ncccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of the compound of Example B229 (256 mg, 0.849 mmol) in methylene chloride (5 ml), and this reaction mixture was stirred at room temperature overnight. After a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (182 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].ClCCl.[BH4-].[Na+].[NH4+].[Cl-]>O.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[O:39])=[CH:34][N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
In a 250 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde (50 mg, 78.4 μmol, Eq: 1.00) was combined with dichloromethane (6 ml) and 2 mL MeOH to give a yellow solution. Sodium borohydride (3.56 mg, 94.1 μmol, Eq: 1.2) was added. The colorless solution was stirred at ambient temperature for 1 h. 1 mL of saturated NH4Cl was added; followed by 5 mL H2O. Mixture was stirred for 5 min. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 1% to 3% MeOH in DCM) to afford the desired product (41 mg) as an off-white powder. (M+H)+=640 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9 H) 3.50-3.85 (s and overlapping m, 11 H) 4.51 (br. s., 2 H) 6.90 (d, J=8.59 Hz, 1 H) 7.51-7.63 (m, 3 H) 7.71 (dd, J=8.59, 2.53 Hz, 1 H) 7.79 (d, J=2.53 Hz, 1 H) 8.26 (br. s., 1 H) 8.37 (d, J=1.52 Hz, 2 H) 8.70 (d, J=5.05 Hz, 1 H) 8.82 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20](O)=[O:21])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(CC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CCO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-ethoxycarbonyl-piperidin-4-ylacetic acid (2.34 g) in tetrahydrofuran (60 ml) was added a 1M borane tetrahydrofuran solution (7.42 ml) at −78° C., and the mixture was allowed to warm to room temperature in 15 hours in stirring. After completion of the reaction, water and potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was washed with hexane. The aqueous layer was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (1.92 g).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][O:13][C:12]=1[CH:21]=[O:22].C(#N)C.C(O)=O>C1COCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Pd]>[C:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][O:13][C:12]=2[CH:21]=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=CC1=C(Cl)c2ccccc2CO1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: O=CC1=C(c2ccccc2)c2ccccc2CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
X-phos Pd G2 (116 mg, 0,147 mmol) and phenylboronic acid (538 mg, 4.41 mmol) were sealed in a closed vessel equipped with a magnetic bar and oxygen removed by Ar/vacuum cycle. A degassed solution of 4-chloro-1H-isochromene-3-carbaldehyde (Intermediate G20.1, 716 mg, 3.68 mmol) in THF (8 ml) was added followed by a degassed solution of K3PO4H2O (1,795 ml, 7.36 mmol) in water (8 ml) and the resulting mixture stirred at rt overnight. The reaction mixture was partitioned between 1M HCl (15 ml) and the same amount of AcOEt. The organic layer was anhydrified over Na2SO4, evaporated in vacuo and purified via reverse phase chromatography with a Biotage C18 SNAP 120 g column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (821 mg, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[CH:5]/[CH2:6][C:7]([CH3:11])([CH3:10])[CH:8]=[CH2:9]>CO>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][CH3:9]
Reactant: C=CC(C)(C)C/C=C(\NC(=O)OCc1ccccc1)C(=O)OC
Solvent: CO
Product: CCC(C)(C)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Reaction time: 8 h
Yield: 80.5 %

Procedure:
R,R-DIPAMP cyclooctadiene Rh(I) tetrfluoroborate (190 mg, 0.25 mmol, 0.04 eq) was added to a solution of (Z)-2-benzyloxycarbonylamino-5,5-dimethyl-hepta-2,6-dienoic acid methyl ester (2.00 g, 6.30 mmol, 1.00 eq) in dry methanol (20 mL) in a Paar hydrogenation flask. The reaction vessel was evacuated and flushed with a hydrogen atmosphere three times, then vigorously shaken under 50 psi of hydrogen overnight. The reaction mixture was concentrated in vacuo then filtered through a plug of silica gel using a gradient of ethyl acetate in hexanes as the eluant to provide (S)-2-benzyloxycarbonylamino-5,5-dimethyl-heptanoic acid methyl ester as a yellow oil (1.63 g, 81% yield); 1H NMR (CDCl3, 400 MHz) δ 0.74-0.90 (m, 9H), 1.10-1.30 (m, 4H), 1.58-1.70 (m, 1H), 1.75-1.90 (m, 1H), 3.75 (s, 3H), 4.30-4.40 (m, 1H), 5.14 (s, 2H), 5.24-5.33 (m, 1H), 7.30-7.37 (m, 5H); [α]20D=+15.57 c=2.00, CHCl3.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([CH3:11])=[CH2:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=1)=[O:2]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([C:12]([F:14])([F:13])[F:15])=[CH:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[N:20][CH:21]=1
Reactant: C=C(C)c1cc(C(F)(F)F)cc(-c2ccc(C(=O)NCCC(=O)OCC)nc2)c1C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(C)C)c2CO)cn1

Procedure:
A solution of ethyl 3-(5-(2-formyl-3-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (150.1 mg, 0.35 mmol) in THF (5 mL) and MeOH (25 mL) was hydrogenated substituting H-Cube (10 Bar H2) at 40° C. at a flow rate of 1 mL/min. The resulting solution was concentrated to yield the title compound.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:29])[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:16][C:17]([O:19]CC)=[O:18])[CH2:8]2>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:29])[CH:15]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:16][C:17]([OH:19])=[O:18])[CH2:8]2
Reactant: CCOC(=O)CC(C(=O)N1Cc2ccc(Cl)cc2C1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(C(=O)N1Cc2ccc(Cl)cc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
With stirring at rt the solution of lithium hydroxide monohydrate (0.29 g) in water (1.5 ml) was added to the solution of ethyl 4-(5-chloro-2-isoindolinyl)-3-(4-chlorophenyl)-4-oxobutanoate (0.64 g) in methanol (10 ml). The cloudy solution was stirred at rt for 2 h. Then the methanol was removed by distillation and the residue was diluted with water (3 ml). With ice-cooling conc. HCl (1 ml) was added dropwise to the stirred solution. The precipitate formed is kept at 0° C. for 0.5 h and collected by suction filtration. After washings with 1M HCl and water the solid is dried in vacuo to provide 4-(5-chloro-2-isoindolinyl)-3-(4-chlorophenyl)-4-oxobutanoic acid (0.56 g) as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[CH:11]=[CH:10][C:9]4[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20]CCCC>>[CH2:19]([N:13]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:14]1=2)[CH3:20]
Reactant: CCCCCC
Reactant: Cc1cccc2c1[nH]c1ccc3ccccc3c12
Product: CCn1c2ccc3ccccc3c2c2cccc(C)c21
Yield: 79.1 %

Procedure:
Using the procedure outlined in Example 34A, 8-methyl-7H-benzo[c]carbazole (Cambridge Chemicals, Inc.) gave a 79.1% yield of 7-ethyl-8-methyl-7H-benzo[c]carbazole, mp 79°-83°, (hexane), (C,H,N).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[N:38][C:33]([Cl:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)nc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 6-chloro-pyridine-3-sulfonyl chloride. Purity (ELSD, based on MW=597.1)=98%.
Reaction SMILES: [OH2:1].[Cl-].[Cl-].IC1C=CC=CC=1.[Na].[CH3:12][C:13]1([CH3:34])[S:17][C@@H:16]2[C@H:18]([NH:21][C:22]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C@H:14]1[C:31]([OH:33])=[O:32]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:12][C:13]1([CH3:34])[S:17](=[O:1])[C@@H:16]2[C@H:18]([NH:21][C:22]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C@H:14]1[C:31]([OH:33])=[O:32]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: O
Agent: [Cl-]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1.5 h

Procedure:
5 ml of water and 3 g (10 mmoles) of iodobenzene dichloride in 40 ml of pyridine were added at -10° C with stirring to a suspension of 7.1 g (20 mmoles) of the sodium salt of benzylpenicillin in 160 ml of pyridine. The solution was stirred for 90 minutes and was poured into 200 ml of water and 500 ml of ethyl acetate. After adjusting the pH to 1.7 with HCl and extraction of the water layer several times with ethyl acetate, the combined organic layers were dried, concentrated and treated with diethyl ether and n-hexane. The obtained precipitate (3 g) was dissolved in water and sodium bicarbonate and the resulting solution was washed with methylene chloride, treated with decolorizing carbon, adjusted to a pH of 1.7 with HCl in the presence of methyl isobutylketone and extracted with methyl isobutylketone. The dried, concentrated organic layer was treated with diethyl ether and n-hexane and the precipitate was filtered off and dried to obtain 1.9 g of a mixture of benzylpenicillin, benzylpenicillin R-sulfoxide and benzylpenicillin-S-sulfoxide. 1.4 g of this precipitate was chromatographed on a column (65 cm in length, 2.5 cm in diameter filled with 180 g of silica gel and the eluent was a 97:3 (v/v) mixture of acetone and acetic acid. Fractions 30 to 71 contained 115 mg of the benzylpenicillin R-sulfoxide which was isolated by evaporating the solvent and dissolving the residue in ethyl acetate followed by precipitation with diethyl ether and n-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:7]2[OH:23].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].O>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:8]2[C:7](=[O:23])[C:6]3[C:11]4=[C:2]([NH:1][C:31](=[O:32])[N:10]4[CH:9]=2)[CH:3]=[C:4]([CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:5]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(=O)[nH]c3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 3, 331 mg) and 1,1′-carbonyl diimidazole (215 mg) in DMF (2.5 mL) is heated at 80° C. for 1 h. A second portion of 1,1′-carbonyl diimidazole (167 mg) is added and heating is continued for an additional 1 h. After cooling, water (8 mL) is added and the resulting precipitate is filtered off, washed with water and dried to afford 261 mg of the title compound. Physical characteristics: M.p. 286° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ2.39, 3.57, 3.62, 4.57, 7.39, 7.61, 8.88, 10.0, 12.0. Anal. Found: C, 60.37; H, 4.78; N, 12.49.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].I[CH3:17]>C1COCC1>[CH3:17][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: CI
Reactant: CC1(C)Nc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
In a 200-mL r.b. flask, a solution of 3,4-dihydro-3,3-dimethylquinoxalin-2(1H)-one (1.00 g, 5.66 mmol) in dry THF was treated with NaH (0.28 g, 7.09 mmol, 1.25 equiv). The reaction mixture was stirred at room temperature for 30 minutes before iodomethane (0.39 mL, 6.24 mmol, 1.1 equiv) was added to the reaction flask. The reaction was then stirred at room temperature overnight then partitioned between EtOAc (100 mL) and H2O (20 mL). The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were then washed with brine (20 mL), dried (MgSO4), filtered, and concentrated to a thick oil. Purification by flash chromatography (25% EtOAc/hexane) afforded 830 mg (78%) of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one as a white solid. Data for 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one: 1H NMR (400 MHz, CDCl3) δ 6.90 (m, 3H), 6.67 (d, J=7.7, 1H), 3.69 (bs, 1H), 3.36 (s, 3H), 1.37 (s, 6H).