Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](=[O:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:25])([CH3:27])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-oxopropyl)-4-phenyl piperidin-2-one (82 mg, 0.2 mmol) in anhydrous THF (20 mL) was added dropwise methylmagnesium bromide (0.4 mL, 3M) at −78° C. under nitrogen. The formed mixture was stirred at rt for 1 h. The reaction mixture was quenched with aq NaHCO3 solution (5 mL). The layers were separated. The aqueous layer was extracted with EtOAc (3×8 mL). The combined organic phase was washed with a satd aq NaCl (5 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to afford (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxy-2-methylpropyl)-4-phenylpiperidin-2-one (60 mg, 70.5%). LC-MS Method 2, tR=2.131 min, m/z=454. 1H NMR (CDCl3): δ 0.85 (s, 3H), 1.05 (s, 3H), 1.46 (m, 3H), 1.85-1.89 (m, 1H), 1.96-2.18 (m, 4H), 2.73-2.76 (m, 1H), 2.89-2.94 (m, 1H), 3.58-3.63 (m, 1H), 5.91-5.96 (m, 1H), 6.95-6.97 (m, 1H), 7.21-7.34 (m, 7H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(O)c1ccccn1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccccn3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-2-yl)but-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(pyridin-2-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 8.61 (d, J=6 Hz, 1H), 8.22 (t, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.66 (m, 2H), 7.57 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.87 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2. found: 528.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=2[O:22]1>>[Br:1][CH:30]([C:25]1[CH:26]=[CH:27][C:28]2[O:29][CH2:21][O:22][C:23]=2[CH:24]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)C(Br)c1ccc2c(c1)OCO2

Procedure:
N-Bromosuccinimide (3.95 g, 22.2 mMol) and AIBN (0.098 g, 0.06 mMol) were added to a solution of methyl (3,4-methylenedioxyphenyl)acetate (3.9 g, 21.2 mMol) and the mixture was refluxed for 2.5 h. The reaction was cooled and filtered. The filtrate was concentrated in vacuo and the residue obtained was purified by flash chromatography on silica-gel using 10% ethyl acetate-hexane. Yield 2.6 g (oil).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: CC(C)=CCN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(CC=C(C)C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 51.5 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (145 mg) was reacted with N-(4-iodophenyl)-N-(3-methyl-2-butenyl)pyrimidin-2-amine (175 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((3-methyl-2-butenyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (133 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=1/1) was used for purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:28])[CH2:15][N:16]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:4]>CO.CCOC(C)=O.O[Pd]O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[CH:14]([CH3:28])[CH2:15][N:16]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:4]
Reactant: C=C1CN(S(C)(=O)=O)CCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Agent: O[Pd]O
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc3c(cc12)C(C)CN(S(C)(=O)=O)CCN3S(C)(=O)=O
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To 2-(4-Fluoro-phenyl)-7,10-bis-methanesulfonyl-5-methylene-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (3 mg, 5.74 umol) dissolved in MeOH:EtOAc (1:1 1 mL) was added Dihydroxypalladium (0.5 mg, 2.87 umol). The reaction was fitted with a balloon of H2 and then stirred overnight. The mixture was filtered through a bed of celite and washed with additional MeOH (10 mL) and EtOAc (10 mL) and then concentrated and purified by HPLC CH3CN/H2O/0.1% TFA) to provide 2-(4-Fluoro-phenyl)-7,10-bis-methanesulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (140 ug, 3%). MS-ES [M+H]+=525.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1([CH3:17])[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C:14]3([CH3:17])[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:27]1)[CH3:23]
Reactant: CCNCC1CCNC1
Reactant: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)CC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4(C)CC4)c3c2F)C1
Yield: 72.9 %

Procedure:
To 0.75 g (2.57 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 15.0 ml of acetonitrile was added 0.38 g (2.57 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.32 g (2.57 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for two hours and was cooled and filtered. The solids were washed with ether to afford 0.76 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro 1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid, mp 261°-263° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:2]=1.Br>C(O)(=O)C>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: COc1ccc(Oc2cccc(C)c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cccc(Oc2ccc(O)cc2)c1
Temperature: 0 °C

Procedure:
77 g of p-(m-tolyloxy)anisole are dissolved in 360 ml of acetic acid and treated with 300 ml of 48% hydrobromic acid. Then the mixture is allowed to react at reflux temperature for 5 hours. The cooled solution is poured into 1.5 l of ice/water and extracted three times with 150 ml of methylene chloride each time. The organic solution is washed three times with 150 ml of water each time and with 150 ml of saturated sodium bicarbonate solution, dried over anhyrous sodium sulfate and evaporated. Distillation of the crude product yields pure p-(m-tolyloxy)phenol; b.p. 88°-89° C./0.04 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:13])[F:14])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O=CO
Solvent: O
Product: CCOC(=O)N(CC(=O)O)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
A suspension of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine, 1,1-dimethylethyl ester (4.68 g, 8.76 mmol) in formic acid (150 mL) was stirred at room temperature under a dry nitrogen atmosphere. After 15 minutes, dissolution occurred. After 11/4 hours, the reaction was diluted with water (1.2 L). The aqueous phase was extracted with ether (2×300 mL). The extracts were combined, dried with magnesium sulfate, and the ether was removed. The residue was suspended in water (150 mL) and filtered. The solid was washed with water (2×30 mL) and dried. The crude product was recrystallized in chloroform:hexane twice to yield the title compound as white needles (2.24 g, 53%), m.p. 167°-168.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([N+:20]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:20][C:5]1[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[CH2:8][O:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(F)ccc(N)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of acetic acid 6-fluoro-3-nitro-2-phenylaminobenzyl ester (3.2 g, 10.5 mmol) in EtOAc (50 mL) was added palladium on carbon (600 mg, 10% by wt) and the reaction mixture stirred at RT under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% DCM in cyclohexane) to give the title compound as a brown solid (2.3 mg, 80%). 1H NMR 400 MHz δ (CDCl3): 7.22-7.15 (2H, m), 6.86 (1H, t, J=8.9 Hz), 6.81 (1H, tt, J=7.4, 1.0 Hz), 6.78-6.71 (1H, m), 6.63-6.58 (2H, m), 6.43 (1H, br s), 5.10 (2H, d, J=1.9 Hz), 3.72 (2H, br s), 1.99 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9]Br.[C:11]([C:14]1[CH:15]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([OH:24])=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:19]=1)(=[O:13])[CH3:12]>CN(C)C=O>[C:21]([N:20]1[C:18]2[CH:19]=[C:14]([C:11](=[O:13])[CH3:12])[CH:15]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]=2[O:24][CH2:9][CH2:8]1)(=[O:23])[CH3:22]
Reactant: BrCCBr
Reactant: CC(=O)Nc1cc(C(C)=O)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C(C)=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 97.8 %

Procedure:
Potassium carbonate (113 g, 818 mmol) and 1,2-dibromoethane (64.1 g, 341 mmol) were added to a solution of the N1-[5-acetyl-3-(tert-butyl)-2-hydroxyphenyl]acetamide (34.0 g, 137 mmol) in dimethylformamide (280 ml) under a nitrogen atmosphere, and then the mixture was stirred at 70° C. for 17 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with water (3 times) and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (36.9 g, 98.1% yield) as light red crystals. These were used without purification for the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]([SH:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]3[S:13][CH2:21][CH2:22][CH2:23][N:11]3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1[nH]nc(-c2cccc(Br)c2)c1-c1ccncc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Yield: 50 %

Procedure:
5-(3-Bromo-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (60 mg, 0.22 mmol), 1,3-dibromopropane (22 ul, 0.22 mmol), K2CO3 (152 mg, 1.1 mmol) and dry DMF (5 ml) were reacted at room temperature for 16 hours. Water was added and the reaction extracted with ethyl acetate. The pooled organic extracts were washed with brine, dried over sodium sulphate and evaporated down. The crude material was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1) to give a white solid (50% yield over two steps).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>CCOC(C)=O>[CH2:17]([O:7][C:6](=[O:8])[C@H:2]([C@@H:3]([CH3:5])[OH:4])[NH:1][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
To a stirred suspension of Boc-Thr-OH (21.91 g, 0.1 mol) in EtOAc (200 ml) at 0° C., TEA (14 ml, 0.1 mol) and bromoacetophenone (19.0 g, 0.1 mol) were added. The reaction mixture was allowed to warm to 20° C., stirred for 2 days and then diluted with EtOAc (500 ml). After washing successively with aq HCl (200 ml, 0.1 N), H2O (100 ml), aq NaBCO3 (200 ml, 1 N) and brine (200 ml), drying (Na2SO4), filtered and concentrated in vacuo, the residue was triturated with Et2O and filtered. The resulting solid was dried in the dark to yield D3 (28.6 g, 85%). Rf=0.55 (hex-EtOAc 1:1, silica); M.p.=114.2° C.; [α]D22 −29.4 (c 2, EtOAc).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])C1C=CC=CC=1>CO.[Pd]>[OH:23][CH2:22][CH2:21][CH:9]1[CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:13][NH:8]1
Reactant: Cc1ccccc1N1CCN(Cc2ccccc2)C(CCO)C1
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1N1CCNC(CCO)C1
Yield: 98 %

Procedure:
1-Benzyl-2-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (3.2 g; 10 mmol) in 50 mL of MeOH containing 150 mg of palladium black was shaken on a Parr apparatus under an atmosphere of hydrogen (55 psig) for 18 h. The catalyst was removed by filtration through Celite and the filtercake was washed with MeOH. The filtrate solvents were evaporated under reduced pressure to give the title compound as an oil (1H-NMR: consistent with structure; FABMS: M+H @ m/e=221; HPLC: 98%, retention time 5.38 min).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Br.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:21](=[O:23])[NH:20][C:19]4[CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:18]=4[C:17]=3[C:16]3[C:34]([CH3:37])=[N:35][NH:36][C:15]=3[N:14]=2)=[CH:9][CH:8]=1>C1COCC1>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:21](=[O:23])[NH:20][C:19]4[CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:26]=[CH:27][C:18]=4[C:17]=3[C:16]3[C:34]([CH3:37])=[N:35][NH:36][C:15]=3[N:14]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)c3c(=O)[nH]c4cc(N5CCNCC5)ccc4c3c12
Reactant: CC(=O)Cl
Agent: Br
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-c2nc3[nH]nc(C)c3c3c2c(=O)[nH]c2cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 9.2 %

Procedure:
132 μl (1.84 mmol, 145 mg) of acetyl chloride is added in several portions to a suspension of 602 mg (1.18 mmol) of 5-(4-hydroxyphenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one hydrobromide in 120 ml of THF at 0° C. The mixture is then stirred for 48 hours at room temperature and then concentrated under reduced pressure. The residue is purified by reverse-phase preparative HPLC to yield 51 mg (8%) of 4-(1-methyl-6-oxo-9-(piperazin-1-yl)-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-5-yl)phenyl acetate in the form of a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)c(Nc3ccccc3)c2)CC1
Reaction time: 2 h

Procedure:
The compound prepared in Step 2 was dissolved in ethanol, added with 10% Pd/C and stirred under hydrogen atmosphere for 2 hours. Upon completion of the reaction, the Pd/C in the reaction mixture was removed using celite and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:17](Br)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br.N1(O)CCCCC1>CC(C)=O>[CH2:17]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:3][CH2:4]1)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: BrCC=Cc1ccccc1
Agent: Br
Agent: ON1CCCCC1
Solvent: CC(C)=O
Product: OC1(c2ccc3c(c2)OCO3)CCN(CC=Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
4.4 g. 4-hydroxy-4-(3.4-methylene dioxy phenyl) -piperidine are dissolved hot in 75 ml. acetone, the solution obtained is mixed with 2.5 g. cinnamyl bromide and the reaction mixture is heated at reflux to boiling over the course of 4 hours. After boiling for 1 hour, part of the hydrobromide of the piperidinol used as the starting compound forms a precipitate and this is filtered off on completion of the reaction. The filtrate is then evaporated to dryness and extracted 3 times with 70 ml. ether each time. The ether solutions are combined, concentrated and mixed with petroleum ether during which time 1-cinnamyl-4-hydroxy-4-(3.4-methylene dioxy phenyl)-piperidine with a melting point of 114° - 115°C precipitates.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][Sn:8](Cl)(Cl)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2].[S-2:18].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][Sn:8](=[S:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC[Sn](Cl)(Cl)CCC(=O)OCC
Reactant: [S-2]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC[Sn](=S)CCC(=O)OCC

Procedure:
To a solution of 78.4g (0.2 mole) bis(ethoxycarbonylethylene)tin dichloride in 160 ml toluene was added 15.6g (0.2 mole) sodium sulfide as a 40% aqueous solution, while warming the mixture to maintain 85°-90° C. After the completion of the reaction, the layers were separated and the toluene solution of the product vacuum stripped to give the product as a viscous liquid, with refractive index 1.573 at 25° C and infra-red absorption peaks at 1700, 1660, and 1190. The product analyzed 33.9% tin, (C2H5OCOCH2CH2)2SnS requires 33.7% Sn.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[N+:19]([O-])=O)#[N:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>ClCCl>[C:1]([C:3]1[C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[NH2:19])#[N:2]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(OCC(F)(F)F)c1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)nitrobenzene using Na2S2O4 following the procedure described in Example 10(f) (87%). Rf 0.27 (dichloromethane). MS m/z 294 (MNH4)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:26]1([S:36](Cl)(=[O:38])=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:16][S:36]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:38])=[O:37])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 3-benzyloxy-5-methylphenol (600 mg, 3.0 mmol), as prepared in step a of Example 3, in methylene chloride (15 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.5 mL) and 1-naphthalenesulfonyl chloride (670 mg, 3.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (200 mL) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (1.05 g, 87%). 1H-NMR (300 MHz, CDCl3) δ 2.16 (s, 3H), 4.73 (s, 2H), 6.23 (t, 1H), 6.37 (dd, 1H), 6.61 (dd, 1H), 7.28 (m, 5H), 7.48 (t, 1H), 7.67 (t, 1H), 7.77 (t, 1H), 7.97 (t, 1H), 8.12 (dt, 2H), 8.19 (dd, 1H).