Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:8]/[N:7]([CH3:10])[CH3:6])/[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CN(C)/C=C(\C=O)c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
Phosphoryl chloride (55.0 mL, 590 mmol) was added dropwise to N,N-dimethylformamide (80.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for an additional 30 min after which 4-bromophenylacetic acid (43.0 g, 200 mmol) was added portion wise. The resulting mixture was heated at 70° C. overnight. After cooling, the reaction mixture was added slowly to a mixture of ice and water with external cooling. Ice was added intermittently to keep the temperature <10° C. When the quenching was complete, potassium carbonate and ice were added slowly until pH 11 was achieved. Small quantities of ethanol were added to control frothing. To the alkaline mixture was added toluene (120 mL), and the reaction mixture was refluxed for 1.5 hours and cooled to ambient temperature. The aqueous layer was extracted with toluene (2×50 mL). The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexanes to give the desired product. (26.5 g, 52%) LCMS: (M+H)=281.0/283.0.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24]CC2C=CC=CC=2)[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6]>C(O)C>[F:32][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC(F)F)c2)cn1
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)COC(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-N-(5-methylpyrazin-2-yl)-5-phenylmethoxy-benzamide (0.48 g, 1.08 mmol) was dissolved in ethanol (10 mL) and THF (10 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (48 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was evacuated and purged with argon (3 times) and the catalyst removed by filtration through celite®. The filtrate was concentrated in vacuo to give the desired compound (0.38 g).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:26])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([CH:24]=[CH2:25])[O:18]1.CCN(CC)CC>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:22][C:21]1([CH3:23])[C:17]([CH3:26])([CH3:16])[O:18][B:19](/[CH:24]=[CH:25]/[C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:20]1
Reactant: Brc1ccc(CCN2CCOCC2)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Product: CC1(C)OB(/C=C/c2ccc(CCN3CCOCC3)cc2)OC1(C)C
Temperature: 80 °C
Yield: 76.8 %

Procedure:
To a mixture of 4-(4-bromophenethyl)morpholine (731 mg, 2.71 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.5 mL, 2.95 mmol, 1.1 eq.) in a 20 mL microwave vial was added Et3N (0.76 mL, 5.4 mmol, 2 eq.), followed by Pd(PtBu3)2 (14 mg, 0.027 mmol, 1 mol %). The resulting mixture was purged with argon, then capped and heated at 80° C. (oil temp.) for 2 h. After cooling to rt, the reaction was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), extracted with EtOAc (30 mL×2) and dried over Na2SO4. After evaporation of the solvents, the residue was purified by Biotage column system (EtOAc/hex gradient: 0-100%) to give (E)-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenethyl)morpholine as a white solid (714 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.0 Hz, 2H), 7.38 (d, J=19.0 Hz, 1H), 7.19 (d, J=7.8 Hz, 2H), 6.13 (d, J=18.3 Hz, 1H), 3.75 (t, J=4.4 Hz, 4H), 2.84-2.77 (m, 2H), 2.63-2.56 (m, 2H), 2.53 (br, pseudo s, 4H), 1.32 (s, 12H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:23]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)=O)[CH:12]=[C:13]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1([CH2:39][C:40]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)CC.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[C:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:40](=[O:41])[C:39]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:12]=[C:11]([C:23]#[C:25][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C(=O)c1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1)c1ccccc1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)=C1c1ccccc1
Temperature: 24 °C
Yield: 76.4 %

Procedure:
A portion of the 3,5-bis(phenylethynyl)benzil (10.87 grams, 0.0265 mole), 1,3-diphenylacetone (5.90 grams, 0.0281 mole), anhydrous 1-propanol (300 milliliters) and anhydrous toluene (17 milliliters), both of which had been sparged with dry nitrogen, were added under a dry nitrogen atmosphere to a predried 500 milliliter glass three neck round bottom reactor containing a predried magnetic stirring bar. The reactor was additionally outfitted with a fan cooled spiral condenser and a thermometer with thermostatically controlled heating mantle. Stirring and heating commenced, and once a refluxing clear light yellow colored solution formed, benzyltrimethylammonium hydroxide (40 percent in methanol) (0.91 gram) was added, immediately inducing a dark red color. After maintaining the reflux for 20 minutes, HPLC analysis indicated that full conversion of the 3,5-bis[phenylethynyl)benzil reactant had been achieved. After a cumulative 30 minutes of reaction, the heating mantle was removed from the reactor, and the stirred contents were maintained at 24° C. for the next 16 hours. The product was recovered via filtration through a medium flitted glass funnel. The product cake on the funnel was washed with two portions (50 milliliters) of 1-propanol, then dried in a vacuum oven to provide 11.84 grams (76.4 percent isolated yield) of 4-(3,5-bis(phenylethynyl)phenyl)-2,3,5-triphenylcyclopentadienone (unsymmetrically substituted 3,5-AAB monomer) as a dark red purple colored crystalline product. HPLC analysis revealed the presence of the desired product at 100 area percent. The product's identity was confirmed by 1H NMR and EI MS analysis.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.[OH-].[Na+]>O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1ccccc1
Yield: 1223 %

Procedure:
3-Phenylpropanol (3.00 g) and 1,6-dibromohexane hydrogen sulphate (0.5 g) and 12.5 M aqueous NaOH (16 ml) for 30 h. The mixture was diluted with H2O (80 ml), extracted with ER (3×100 ml), and the combined organic extracts were washed consecutively with H2O (80 ml) and BR (80 ml). The dried extracts were evaporated and the residual oil purified by [FCS], eluting with CX (one columnful), followed by EA-CX (1:20) to give the title compound (5.35 g) as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[NH2:21][CH2:22][CH:23]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1)[C:24]([O:26][CH3:27])=[O:25].O>ClCCl>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:21][CH2:22][CH:23]([N:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:32][CH2:33]2)[C:24]([O:26][CH3:27])=[O:25])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Reactant: COC(=O)C(CN)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CNS(=O)(=O)c1ccc(O)cc1)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 4.2 %

Procedure:
2.1 ml (15 mmol) of triethylamine and then 920 mg (5 mmol) of 4-hydroxybenzenesulfonyl chloride in 20 ml of dichloromethane are added dropwise to a solution of 1.1 g (3 mmol) of benzyl 4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate dihydrochloride in 30 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is then stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with dichloromethane. The organic phase is with water and then dried over magnesium sulfate, filtered and concentrated under vacuum. The crude residue obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 60 mg (46%) of benzyl 4-[2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]piperazine-1-carboxylate are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([F:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:19][CH2:20][C:21]([F:25])([CH3:24])[CH2:22][CH2:23]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(F)CC2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(F)CC2)c1Br
Temperature: 25 °C
Reaction time: 120 h
Yield: 155.2 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (600 mg, 1.44 mmol) and 0.14 mL of 70% HClO4 in DCM (15 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 5 days. The reaction was diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-25% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 529 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) 6 (br. s, 1H), 4.92-4.89 (m, 1H), 4.04 (br. s, 1H), 3.51-3.48 (m, 1H), 3.37-3.36 (m, 1H), 2.85 (br. s, 1H), 2.53 (s, 3H), 2.44 (br. s, 3H), 1.95-1.67 (m, 4H), 1.42/1.36 (s, 3H), 1.17-1.14 (m, 12H), 1.0 (d, J=6.2 Hz, 3H). UPLC (M+H)=475.2.
Reaction SMILES: [CH3:1]NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]3[N:23](C)[N:24]=[CH:25][CH:26]=3)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]3[CH:26]=[CH:25][N:24]([CH3:1])[N:23]=3)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: CNN
Solvent: c1ccncc1
Product: Cn1ccc(-c2cc(NC(=O)Nc3ccc(Cl)cc3)ccc2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
To a cooled and stirred solution of methyl hydrazine (1.46 g, 31.6 mmol) in pyridine was added slurry of Compound 119 (2.5 g, 7.9 mmol) in pyridine over a period of 10 mins. The reaction mixture was left at this temperature for another 2 hrs and then warmed to room temperature slowly. After 6 hrs the reaction mixture turned clear. The reaction was stirred at this temperature for 18 hrs. Then pyridine was evaporated. The dark colored residue was dissolved in DMSO and purified using Varian Preparative HPLC system at a flow rate of 60 mL/Min. and λ=240. The regio isomers were separated. The fractions containing Compound 154 were dried in vacuo to produce an off-white solid 1-(4-Chloro-phenyl)-3-[4-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-phenyl]urea (0.3 g, 12%). LCMS m/z (%)=343 (M+H, 35Cl 100), 345 (M+H, 37Cl, 32.5). 1H NMR (400 MHz, DMSO-d6) δ: 10.26 (bs, 1H), 8.73 (bs, 1H), 8.46 (bs, 1H), 7.82 (d, J=2.32 Hz, 1H), 7.77 (d, J=3.62 Hz, 1H), 7.44-7.49 (m, 2H), 7.16-7.19 (dd, J=8.74, 2.62 Hz, 1H), 6.83-6.85 (d, J=8.72 Hz, 1H), 6.71-6.72 (d, J=2.36 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C@@H:26]([CH3:48])[CH2:27][O:28]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C1C=CC=CC=1.[ClH:55]>CO>[ClH:55].[ClH:55].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:48])[CH2:27][OH:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(O[C@@H](C)COC(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)cc3ccccc23)CC1
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(OC(C)CO)cc3)cc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the resulting 1-(4-ethylpiperazin-1-yl)-3-{4-[2-trityloxy-1-(S)-methylethoxy]phenyl}isoquinoline (1.21 g) were added benzene (10 ml), methanol (50 ml) and 2N hydrochloric acid (10 ml) and dissolved, and the resulting mixture was stirred at room temperature for 45 min. The solvent was evaporated, and the resulting residue was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, to give 0.36 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[CH3:31][Si:32]([CH3:50])([CH3:49])[CH2:33][CH2:34][S:35]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([CH:47]=O)=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(=[O:37])=[O:36]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:47][C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([S:35]([CH2:34][CH2:33][Si:32]([CH3:31])([CH3:50])[CH3:49])(=[O:36])=[O:37])[CH:39]=[CH:40]2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(C=O)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-α-phophonoglycine trimethyl ester (1.88 g, 5.69 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C., and a solution of 1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carbaldehyde (1.6 g, 5.17 mmol) in tetrahydrofuran (15 mL) was added slowly. The resulting reaction mixture was stirred at −78° C. for 2 h and then warmed to room temperature in 3 h. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using methylene chloride/hexanes (1:1.5) with 1% triethylamine as eluent to afford the title compound as a 92:8 Z/E mixture (determined by integration of CO2CH3, for Z isomer at 3.79 ppm, and E isomer at 3.65 ppm). For the Z isomer: 1H-NMR (CD3CN, 500 MHz) δ 7.96 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d, J=3.7 Hz, 1H), 7.51 (s, 1H), 7.43–7.35 (m, 5H), 7.67 (d, J=3.7 Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 3.42–3.38 (m, 2H), 0.87–0.83 (m, 2H), −0.04 (s, 9H). Mass spec. 515.20 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:30]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[6-(3,4-dichloro-phenylmercapto)-hexyloxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)c(F)c2)cc1
Yield: 61.4 %

Procedure:
3-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.42 g, 62%) was prepared as an off-white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.58 g, 2.82 mmol), 4-bromo-2-fluorophenol (0.5 g, 2.57 mmol), 2M Na2CO3 (15 mL) and Pd(PPh3)4 (30 mg 0.03 mmol) in DME (15 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.5 Hz), 7.40-7.30 (m, 2H), 7.11 (t, 1H, J=8.6 Hz), 5.22 (d, 1H, J=4.1 Hz), 3.08 (s, 3H); LRMS (APCI), m/z 267 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([OH:20])=[O:19])[CH2:15][CH2:16][CH3:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[N+](=[CH2:31])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([O:20][CH3:31])=[O:19])[CH2:15][CH2:16][CH3:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1
Reactant: CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxybutylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:7][CH:8]=1.[ClH:13].[NH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[NH2:15].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[ClH:13].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]=[N:15][NH:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC=O)c1
Reactant: NNc1ccncc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: COc1cccc(CCC=NNc2ccncc2)c1
Reaction time: 0.75 h
Yield: 61 %

Procedure:
A slurry of 3-(3-methoxyphenyl)propionaldehyde (6.46 g), 4-hydrazinopyridine hydrochloride (6.30 g) and magnesium sulfate (5 g) in ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for 45 mins. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to give 7 g (61%) of product, mp 155-156° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1)[NH2:3].[CH3:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=O.C(O)C.CO>C(O)C.O>[CH3:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=[N:3][NH:2][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1
Reactant: COc1cc2c(cc1OC)C(NN)=NCC2
Reactant: CC(C=O)=Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(NN=CC(C)=Cc1ccccc1)=NCC2

Procedure:
In a manner similar to that of Example 18 condensation of 1-hydrazino-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (9 g.) and α-methylcinnamaldehyde (5.62 g.) and recrystallization of the resulting product first from ethanol-methanol and then from ethanol-water afforded 1-[2-(2-methyl-3-phenylallylidene)hydrazino]-6,7-dimethoxy-3,4-dihydroisoquinoline (I: X= C6H5CH=C(CH3), X' = Y = Y' = H, Z = Z' = CH3O) hydrochloride monohydrate (10.2 g., m.p. 215°-217° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>C(#N)C.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>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.00 g, 1.91 mmol) in 20 mL of degassed acetonitrile and add 2,4-difluorophenyl boronic acid (0.60 g, 3.82 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.27 g, 0.38 mmol) and sonicate briefly. Next add cesium fluoride (2.61 g, 17.19 mmol) and heat to 75° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol to isolate the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39]>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone (5.3 g, 22 mmol), and dimethylfornamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MGSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C.