Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[S:9]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1c(Br)cccc1Br
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A solution of 2,6-dibromobenzenesulfonyl chloride (4.7 g, 14.0 mmol) in tetrahydrofuran (20 mL) was treated with potassium carbonate (5.8 g, 42 mmol) and t-butyl amine (1.2 g, 16.8 mmol). The resulting mixture was stirred at ambient temperature over 18 h then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2,6-dibromo-N-(1,1-dimethylethyl)benzenesulfonamide (4.5 g, 87%) as the white solid, which was used without further purification. 1H NMR (CD3OD): δ1.22 (s, 9H), 7.22 (t, 1H), 7.85 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](=[O:5])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=1[OH:20]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: COc1cccc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 30 g of 2,5-difluorobenzoyl chloride and 23.5 g of 1,3-dimethoxybenzene in 300 ml 1,2-dichloroethane, 23 g of aluminum chloride is added in portions with the internal temperature maintained at approximately 8°-12° C. The reaction mixture is stirred 0.5 hr and refluxed one hr. The reaction mixture is poured into concentrated hydrochloric acid and ice. The organic layer is separated, washed, dried over anhydrous sodium sulfate and evaporated. Trituration of the crude residue gives 2',5'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 109° C. followed by recrystallization from toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]#[CH:26])[CH:24]=1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]#[C:26][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[CH:24]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: COc1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
Dissolve 1-fluoro-4-iodo-2-methoxybenzene, (prepared as described in PREPARATION 47), (480 mg, 1.9 mmol) in triethylamine (7 mL, 53 mmol) and add 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.8 mmol) followed by bis(triphenylphosphine)palladium (II) dichloride (51 mg, 0.07 mmol) and copper (I) iodide (28 mg, 0.15 mmol). Stir for 18 h at room temperature, concentrate, and purify by silica gel chromatography, eluting with 3:1 hexanes:ethyl acetate. Further purify on silica gel, eluting with 100% dichloromethane, to give the title compound as a white solid (450 mg, 94%).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O.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>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:23]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Brc1cccs1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccsc2)CCN(C)C1
Temperature: 80 °C

Procedure:
5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (165 mg, 0.736 mm 2-bromothiophene (100 mg, 0.613 mmol), TBAF.3H2O (580 mg, 1.84 mmol), and dichlorobis (triphenylphosphine)palladium (II) (13 mg, 0.018 mmol) were placed in microwave vial and heated by microwave at 80° C. for 5 min. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain product, which was subjected to preparative HPLC to yield 20 mg of 2,8-dimethyl-5-thiophen-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.40 (d, 1H), 7.30-7.25 (m, 2H), 7.19 (s, 1H), 7.10-6.0 (m, 2H), 3.65 (s, 2H), 2.95 (t, 2H), 2.90 (t, 2H), 2.59 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC/C=C/c1cccc(Br)c1
Solvent: CCO
Product: O=C(O)CCCCc1cccc(Br)c1
Reaction time: 5 h
Yield: 98.5 %

Procedure:
J.1, (E)-5-(3-Bromophenyl)pent-4-enoic acid (4 g, 15.8 mmol) was dissolved in absolute ethanol (200 mL) and flushed with nitrogen before addition of 5% platinum sulfide on carbon (2.5 g). The solution was flushed with hydrogen at atmospheric pressure and stirred 5 h. The catalyst was removed by filtration over diatomaceous earth (Celite®) and the solvent immediately removed by rotory evaporation (in order to minimized esterification) to give J.2, 5-(3-bromophenyl)pentanoic acid 4 g (99%) which was carried forward without further purification. 1H NMR (500 MHz, CDCl3) 7.31-7.30 (m, 2H), 7.13 (t, J=7.6 Hz, 1H), 7.09-7.07 (d, J=7.6 Hz, 1H), 2.60 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 1.68-1.65 (m, 4H). LC (Cond.-J1): RT=2.1 min; LRMS: Anal. Calcd. for [M−H]− C11H13BrO2: 255.00; found: 254.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1Cl
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(Cl)cc3Cl)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.4 %

Procedure:
(2R,4S)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (334 mg, 0.90 mmol) was diluted with hydrogen bromide (33% in AcOH, 4.7 mL, 26.99 mmol) and stirred at ambient temperature for 24 h. Evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2,4-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (173 mg, 61%). 1H NMR (600 MHz, dmso) δ 1.22 (q, 1H), 1.47 (dq, 1H), 1.85-1.90 (m, 1H), 1.97-2.02 (m, 1H), 2.74 (dt, 1H), 2.87 (tt, 1H), 3.09-3.14 (m, 1H), 3.96 (dd, 1H), 5.73 (d, 1H), 7.40 (dd, 1H), 7.54 (d, 1H), 7.64 (d, 1H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0493
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH2:15].C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:19][C:13]=1[Cl:12])=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (36 mg, yield 48%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CN(C)C=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
4-Hydroxy-3-methoxybenzaldehyde (1a, 2.00 g, 13.1 mmol) and potassium carbonate (9.00 g, 65.1 mmol) were combined in dimethyl formamide (30 ml) and stirred for 15 min at room temperature. Chloromethyl methyl ether (1.60 ml, 21.1 mmol) was added and stirring was continued for 6 hr at room temperature. The resulting mixture was filtered and the filtrate extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 2.55 g (99%) of a white solid: mp 39-40° C. [expected mp 41° C.]; 1H NMR: δ 3.40 (s, 3H), 3.83 (s, 3H), 5.21 (s, 2H), 7.15 (d, 1H, J=8.7 Hz), 7.30 (dd, 1H, J=6.0, 2.0 Hz), 7.32 (s, 1H), 9.75 (s, 1H); 13C NMR: δ 55.8, 56.2, 94.8, 109.4, 114.6, 125.9, 130.9, 149.8, 151.7, 190.4.
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].S([O-])(O)=O.[Na+].O>C(O)C>[NH:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:23]=[C:2]1[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14]
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Reactant: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (2.1 g) and o-phenylenediamine (1.1 g) were suspended in ethanol (20 ml). Sodium hydrogensulfite (5.2 g) was added, and the mixture was heated and stirred overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (2.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C1C(=O)N([Br:30])C(=O)C1>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:30])=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 7b (55 mg, 0.172 mmol) is dissolved in 1:1 THF/MeOH (2 mL) and cooled to −78° C. under an atmosphere of nitrogen. TsOR.H2O (49 mg, 0.258 mmol) is added followed by NBS (31 mg, 0.174 mmol). After 10 minutes, the reaction mixture is warmed to 0° C. and then 2 hours later warmed to room temperature. After 16 hours, the reaction mixture is quenched by the addition of 10% Na2S2O3 and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with methylene chloride to give 58 mg (85%) of pure desired product as a tan solid.
Reaction SMILES: [CH:1]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])([P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6])[CH3:2].CCCCCC.C([Li])CCC.CSC1C=CC(S[Cl:39])=CC=1>O1CCCC1>[Cl:39][C:1]([P:3]([O:4][CH2:5][CH3:6])(=[O:7])[O:8][CH2:9][CH3:10])([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C)P(=O)(OCC)OCC
Reactant: CSc1ccc(SCl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)(Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 13.29 (40 mmol) of tetraethyl ethane-1,1-diphosphonate in 120 ml of dry tetrahydrofuran was cooled to -78° C. in an argon atmosphere followed by the addition of 24.24 ml (40 mmol) of a n-butyllithium hexane solution (1.65 mmol/ml) and stirring for 30 minutes. After adding a solution of 7.63 g (40 mmol) of 4-methylthiobenzenesulfenyl chloride in 50 ml of dry tetrahydrofuran to this mixture, the reaction mixture was allowed to warm up to room temperature followed by stirring for 3 hours. After pouring the resulting mixture into icewater, the mixture was extracted with ethyl acetate (3×150 ml). The solvent was distilled off under reduced pressure after the combined organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. A mixture of tetraethyl 1-[(4-methylthiophenyl)thio]ethane-1,1-diphosphonate and tetraethyl 1-chloroethane-1,1-diphosphonate was obtained as the residue. This mixture was then carefully purified with column chromatography (developing solvent: ethanol:ethyl acetate=5:95) to obtain 7.12 g of the target compound in the form of a yellow oily substance. Yield: 39%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:32])/[CH:17]=[CH:18]/[CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:11]1)=[O:9])[CH3:2].Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:32])/[CH:17]=[CH:18]/[CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH2:11]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester (0.8 g) in ethyl acetate (8 ml) was added 4N HCl in ethyl acetate (4.3 ml) at 0° C., and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, and resolved in water, neutralized with saturated aqueous NaHCO3, desalted by using the resin of HP-20 eluting with isopropanol-H2O (1:1), then freeze-dried to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester (458 mg).
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH:28]=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:4]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:2])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NO
Reactant: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C=O)CC3)cc2)nc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCc1ccc(-c2ccc(C3CCC(C#N)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.7 g of hydroxylamine hydrochloride in 1.58 g of pyridine is treated with 3.41 g of 5-hexyl-2-[p-(trans-4-formylcyclohexyl)phenyl]pyridine and stirred at room temperature for 5 minutes. The reaction mixture is then treated with 20 ml of toluene and heated to reflux for 4 hours under water separation. The cooled reaction mixture is filtered. The filtrate is diluted with diethyl ether, washed several times with water and dried over magnesium sulphate. After evaporation there is obtained 5-hexyl-2-[p- -(4-cyanocyclohexyl)phenyl]pyridine as a cis/trans mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:21]1([OH:31])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:21]1([O:31][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:19]=[N:18][CH:17]=2)[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Oc1cccc2c1CCCC2
Product: COc1cc(Nc2cncc(Oc3cccc4c3CCCC4)n2)cc(OC)c1OC
Yield: 13 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 5,6,7,8-tetrahydro-1-naphthol, the title compound was obtained (27 mg). Yield: 13%. 1H NMR (250 MHz, DMSO-d6) δ 1.65-1.69 (m, 4H), 2.53-2.56 (m, 2H), 2.72-2.77 (m, 2H), 3.42 (s, 6H), 3.54 (s, 3H), 6.74 (s, 2H), 6.89 (d, 1H, J=7.9 Hz), 6.95 (d, 1H, J=6.6 Hz), 7.11 (t, 1H, J=7.8 Hz), 7.71 (s, 1H), 7.91 (s, 1H), 9.55 (bs, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 22.01, 22.26, 23.12, 28.78, 55.36, 60.03, 95.72, 118.40, 120.56, 125.66, 126.09, 127.60, 129.06, 132.10, 136.39, 138.76, 150.59, 151.46, 152.70, 157.65. m/z 408.2 [(M+H)+ calcd for C23H25N3O4 407.2].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[C:7]([O:27]C)=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].CN(C)C1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[C:7]([OH:27])=[C:8]([C:13]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Yield: 82.9 %

Procedure:
Aluminium chloride (0.7 g) was added to a stirred solution of methyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 68, 0.76 g) and N,N-dimethylaniline (1.27 g) in DCM (8 ml) and the resultant mixture was stirred for 30 minutes. The mixture was partitioned between ethyl acetate and hydrochloric acid (1M) and the organic layer was washed with sodium bicarbonate (saturated aqueous solution), dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether. The solid was collected by filtration to give methyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-hydroxybenzoate (0.61 g) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:25]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:32][CH2:33]2)=[O:12])[CH:3]=[CH:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1cccc2cc[nH]c12)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a chilled solution of indole-7-carboxylic acid (3.22 g; 0.02 mole) in 30ml dimethylformamide was added 1,1'-carbonyldiimidazole (3.24 g; 0.02 mole). This was stirred at ice bath temperature for 40 minutes after whicha solution of 1-(2-pyrimidyl)piperazine (4.1 g; 0.025 moles) was added. This was stirred at ambient temperature for 3 hours and the solvent was concentrated in vacuo. The resulting oil was triturated with water to give5.7 g (93%) of a solid, m.p. 194°-197° C. The solid was recrystallized from methanol/water to give 4.7 g (76%) of 1-(1H-Indol-7-ylcarbonyl)-4-(2-pyrimidinyl)piperazine, m.p. 200°-202° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:20][C:21]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[O:23][N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[CH2:1]([C:4]1[N:5]([CH2:20][C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)[O:23][N:22]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.20 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.062 g, 0.24 mmol), Cs2CO3 (0.078 g, 0.24 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). Drying (MgSO4), filtration, and concentration were followed by purification (SiO2; 0-30% EtOAc in hexanes) to afford the title compound (0.070 g, 74%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 5.88 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 1.78-1.61 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS m/z 479 (M+H).
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[C:21]([O:23]C)=[O:22].[ClH:37].[Cl:38]CCl.CO>CO.O>[ClH:38].[ClH:37].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCC4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C

Procedure:
2 cm3 of 5N aqueous sodium hydroxide solution were added, with stirring and under an inert atmosphere, to a solution of 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylate in 10 cm3 of methanol. After heating the mixture for 16 hours at a temperature in the region of 60° C., the reaction mass was evaporated under reduced pressure (2.9 kPa) at a temperature in the region of 60° C. and the residue obtained was taken up in 4.3 cm3 of distilled water to which had been added 4.3 cm3 of 28% hydrochloric acid. The remaining insoluble material was filtered off and then the filtrate was evaporated under the same conditions as above. The residue obtained was stirred in a dichloromethane/methanol (90/10 by volume) mixture. The resulting precipitate was filtered off and washed with 3 times 2.5 cm3 of the same mixture. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a foam with a green color melting with softening at a temperature in the region of 156° C.