Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-8-(2,4-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (2.0 g, 5.6 mmol) in DCM (100 ml) was added a solution of serinol (650 mg, 7.1 mmol) in DMF (5 ml). The mixture was stirred for 2 h, washed with water (2×50 ml), dried (Na2SO4), and evaporated. Flash chromatography (EtOAc/Hexane, 3:1) provided the title compound as a white solid (1.1 g, 50%): LC-MS m/z 383 (M+H)+ retention 2.45 min.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@@H:16]12[N:9]([C:5]3[CH:4]=[C:3]([N:2]([CH3:24])[CH3:1])[CH:8]=[CH:7][N:6]=3)[CH2:10][C@@H:11]1[CH2:12][CH2:13][NH:14][CH2:15]2
Reactant: CN(C)c1ccnc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)c1
Temperature: 25 °C

Procedure:
A solution of (1R,6S)-tert-butyl 8-(4-(dimethylamino)pyridin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (150 mg, 0.45 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was allowed to stir at ambient temperature. After 16 hours the crude mixture was concentrated under reduced pressure. The resulting trifluoroacetic acid salt of the title compound was used without further purification. MS (ESI) mass calcd. for C13H20N4, 232.2; m/z found, 233.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl isonipecotate (27.6 g, 175 mmol) in dichloromethane (50 ml) was added dropwise over 10 minutes to a solution of 3-chlorobenzoyl chloride (20 ml, 160 mmol) and triethylamine (28 ml, 200 mmol) in dichloromethane (500 ml) cooled to between 10 and 15° C. The reaction was then stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was diluted with ether, the solution washed with 1N hydrochloric acid, sodium carbonate solution (×3) and brine. It was then dried over MgSO4 and evaporated under reduced pressure, to give the title compound as a solid, 44.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C:22](=[O:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4].[BH4-].[Na+]>CO>[OH:25][C@H:16]1[CH2:17][CH2:18][C@@:19]2([CH3:20])[C:14]([CH2:13][CH2:12][C@@H:11]3[C@@H:21]2[C:22](=[O:24])[CH2:23][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH2:10][C@@H:5]2[C:3]([O:2][CH3:1])=[O:4])=[CH:15]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
17β-Methoxycarbonylandrost-4-ene-3,11-dione (2.8 g.) was dissolved in dry methanol (250 ml.) and to the stirred solution was added sodium borohydride (600 mg.) in portions over 2 hours. The reaction was then left to stand for 30 minutes, and then concentrated by evaporation under reduced pressure and poured on to ice. The precipitate was extracted into chloroform and the organic solution was dried over sodium sulphate and evaporated to an oil which was purified by preparative TLC to give 3β-hydroxy-17β-methoxycarbonylandrost-4-en-11-one (506 mg.) as colourles plates, m.p. 197°-201°, [α]D 30 144°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C:19]6[C@@:25]([CH3:26])([C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:24][CH2:23][C:21](=[O:22])[CH:20]=6)[CH2:4][CH2:3]1>O1CCCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:20][C:21](=[O:22])[CH2:23][CH2:24][C@:25]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Diosgenone (500 g) was dissolved in tetrahydrofuran (THF) (2500 ml) at 40-45° C. and inerted with nitrogen. 5% Pd—BaSO4 (reduced) (100 g) was added; the flask was purged with hydrogen and stirred under an atmosphere of hydrogen for ca. 6.5 hours. The flask was cooled to ambient temperature and the catalyst removed by filtration through a pad of Celite (50 g). The solvent evaporated to yield crude smilagenone as a solid residue.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]=[N+:44]=[N-:45])[C:21]=1[O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]=[N+:32]=[N-:33])[C:16]([O-:18])=[O:17])=[N+:2]=[N-:3].O.Cl>C1COCC1>[N:43]([CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][C:20]1[CH:19]=[C:15]([CH:14]=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:21]=1[O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]=[N+:32]=[N-:33])[C:16]([OH:18])=[O:17])=[N+:44]=[N-:45]
Reactant: [N-]=[N+]=NCCOCCOCCOc1cc(C(=O)[O-])cc(OCCOCCOCCN=[N+]=[N-])c1OCCOCCOCCN=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCOCCOCCOc1cc(C(=O)O)cc(OCCOCCOCCN=[N+]=[N-])c1OCCOCCOCCN=[N+]=[N-]
Temperature: 25 °C
Yield: 136.1 %

Procedure:
To a solution in which the 3,4,5-tris(2-(2-(2-azidoethoxy)ethoxy)ethoxy)benzoate (2.18 g, 3.32 mmol) of Chemical Formula 11 was dissolved in THF, water-soluble LiOH (1 M) (9.96 mL, 9.96 mmol) was added at room temperature, and the mixture was heated under reflux for 4 hours. The post-reaction mixture was cooled to room temperature, and was acidified to pH 4 by adding 0.1 N HCl. This mixture was partitioned to distilled water (40 mL) and ethyl acetate (100 mL), the organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, then filtered, and the resulting filtrate was vacuum distilled to give 3,4,5-tris(2-(2-(2-azidoethoxy)ethoxy)ethoxy)benzoic acid (2.90 g, 98%). 1H NMR (500 MHz, CDCl3) δ 7.35 (s, 2H), 4.18-4.29 (m, 6H), 3.81-3.88 (m, 6H), 3.73 (m, 6H), 3.65-3.68 (m, 12H), 3.38 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 170.9, 152.4, 143.3, 124.0, 109.6, 72.5, 70.9 (3), 70.8 (3), 70.6, 70.1 (3), 69.8 (2), 68.9 (2), 50.7 (3).
Reaction SMILES: C[C@:2]1([C:34]([OH:36])=[O:35])[CH2:7][CH2:6][C@:5](O)([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:4][C:3]1([CH3:33])[CH3:32].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:51](=O)(O)[O-].[Na+]>>[CH3:32][C:3]1([CH3:33])[CH:4]=[C:5]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:6][CH2:7][CH:2]1[C:34]([O:36][CH3:51])=[O:35]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@](C)(C(=O)O)C(C)(C)C3)s2)c1
Reactant: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: COC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)=CC1(C)C
Temperature: 65 °C
Yield: 73 %

Procedure:
A suspension of methyl (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (200 mg, 0.38 mmol) in phosphorous pentoxide (2.2 g, 15.4 mmol) was heated at 65° C. for 3 hours. The resulting mixture was cooled to room temperature, slowly poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (ethyl acetate/hexanes) afforded methyl 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohex-3-ene-1-carboxylate (141 mg, 0.28 mmol, 73% yield) as a colorless oil. MS ESI: [M+H]+ m/z 503.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>C1(C)C=CC=CC=1>[CH:23]1([NH:29][C:30]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCCCC4)cc3)c2cc1OC
Temperature: 85 °C
Yield: 73.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (200 mg) was dissolved in toluene (5 ml) with heat, cyclohexyl isocyanate (340 mg) was added, and the admixture was stirred with heat at 80-90° C. for 30 minutes. After the addition of water, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 210 mg of the title compound (yield: 74%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[BH4-].[Na+].CC(O)(C)C>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: N#Cc1cnccn1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: NC(c1ccc(Cl)cc1)c1cnccn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
Pyrazine-2-carbonitrile (10.5 g, 100 mmol) was dissolved in PhMe (100 mL) at 0° C. and 4-chlorophenyl magnesium bromide (100 ml, 1.0 M in Et2O, 100 mmol) was added portion-wise over 5 min. The reaction mixture was stirred for 6 h and NaBH4 (7.58 g, 201 mmol) and tBuOH (100 mL) were added. The reaction mixture was warmed to 60° C. for 18 h and quenched with 1 M aq NaOH solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (DCM:EtOH:NH3 200:8:1 to 50:8:1) to give the title compound as a brown oil (7.46 g, 34%). MS (ESI+) m/z=220.0 (M+H)+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.F[C:15](F)(F)[C:16](OC(=O)C(F)(F)F)=[O:17]>C1C=CC=CC=1>[C:16]([O:12][C:10]1[C:3]2[C:4](=[CH:5][CH:6]=[C:1]([CH3:13])[CH:2]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:17])[CH3:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(CCCC(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=O)Oc1cccc2ccc(C)cc12

Procedure:
To a 2 liter round-bottomed flask equipped with condenser and a nitrogen inlet were added 98.3 grams (0.552 mol) 4-(p-tolyl)butyric acid and 900 mL dry benzene. After the acid had dissolved, 132.6 mL (0.939 mol) trifluoroacetic anhydride was added dropwise over 35 minutes. The reaction was then refluxed for 20 hours (starting material confirmed to be consumed by thin layer chromatography (tlc), Rf 0.1 to 0.6 (DNP +ve) in 2/1 ethyl acetate (EtOAc)/hexane) cooled, and evaporated to remove most of the trifluoroacetic acid. The reside was taken up in ethyl acetate, washed with dilute aqueous ammonium hydroxide, water and brine, dried over sodium sulfate, and evaporated. The resulting solid was suitable for use in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:10]2[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:15]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(Nc3cccc(C=Cc4ccccc4)c3)ncnc2n1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
A mixture of the product from Example 240A (0.063 g, 0.20 mmol), styrene (0.0412 g, 0.40 mmol, 2.0 eq), palladium(II) acetate (0.9 mg, 0.004 mmol, 0.02 eq), tri-o-tolylphosphine (2.4 mg, 0.008 mmol, 0.04 eq), and triethylamine (0.0607 g, 0.60 mmol, 3.0 eq) in dimethylformamide (2 mL) was heated in a 120° C. oil bath for 4 hours. The mixture was then cooled to room temperature and the solvent evaporated under a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water and the aqueous layer further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from methanol and dried to provide the title compound as yellow crystals (11.8 mg, 17%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.01 (s, 1H), 8.89 (d, J=8.46 Hz, 1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.72-7.85 (m, J=6.07, 2.76 Hz, 1H), 7.64 (d, J=6.99 Hz, 2H), 7.57 (d, J=8.82 Hz, 1H), 7.35-7.49 (m, 4H), 7.24-7.35 (m, 3H), 2.63-2.74 (m, 3H); MS (ESI+) m/z 339.1 (M+H)+, (ESI−) m/z 337.1 (M−H)−.
Reaction SMILES: I.C(O[C:6](=O)[CH3:7])(=O)C.[PH2](O)=O.[CH3:12][C:13]1[NH:14][CH:15]=[C:16]([CH3:21])[C:17]=1[C:18](=[O:20])[CH3:19]>C1(=O)CCCCC1.O>[CH3:12][C:13]1[NH:14][C:15]([CH:7]2[CH2:6][CH2:16][CH2:17][CH2:13][CH2:12]2)=[C:16]([CH3:21])[C:17]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(=O)OC(C)=O
Agent: I
Agent: O=[PH2]O
Solvent: O=C1CCCCC1
Solvent: O
Product: CC(=O)c1c(C)[nH]c(C2CCCCC2)c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of 50% hypophosphorous acid was stirred magnetically at 40° C. while 548 mg of 2,4-dimethyl-3-acetyl-pyrrole were dissolved in it, 0.5 ml of cyclohexanone was then added, and an additional 0.5 ml of cyclohexanone was added after a few minutes'. The solution was stirred at 40° C. for 11/2 hrs. then poured into water. The crude product which separated, m.p. 186°-188° C. was recrystallized from ethanol as colourless rhombic prisms (82%), m.p. 188.5°-189° C. after changing to flat prisms above 153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxyphenylboronic acid (639 mg) and ethyl 2-bromobenzoate (479 mg) were suspended in a mixed solvent of toluene (20 mL) and THF (15 mL), and to the suspension 2M sodium carbonate (6 mL) and tetrakis (triphenylphosphine) palladium(0) (175 mg) were added. The mixture was stirred overnight at 90° C. under an argon atmosphere. Ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.O.[NH2:19][NH2:20]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:19][NH2:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: NN
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1cc(Cl)ccc1N)c1ccccc1F

Procedure:
In the manner given in Preparation 1, 2-amino-5-chloro-2' -fluorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2'-fluorobenzophenone hydrazone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O=P(Cl)(Cl)Cl.[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][C:34]2=[O:42])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[C:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:34]2=[O:42])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Reactant: O=C1CCCN1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1C(=C2CCCN2Cc2ccccc2)c2ccccc2N1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
N-benzyl-2-pyrrolidone (1.58 ml, 9.85 mmoles) was combined with 2 ml toluene under N2 and cooled to 0°-5°. POCl3 (0.5 ml, 5.9 mmoles) was added and the mixture stirred 30 minutes. Toluene (3 ml) and 1-(3-chlorophenyl-2(1H,3H)-indolone (1.2 g, 4.92 mmoles) were added and the stirred reaction mixture warmed to 25° for 30 minutes and then to 70°-75° for 18 hours. The reaction mixture was cooled, diluted with 100 ml CH2Cl2, washed with saturated NaHCO3, H2O and brine, dried and concentrated in vacuo to an oil (2.6 g). The oil was chromatographed on silica gel (45×150 mm) using CH2Cl2 as eluant, yielding title product, initially an oil which was crystallized from ether/pentane, 1.04 g (53%), m.p. 72°-75°.
Reaction SMILES: C1CCCC(OC2C=C3C(C=CC=C3CCNC(C3CC3)=O)=CC=2)C=1.[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([O:32][C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[C:40]3[CH2:43][CH2:44][NH:45][C:46]([CH:48]3[CH2:51][CH2:50][CH2:49]3)=[O:47])=[CH:35][CH:34]=2)[CH:27]=1>>[CH:28]1([O:32][C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[C:40]3[CH2:43][CH2:44][NH:45][C:46]([CH:48]3[CH2:49][CH2:50][CH2:51]3)=[O:47])=[CH:35][CH:34]=2)[CH2:27][CH2:26][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NCCc1cccc2ccc(OC3C=CCCC3)cc12)C1CCC1
Agent: O=C(NCCc1cccc2ccc(OC3C=CCCC3)cc12)C1CC1
Product: O=C(NCCc1cccc2ccc(OC3CCCCC3)cc12)C1CCC1

Procedure:
Using the procedure described in Example 28, but replacing the compound obtained in Example 25 by the compound obtained in Example 42, N-[2-(7-cyclohexyloxy-1-naphthyl)ethyl]cyclobutanecarboxamide is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)c1nc(Oc2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 1.399 g of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (5 mmol) and 2.86 g of phenol was heated at 145° C. to 150° C. for 24 h. After cooling to ambient temperature the mixture was suspended in 50 ml of aqueous 2N NaOH and the mixture was extracted with 4×25 ml of ethyl acetate. The combined organic phases were washed with 3×25 ml of aqueous 2N NaOH, 50 ml of brine, dried over MgSO4, and evaporared in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (9:1) and (95:5). 0.650 g of the title compound were obtained; 1H NMR (CDCl3): δ=11.52 (s, 1H), 8.32 to 8.39 (m, 2H), 7.72 to 7.86 (m, 2H), 7.13 to 7.42 (m, 5H), 4.31 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6].CCN(CC)CC.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][O:6][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Cl)cc(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(COS(C)(=O)=O)c1
Yield: 93.1 %

Procedure:
To a solution of 3-chloro-5-methoxybenzyl alcohol (14.7 mmol, 2.54 g) in DCM (20 ml) was added Et3N (22 mmol, 2.23 g, 3.1 ml) and the solution was cooled to −10° C. on an acetone-ice batch. Methanesulfonic chloride (17.7 mmol, 2.03 g, 1.4 ml) was added dropwise under stirring. After 45 min the mixture was separated between DCM and H3PO4 (5% v/v in water, cold). The organic phase was washed with H3PO4 (5% v/v in water, cold), NaHCO3 (10% in water, cold), brine and dried (MgSO4). Filtration and removal of solvents under reduced pressure yielded the title compound (3.43 g, 93%) as a white solid. The product was used in the next step without further purification. 1H NMR (CDCl3, 500 MHz) δ 2.97 (s, 3H), 3.82 (s, 3H), 5.16 (s, 2H), 6.82 (s, 1H), 6.90 (s, 1H) and 6.98 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])(=[O:31])=[O:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:41][O:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[S:29]([N:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:28][CH2:27]1)(=[O:30])=[O:31]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: COc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c(OC)c1
Product: COc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c(OC)c1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-[(2,4-dimethoxyphenyl)sulfonyl]piperazine to give 1-[(2,4-dimethoxyphenyl)sulfonyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.