Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>ClCCl.CCOC(C)=O>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: COc1ccc(C=O)c(O)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03 g, 20 mmol) in 25 mL of dichloromethane was cooled to 0° C. and treated dropwise with a solution of bromine (3.41 g, 21 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was removed by rotary evaporation to give a residue. The residue was taken up in EtOAc and washed with 3 portions of water. The organic layer was dried over MgSO4. The drying agent was removed by filtration, and solvent was removed by rotary evaporation to give 3.9 g of the desired 5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p. 111-115° C.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:8]1[C:20]([O:21]C)=[CH:19][C:18]2[N:17]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:16]3[CH:15]=[CH:14][C:13]4[C:29](=[O:32])[CH2:30][CH2:31][C:12]=4[C:11]=3[C:10]=2[CH:9]=1)(=[O:7])[CH3:6].C(Cl)Cl.CO.Cl>C(Cl)Cl.O1CCOCC1>[C:5]([C:8]1[C:20]([OH:21])=[CH:19][C:18]2[N:17]([CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:16]3[CH:15]=[CH:14][C:13]4[C:29](=[O:32])[CH2:30][CH2:31][C:12]=4[C:11]=3[C:10]=2[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1cc2c(cc1C(C)=O)c1c3c(ccc1n2CCCN(C)C)C(=O)CC3
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1cc2c3c4c(ccc3n(CCCN(C)C)c2cc1O)C(=O)CC4
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
A 0.5 M solution of BBr3 (16.5 mL, 5 eq.) was added dropwise under argon to a solution of compound 38 (0.658 g, 1.74 mmol) in CH2Cl2 (100 mL) cooled to −40° C. The mixture was kept for 10 min; then a cooling bath was removed and the mixture was heated to room temperature and kept for 1-2 h (TLC monitoring, eluent: CHCl3/NH3-MeOH, 9:1). The resulting mixture was poured in a mixture of aqueous NaHCO3 solution and CH2Cl2. The organic layer was separated; the aqueous one was extracted with CH2Cl2, dried over Na2SO4, evaporated, and dissolved in a mixture: CHCl3-MeOH-water, 40:9:1. The product was purified in a silica gel column with the use of the latter mixture as an eluent. Yield of Example 4: 0.258 g (41%). For the preparation of hydrochloride, the product isolated was dissolved in a mixture: CH2Cl2-MeOH; a solution of HCl in dioxane was added. The resulting mixture was evaporated to dryness; the residue was washed with ether.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O.C(O)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Reaction time: 2.5 h
Yield: 91 %

Procedure:
305 ml of a 1M solution of (NH4)2Ce(NO3)6 in H2O are added slowly at 10°-15° C. to 20 g (0.106 mol) of 2-butyl-4-chloro-5-hydroxymethylimidazole in 350 ml of glacial acetic acid. After 2.5 h at RT, the pH is adjusted to 4 with 2N KOH (20° C. during addition of the base). After extraction 4× with 500 ml of CH2Cl2 each time the combined organic extracts are washed 3× with 300 ml of saturated aqueous NaHCO3 solution each time, dried with Na2SO4 and concentrated, resulting in the title compound as a colorless solid (18 g). Melting point was 90° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.[Cl:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:16]1([P: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)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C1(C)C=CC=CC=1>[Cl-:8].[C:29]1([P+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To an ice-cooled 2-phase mixture of 55.8 g (195 mmol) Na2CO3.10 H2O in 200 ml water and 100 ml toluene, 21.3 g (133 mmol) 3-chloromethylpyridine hydrochloride is added in portions. The mixture is stirred at 0° C. until a clear solution is obtained, the aqueous phase separated off, and the mixture extracted twice with 50 ml toluene. The toluene phases are dried (Na2SO4) and evaporated in the RE (10 mbar, 30° C.) to about half its original volume. To the yellowish solution, 68.1 g (259 mmol) triphenylphosphine is added and the mixture stirred for several days under a N2 atmosphere at 70° C. The title compound is precipitated off in the process. It is filtered off and washed with toluene and hexane; 1H-NMR (DMSO-6) 8.47 (m, 1HPy), 8.18 (sb, 1HPy), 7.91 (m, 3H), 7.72 (m, 12H), 7.37 (m, 1HPy), 7.26 (m, 1HPy), 5.33 (d, J=15 Hz, H2C); FAB-MS (M-Cl)+=354; an. calc. (C24H21NClP.0.17 H2O) C, 73.36%; H, 5.47%; N, 3.56%; Cl, 9.02%; P, 7.88%; H2O, 0.78%; meas. C, 73.11%; H, 5.43%; N, 3.82%; Cl, 9.49%; P, 7.98%; H2O, 0.77%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1(=[O:19])[O:14][C:12](=O)[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>>[CH:16]1[CH:17]=[CH:18][C:10]([C:9]([OH:14])=[O:19])=[C:11]([C:12]2[C:6]3[CH:4]=[CH:3][C:1]([OH:2])=[CH:8][C:7]=3[O:5][C:4]3[C:6]=2[CH:7]=[CH:8][C:1]([CH:3]=3)=[O:2])[CH:15]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Yield: 89.9 %

Procedure:
Resorcinol (470 g, technical grade 99.4%, white flakes) was added to a one-liter jacketed glass vessel and heated to 135 C. in order to melt the resorcinol. Once melted, phthalic anhydride (124 g, technical grade 99.7%, white flakes) was added to the vessel, and the reaction mixture was blanketed with nitrogen, mixed and heated to 200 C. The reaction mixture was held at 200-215 C. for approximately 2 hours while the water (24 g) was removed by distillation. Upon completion, the reaction mixture was cooled to 185 C. and quenched with water by transferring the reaction mixture under nitrogen to a stirred vessel containing water (approximately 500 ml). The vessel was then rinsed with water to transfer all of the precipitated product. The combined product slurry in water was digested at 75 C. (to dissolve any unreacted intermediates) and cooled to 35 C. The product was recovered by vacuum filtration in the form of a filter cake. This filter cake was washed free of dissolved impurities, such as resorcinol, by mixing and heating with fresh water (approximately 1L), filtering and rinsing with about 800 ml boiling hot water. This cake upon drying yielded fluorescein (250.1 g).
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].Cl.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+].C(N)C1C=CC=CC=1>C1COCC1>[CH2:19]([N:21]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[CH3:20]
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CCN1CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), ethylamine hydrochloride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to 105° C. under nitrogen. After one hour, another portion of benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to room temperature. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound (0.267 g, 46% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC.C1(C)C=CC=CC=1>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.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (7) (8.0 g, 16 mmol), 2-tributylstannylthiophene (2.98 g, 8.0 mmol), tetrakis(triphenylphosphine)palladium (0) (200 mg, 1.73×10−4 mol) aqueous sodium carbonate (2M, 2 cm3), toluene (5 cm3) and ethanol (2 cm3) was heated under reflux for 24 h under argon. Toluene and ethanol were removed and hexane (10 cm3) and aqueous KI (2%, 10 cm3) added and the mixture stirred vigorously for 1 h. Diethyl ether (10 cm3) and dilute HCl(aq)(3M, 10 cm3) were added, the aqueous layer separated and washed with diethyl ether (2×10 cm3). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to a dark brown oil which was purified by column chromatography [silica gel, hexane] to yield a pale jade coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13]OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.ClCCl.CO>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1c[nH]cn1
Reactant: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: C=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Yield: 70.3 %

Procedure:
4-(3,4-Dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) (see Preparation 23) and imidazole (3.6 g) were dissolved in anhydrous acetonitrile (40 ml) and the mixture heated under reflux for 100 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and washed with sufficient aqueous sodium carbonate solution to ensure that the aqueous phase reached pH14. The two phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were combined and the solvent removed under reduced pressure to give a residue which was chrornatographed on silica gel eluting with a solvent gradient of 100:0 changing to 98:2, by volume, dichloromethane:methanol, to give 4-(3,4-dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (3.45 g) as an orange oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[F:17].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([NH2:14])=[C:11]([F:13])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(F)c(Cl)cc1F
Temperature: 70 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Tin (II) chloride dihydrate (15.5 g, 68.7 mmol) was dissolved in ethyl acetate (50 mL) and 1-chloro-2,5-difluoro-4-nitrobenzene (2.65 g, 13.7 mmol) was added dropwise. The reaction mixture was then stirred at 70° C. for 1 h. The reaction mixture was then carefully added to saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic phase was washed several more times with water, dried, filtered, concentrated and purified by flash chromatography on silica gel (hexane/diethyl ether) to give the title compound as a white solid (1.65 g, 73.9% yield): 1H NMR (CDCl3): δ 7.02 (dd, 1H), 6.57 (dd, 1H), 3.81 (br s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C>[Br:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=[CH:8][C:6]=1[NH2:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To 4-ethylaniline (1.76 g, 14.52 mmol) and NBS (2.58 g, 14.52 mmol) was added DMF (67 mL) and the reaction mixture was stirred at 0° C. for 10 min. The reaction mixture was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to provide 2-bromo-4-ethylaniline (2.7 g, 93% yield). LC/MS m/z 201.0 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br.FC(Br)C1C=CC=CC=1>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([F:38])[CH:40]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:27][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: Fc1cccc(CBr)c1
Agent: FC(Br)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (9.128 g, 24.05 mmol) in acetonitrile (150 mL)) was added to sodium iodide (360 mg, 2.4 mmol) and stirred under nitrogen during the addition of triethylamine (12 mL, (8.76 g), 86.6 mmol), followed by 3-fluorobenzyl bromide (5.9 mL, (9.09 g), 48.1 mmol). An immediate turbidity was observed on addition of the fluorobenzyl bromide, thickening to a white crystalline precipitate over one hour. The reaction mixture was stirred under nitrogen overnight at room temperature. The solvent was removed by evaporation, and saturated sodium bicarbonate solution (25 mL) added to the residue. The copious white precipitate was filtered off, washed well with water and dried under vacuum at room temperature to give 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide (10.54 g, 89.2%). Calc. for C31H38FN3O 0.2 H2O: C, 75.79; H, 7.88; N, 8.55; F, 3.87. Found C, 75.80; H, 7.78; N, 8.49; F, 3.75%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(O)c1
Yield: 893.9 %

Procedure:
A suspension of 3-hydroxyphenylacetic acid (5.4 g) and para-toluensulfonic acid (650 mg) in 80 ml of ethanol is refluxed for 4 hours, then the solvent is evaporated off and the residue is dissolved in ethyl acetate and washed twice with a saturated aqueous solution of sodium hydrogencarbonate. The organic phase is dried over sodium sulfate and the solvent is evaporated off to give 6.08 g of the product as a yellow oil.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=2)[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:2]1.C(O)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>[Pd].C(OCC)(=O)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:18][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:17][C:16]3=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:33])=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1cc2c(cc1C=Cc1ccccn1)OCO2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2cc3c(cc2CCc2ccccn2)OCO3)cc1
Reaction time: 0.5 h

Procedure:
2-(4,5-Methylenedioxy-2-nitrostyryl)pyridine (10.8 g., 0.04 mole) is hydrogenated on a Parr apparatus in 200 ml. of ethanol with 2.0 g. of 10% palladium on carbon as catalyst. After the reduction is complete, the mixture is filtered and the solvent evaporated. The residue consisting of 2-(4,5-methylenedioxy-2-aminophenethyl)pyridine is immediately dissolved in pyridine (100 ml.) and anisoyl chloride (7.5 g., 0.044 mole) added. The solution is stirred for 30 min. A basic workup according to the procedure of Example 25 affords 10 g. of 4-methoxy-4',5'-methylenedioxy-2'-[2-(2-pyridyl)ethyl]benzanilide obtained analytically pure by crystallization from ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:18][CH2:17]3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([N:16]3[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:21]3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A mixture containing ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate (50 mg), concentrated hydrochloric acid (1 ml) and dioxan (4 ml) was stirred at 50°-60° C. for 1 hour,then concentrated to give a foam which was triturated with hot isopropanol. Filtration gave the title compound (48 mg) as pale cream prisms, m.p. 188°-190° C. NMR (d6DMSO+d4AcOH) δ1.0-1.3(2H,m); 1.5-1.6(3H,m); 1.8(2H,d); 2.3(2H,t); 2.6-2.8(1H,m); 2.95-3.15(1H,m); 3.5(4H,brs); 3.6-3.7(1H,m); 4.0-4.2(4H,brs); 4.3-4.5(3H,m); 7.25(2H,d); 8.35(2H,d); m/e 361(M+H)+ ; calculated for C19H28N4O3 2HCl. H2O: C,50.6;H, 7.2; N, 12.4; H2O, 4.0; found: C,50.3; H, 7.2; N, 12.2; H2O, 4.0%.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl.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.[Pd]>[CH3:2][N:3]1[C@H:4]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:9][C:8]([C:2]4[NH:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:7][C:18]=3[CH2:19][CH2:5]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: C1CCOC1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4nc5ccccc5[nH]4)cc3CC[C@@H]12
Reaction time: 16 h
Yield: 25 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (187 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol), 2-chlorobenzimidazole (104 mg, 0.68 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. An additional 23 mg of the palladium reagent was added, and let stir an additional 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-5% methanol/ethyl acetate eluent gradient) to give 57 mg (25%) of the title compound as an amorphous foam. mp 183°-186°. FDMS: m/e=345.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
4-Bromo-4'-hydroxybiphenyl (2.49 g) was added over 30 minutes to a stirred suspension of sodium hydride (0.42 g of 60% dispersion in mineral oil) in dimethylformamide (10 ml) whilst keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at a temperature below 10° C. for a futher 5 minutes. Ethyl iodide (1.87 g) was added over 10 minutes and stirring continued at room temperature for 2 hours. Water (200 ml) was added to the mixture and the mixture extracted with diethyl ether (3×50 ml). The ether extracts were combined, washed with 1M sodium hydroxide solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to give a residue which was crystallised from hexane to give, as a colourless solid, 4-bromo-4'-ethoxybiphenyl (2.15 g), m.p. 139° C.; NMR (CDCl3): 1.4(3H, t), 4.0-4.1(2H, q), 6.9(2H, d) and 7.35-7.55(6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O(CCCC)CCCC>[Fe].O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: CCCCOCCCC
Solvent: O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Temperature: 80 °C
Yield: 64 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8nitro-5-(9-phenylnonoxy) quinoline (11 g, 0.025 mol), degreased 40 mesh Fe filings (30 g), H2O (100 ml), HOA c (20 ml) and n-Bu2O (20 ml) was heated at 80° C. for 2 h, cooled and filtered. The solid residue and the filtrate were thoroughly extracted with warm Et2O and the combined extracts were dried (Na2SO4), treated with Darco, and concentrated. The resulting solid was dissolved in pet ether (Darco) and cooled in dry ice--Me2CO to give 6.5 g (64) of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline as pale yellow crystals, mp 32°-32.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C)C=O>[CH3:16][C:15]1[C:10]2[N:11]([CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of the product of Example 27 Step B (195 mg) in N,N-dimethylformamide (2 mL) was added triethylamine (0.12 mL) and the mixture cooled to 0° C. 3-chloropropanesulfonyl chloride (0.11 mL) was added dropwise and the mixture stirred for 1.5 hours before the addition of H20 (2 mL). The reaction mixture was partitioned between H2O (15 mL) and ethyl acetate (15 mL). The aqueous layer was brought to pH=9-10 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, decanted, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (210 mg).