Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Cl-].[CH3:3][Zr:4]([CH3:34])(=[SiH2:33])([C:24]1[CH:28]([CH3:29])[C:27]([CH3:30])=[C:26]([CH3:31])[C:25]=1[CH3:32])[CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17](C(C)(C)C)=[CH:16][CH:15]=2)=[CH:6]1>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH3:34][Zr:4]([CH3:3])(=[SiH2:33])([C:24]1[CH:28]([CH3:29])[C:27]([CH3:30])=[C:26]([CH3:31])[C:25]=1[CH3:32])[CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6]1
Reactant: CC1=C(C)C(C)C([Zr](C)(C)(=[SiH2])C2C=C(c3ccc(C(C)(C)C)cc3)c3ccccc32)=C1C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)C([Zr](C)(C)(=[SiH2])C2C=C(c3ccccc3)c3ccccc32)=C1C
Reaction time: 0.25 h

Procedure:
30 wt % MAO in toluene (6.27 g, 32.4 mmol, 120 eq.) and toluene (6.50 g) were combined and stirred for 15 minutes to give a clear solution. To this MAO solution was added dimethylsilylene(2,3,4,5-tetramethyl-1-cyclopentadienyl)(3-(4-t-butylphenyl)-1-indenyl)zirconium dichloride (Metallocene II, 0.158 g, 0.269 mmol, 1.00 eq.). The reaction was stirred for 15 minutes and then DAVISON™ 948 silica (5.00 g, dried at 600° C. for 16 hours) was added. The slurry was mixed for 10 minutes and then dried under vacuum for 24 hours. Yield 6.92 g (98%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:17]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][CH3:16])[CH2:11][CH2:10]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:17]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:16])[S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Product: CN([C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)S(C)(=O)=O

Procedure:
Prepared analogously to example IV.3 from 0.305 g trans-[4-(5-fluoro-2-nitrophenoxy)-cyclohexyl]-methyl-amine hydrochloride and methanesulfonyl chloride.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][C:10](=O)[CH2:9]1)=[O:7].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[NH:38][C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>CO.[Pd]>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1)[C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][C@H:10]([N:44]2[CH2:45][CH2:46][N:41]([CH2:40][C:39]([NH:38][C:32]3[C:33]([CH3:37])=[CH:34][CH:35]=[CH:36][C:31]=3[CH3:30])=[O:47])[CH2:42][CH2:43]2)[CH2:9]1)=[O:7]
Reactant: O=C1CC(Cc2ccccc2)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2C[C@@H](Cc3ccccc3)N(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)CC1
Yield: 14.6 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (0.0037 mol) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0037 mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%, 1 g) as a catalyst in the presence of tiophene solution (1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was dried and then crystallized from DIPE. The precipitate was filtered off and dried, yielding 0.35 g (15%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 131).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-fluoro-3-nitrobenzotrifluoride (1.00 g, 4.78 mmol) in THF (25 mL) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.84 mL, 5.7 mmol) and NaHCO3 (1.1 g, 13 mmol). The resulting mixture was stirred for 1 h at RT, diluted with CH2Cl2, and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].Br[C:36]1([C:41]([O:43][CH3:44])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:36]4([C:41]([O:43][CH3:44])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: COC(=O)C1(Br)CCCC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OC3(C(=O)OC)CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in N,N-dimethylacetamide (10 mL) were added methyl 1-bromocyclopentanecarboxylate (1.4 g) and cesium carbonate (2.2 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.94 g, 77%) as a pale-yellow solid.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[F:34])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:25]=1[F:34]
Reactant: O=C(c1ccc(F)cc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(C(F)(F)F)cc3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccc(F)cc3)cn2c1-c1ccc(C(F)(F)F)cc1F

Procedure:
The 2-trifluoroacetamido-3-(2-fluoro-4-trifluoromethylphenyl)-6-(4-fluorobenzoyl)-imidazo[1,2-a]pyridine (6.75 g, 13.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 4.66 g. (85%). EA, MS(FD).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35]Br.O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:20]=[CH:19][CH:18]=[C:16]([N:17]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:15]=3)=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: Cc1cccc(-c2[nH]c(Cc3cccc(N)c3)nc2-c2ccc3ncccc3c2)n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3cccc(N4CCCC4)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 120 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
To a solution of 6-(5-(6-methylpyridin-2-yl)-2-(3-nitrobenzyl)-1H-imidazol-4-yl)quinoline (500 mg, 1.186 mmol, prepared according to the method described in US 2008/0319012 A1) in MeOH (5 mL) was added Pd/C (0.5 mg, 10% w/w) and the mixture was stirred under H2 at atmospheric pressure for 5 hours. The reaction mixture was filtered through celite and the filterate was concentrated under reduced pressure. The residue was purified by MPLC on silica gel (MeOH:CH2Cl2=1:50) to afford the 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (424 mg, 91%). The obtained compound, 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (30 mg, 0.077 mmol) was dissolved in DMF (3 mL), treated with 1,4-dibromobutane (17 mg, 0.080 mmol), and stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, added H2O (30 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v)) and on NH silica gel (MeOH:CH2Cl2=1:100 (v/v)) to afford the title compound (7 mg, 20.5%). (300 MHz, CDCl3) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H, m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41 (1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH2:18]Br>CN(C=O)C>[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH2:18][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: Oc1ccc2ccccc2n1
Reactant: CON=C(CBr)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(Cn1c(=O)ccc2ccccc21)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
To a suspension of 2-hydroxyquinoline (242 mg, 1.63 mmol) in DMF (5 mL) was added NaH (125 mg, 3.13 mmol). After 5 minutes of stirring at room temperature, 2-bromo-1-p-tolylethanone O-methyl oxime (400 mg, 1.65 mmol) was added and the mixture was stirred for 30 additional min. The mixture was poured on ice, extracted with Et2O, and dried over MgSO4. Purification by flash chromatography on silica gel (1% MeOH/CH2Cl2) gave a pure product in 28% yield: mp 129-132° C.; 1H NMR 400 MHz (DMSO-d6) δ 2.15 (s, 3H), 4.07 (s, 3H), 5.59 (s, 2H), 6.58 (d, 1H, J=9.2 Hz), 6.98 (d, 2H, J=7.0 Hz), 7.20 (m, 4H), 7.60 (s, 2H), 7.80 (d, 1H, J=8.8 Hz); Elem. anal. found: C, 74.12; H, 5.85; N, 9.00% (calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14%); MS (ESI) m/z 329.00 (MNa+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:3][C:9]1[C:8]2[C:13](=[CH:14][C:15]([F:17])=[CH:16][C:7]=2[F:6])[N:12]=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cc(F)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
Phosphoryl chloride (3.32 ml) was added to a stirred mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (5 g), diisopropylethylamine (7.16 ml) and acetonitrile (120 ml) that was cooled in an ice bath. The resultant reaction mixture was heated to 80° C. for 2 hours. A second portion of phosphoryl chloride (1.52 ml) was added and the reaction mixture was heated to reflux for a further 2.75 hours to provide a solution of 4-chloro-5,7-difluoroquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (International Application WO 01/94341, Example 17, Note [30]; 4.95 g) in acetonitrile (15 ml) was added and the reaction mixture was heated to 80° C. for 4 hours. The resultant reaction mixture was stirred at ambient temperature for 16 hours. A solution of a second portion of 6-chloro-2,3-methylenedioxyaniline (1.18 g) in acetonitrile (5 ml) was added and the reaction mixture was reheated to 80° C. for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was stirred for one hour. The resultant slurry was filtered and the isolated solid was washed with acetonitrile (20 ml) and dried. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline as a mono-hydrochloride salt (7.88 g, 99.3% HPLC purity using Method A, retention time 4.46 minutes); NMR Spectrum: (DMSOd6) 5.5-6.0 (br s, 1H), 6.15 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.7 (s, 1H), 1.9-2.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([O-])([O-])=[O:12].[K+].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:12][CH3:11])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: CO
Product: COc1cnc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
To a solution of 10 g (55.9 mmol) 2,4-dichloro-5-methoxy-pyrimidine in 200 mL MeOH was added 7.7 g (55.9 mmol) K2CO3. The reaction mixture was stirred at room temperature for 24 h, then the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL) and water (100 mL). The organic layer was separated, dried (Na2SO4), and evaporated affording 9.0 g (92%) 2-chloro-4,5-dimethoxy-pyrimidine as a fluffy white solid which was used in subsequent steps without further purification. LCMS [M+H]+=175.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:19]([C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1)#[N:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=2)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CCOC(=O)c1cnc(-c2cccnc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(-c2cccnc2)nc1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 14d (1.0 g; 3.79 mmol), 3-cyanophenol (0.587 g; 4.93 mmol) and Cs2CO3 (4.93 g; 15.13 mmol) in CH3CN (25 mL) was stirred at room temperature for 2 h. The suspension was poured into ice-water and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over MgSO4 and concentrated to afford Compound 14e. 1H NMR (300 MHz, CDCl3): δ 9.40 (s, 1H), 9.25 (s, 1H), 8.70 (d, 1H), 8.45 (m, 1H), 7.45-7.65 (m, 4H), 7.35 (m, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 347.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([CH:18]([C:35]([CH3:37])=[CH2:36])[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:15]1=[O:38])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(O)[O-].[Na+]>O1CCCC1.O>[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([C:18](=[C:35]([CH3:37])[CH2:36][Br:1])[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:15]1=[O:38])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CBr)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a solution of 4.1 ml of 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) and 1.6 ml of bromine in 90 ml of tetrahydrofuran (THF) at -78° was added 4.36 g (9.0 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-3-butenoate in 20 ml of THF. The reaction mixture was placed in an ice bath and stirred for 20 minutes. Sodium bisulfite (3 g) in 30 ml of water was then added. After 10 min. the THF was removed under reduced pressure. Ethyl acetate was added to the resulting aqueous mixture. The organic layer was washed with dilute acid, sodium bicarbonate solution and brine (2X), dried, and evaporated in vacuo to provide 3.6 g (77%) of the title product: nmr (CDCl3) δ 2.13 and 2.28 (s, 3, CH3), 4.2 (m, 2, --CH2Br), 3.67 (m, 2, C4 --H), 4.97 (m, 1, C3 --H), 4.50 (s, 2, side chain CH2), and 7.2 (b, ArH).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:17](=[O:27])[CH2:16][CH2:15]1.N1C=CC=CC=1.[Br:34]Br>C(Cl)Cl>[Br:34][CH:16]1[CH2:15][CH:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:7])[CH2:20][CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:18][C:17]1=[O:27]
Reactant: Cc1ccccc1C1CCC(=O)NC(c2ccccc2)C1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C1CC(Br)C(=O)NC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a 250 mL round-bottomed flask equipped with addition funnel and nitrogen inlet were added 3.5 grams (16.8 mol) phosphorus pentachloride and 25 mL dry methylene chloride. The mixture was cooled with stirring to 0° C., and a solution of 4.7 grams (16.8 mmol) 5-(2-methlphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-2-one and 2.7 mL (33.6 mmol) pyridine in 50 mL methylene chloride was added drop wise over 20 minutes. The reaction was stirred 5 minutes at 0° C., then 1.9 mL (37.0 mmol) bromine in 5 mL methylene chloride was added drop wise over 5 minutes. The reaction was stirred 5 minutes at 0° C., then 1.8 hours at room temperature. The reaction was evaporated, taken up in 40 mL of 1:1 tetrahydrofuran: water, and stirred for 1.2 hours. The reaction was then poured into water and extracted into ethyl acetate. The organic layer was washed with aqueous sodium bisulfite solution and brine, dried over sodium sulfate, and evaporated to an oil. At this point, a little of the desired monobrominated product can be recovered by chromatography, as described below; the remainder, mostly dibromo adduct, is treated an follows. The oil was taken up in 20 mL methylene chloride and 20 mL ethanol, and hydrogenated under 42 p.s.i. hydrogen in the presence of 0.70 grams 10% palladium-on-carbon and 7 drops of quinoline for 1 hour. Tlc showed mostly desired monobromo product at Rf=0.5, with a little dibromo precursor at Rf=0.7 and starting lactam at Rf=0.15, in 1/1-ethyl acetate/hexane. The reaction was filtered through Celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 2/1-hexane/ethyl acetate as eluent to afford 2.8 grams (46%) of a foam, a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[C:27]2[C:26](=[O:28])[N:24]([CH3:25])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=2[N:20]=[CH:19]1.O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH2:16][CH2:17][N:18]2[C:27]3[C:26](=[O:28])[N:24]([CH3:25])[C:23](=[O:29])[N:22]([CH3:30])[C:21]=3[N:20]=[CH:19]2)=[O:9])=[CH:13][CH:14]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: Cn1c(=O)c2c(ncn2CCO)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cn1c(=O)c2c(ncn2CCOC(=O)C(C)(C)Oc2ccc(Cl)cc2)n(C)c1=O
Yield: 55.1 %

Procedure:
107.3 g (0.5 mol) 2-(p-chlorophenoxy) isobutyric acid and 56.0 g (0.25 mol) 7-hydroxyethyltheophylline were suspended together in 250 ml xylene and heated for 15 hours in a water separator after addition of 1.5 g p-toluenesulfonic acid. The solution was next agitated with dilute sodium bicarbonate solution (0.5 mol NaHCO3), waterwashed and evaporated in a rotary evaporator. The residue was crystallized from isopropanol, yielding 58.0 g (55% yield) 1-(7-theophyllinyl)-2-ethyl [2-(p-chlorophenoxy)-isobutyrate] with a melting point 131°-132°C.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH:26]=[C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][C@H:29]([O:37][C:38](=[O:40])[CH3:39])[CH2:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:38]([O:37][C@H:29]1[CH2:30][CH2:31][C@@:32]2([CH3:33])[C:27](=[CH:26][CH2:25][C@@H:24]3[C@@H:34]2[CH2:35][CH2:36][C@@:19]2([CH3:20])[C@H:21]3[CH2:22][CH:23]=[C:18]2[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:28]1)(=[O:40])[CH3:39]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Diethyl(3-pyridyl)borane (3.38 g, 23 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (6.94 g, 15 mmol) in THF (75 ml) containing bis(triphenylphosphine)palladium(II) chloride (0.105 g, 0.15 mmol). An aqueous solution of sodium carbonate (2M, 30 ml) was then added and the mixture heated, with stirring, by an oil bath at 80° C. for 1 h, and allowed to cool. The mixture was partitioned between diethyl ether and water, the ether phase was dried (Na2CO3), filtered through a short plug of silica, and concentrated. Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the title compound (4.95 g, 84%) which crystallised from hexane, m.p. 144°-145° C., 1H-NMR(CDCl3) inter alia δ1.05(3H,s, 19-CH3), 1.08(3H,s,18-CH3), 2.04(3H,s,CH3CO2), 4.60(1H,m,3α-H), 5.42(1H,dm, J 4.7 Hz,6-H), 5.99(1H,m,16-H), 7.23(1H,m,Py 5-H) 7.65(1H,m,Py 4-H), 8.46(1H,m,Py 6-H), 8.62(1H,m,Py 2-H). Anal. Calcd: C, 79.75; H, 8.50; N, 3.58. Found: C, 79.78; H, 8.52; N, 3.54%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:6]([OH:8])[CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[O:8][C:6]=2[CH:7]=1
Reactant: Cc1ccc(-n2cccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Yield: 59.6 %

Procedure:
To 5-methyl-2-pyrrol-1-yl-phenol (6.0 g, 33.6 mmol) in dichloromethane (75 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6.61 g, 33.6 mmol) then trifluoroacetic acid (3.1 mL, 40.3 mmol) and the mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated and the crude residue was purified by column chromatography utilizing a gradient of 0-100% dichloromethane in hexanes to yield tert-butyl 7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (7.1 g, 59%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 6.88 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.29 (t, J=3.2 Hz, 1H), 6.00-5.98 (m, 1H), 5.30 (s, 1H), 3.97 (s, 2H), 3.26 (t, J=12.2 Hz, 2H), 2.32 (s, 3H), 2.09-2.01 (m, 2H), 1.87 (dt, J=13.3, 4.9 Hz, 2H), 1.48 (s, 9H). ESI-MS m/z calc. 354.4. found 355.5 (M+1)+; Retention time 2.28 minutes (3 min run).