Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24]>>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:3]=2)=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cc(N)ccc1F
Product: COc1cc(Nc2cc(C)nc(-c3ccccn3)n2)ccc1F

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 4-fluoro-3-methoxyaniline (56.4 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (96.7 mg, 78%). 1H NMR (CDCl3): 8.63 (d, J=4.2 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.42 (s, 1H), 7.20 (m, 1H), 7.0 (d, J=7.5 Hz, 1H), 6.90 (m, 1H), 6.69 (m, 1H), 3.71 (s, 3H), 2.30 (s, 3H),
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:23](=[O:25])[CH3:24])[CH:31]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(=O)c1cccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)c1
Yield: 11 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-acetylbenzeneboronic acid were coupled in the same way as in Example 30 to give 1-{2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-3-yl}ethanone as an off-white solid (14 mg, 11%): m/z (ES+) 407 [MH+].
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([CH2:17][CH3:18])=[C:11](C)[N:10]=1.O>CN(C)C=O>[C:1]([S:5][C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C#N)c(Cl)nc1C
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(SC(C)(C)C)c(C#N)c1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
t-Butylmercaptan (0.40 mL, 3.55 mmol) was added to a suspension of 60% sodium hydride in mineral oil (158 mg, 3.85 mmol) in dry dimethylformamide (5 mL). After 10 minutes, when gas evolution ceased, 2-chloro-3-cyano-5-ethyl-6-methylpyridine (542 mg, 3.0 mmol) was added. After stirring for one hour, water was added and product extracted into diethyl ether. This extract was dried (Na2SO4), filtered and the solvent removed to give 648 mg (92%) of crystalline product, m.p. 63°-66° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH2:9][CH2:10][CH3:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:14][NH:15][CH2:16]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC1(c2ccccc2F)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2F)CNC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 104 mg (0.3 mmol) of 3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine in 3 ml of dichloromethane at 0° C. After stirring for 30 minutes, the reaction medium is evaporated off under a stream of nitrogen. 126 mg of 3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate are obtained in the form of a pale yellow oil with a yield of 100%.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCO[CH2:14][CH2:13]1.Cl>C(O)C>[N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCO1
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
5 g of 5-nitrothiophene-2-carboxylic acid was stirred in 100 ml of ethanol. 20 ml of dioxane containing 4 M of hydrogen chloride was added to the obtained mixture, and they were stirred at 60° C. for 2 days. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[C:17](=[O:20])[CH2:18][CH2:19][C:15]=3[N:14]=[C:13]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[CH:17]([OH:20])[CH2:18][CH2:19][C:15]=3[N:14]=[C:13]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CC2
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
Sodium borohydride (155 mg) was added to a stirred solution of Intermediate 21 (660 mg) in dichloromethane (2 mL) and methanol (2 mL). The reaction mixture was stirred for 2.5 hours. More sodium borohydride (155 mg) was added. The RM was left stirring at room temp. under nitrogen for 1 hour. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated; the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (660 mg). LC/MS MH+ 325, 327, Rt 1.63 min (5 minute run).
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:7][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])[C:4]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:6]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Reactant: C1COCCN1
Agent: Cl
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)N3CCOCC3)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and morpholine using a procedure analogous to that of Example 128.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>C1COCC1>[Li:5][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Reaction time: 0.17 h

Procedure:
A solution of butyllithium, 2.5M in hexanes (1.718 mL, 4.30 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (0.802 mL, 4.73 mmol) in 15 ml THF at −78° C. The flask was removed from the −78° C. bath, and stirred at ca 0° C. for 10 minutes, then recooled to −78° C. to give a pale yellow solution of LiTMP. A solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42, 1.1 g, 2.15 mmol) 20 ml THF was cannulated into the LiTMP solution to give a yellow solution which was stirred at −78 for about 1 hour; then N-methoxy-N-methylpyrazine-2-carboxamide (1.077 g, 6.44 mmol) was added. The mixture was stirred at −78° C. After 5 hours the reaction was worked up by adding saturated NH4Cl to the −78° C. solution and extracting with EtOAc (3×). After drying over MgSO4, concentration of the mixture gave material that was purified on SiO2 using 0-10% acetone/hexanes to recover 891 mg (67%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]3[CH3:23])=[CH:14][CH:15]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])C>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]3[CH3:23])=[CH:14][CH:15]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:9]1[C:30]([NH:39][C@H:38]([C:37]([OH:44])=[O:36])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2Cc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: O
Product: Cc1ccc(C)n1-c1ccc2c(c1)c(-c1ccccc1)c(C(=O)N[C@@H](CC(C)C)C(=O)O)n2Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenyl-1H-indole-2-carboxylic acid and L-leucine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as an off-white solid: 1H NMR (DMSO-d6) δ 0.77 (d, J=6.3 Hz, 3 H), 0.78 (d, J=6.3 Hz, 3 H), 1.25-1.40 (m, 1 H), 1.40-1.50 (m, 1 H), 1.90 (s, 6 H), 4.30-4.40 (m, 1H), 5.56 (d, J=16.0 Hz, 1 H), 5.63 (d, J=16.0 Hz, 1 H), 5.76 (s, 2 H), 7.05-7.65 (m, 13 H), 8.95 (d, J=13.3 Hz, 1 H), 12.35 (br s, 1 H); MS (ESI) m/z 534 (MH−); MS (ESI) m/z 532 ([M-H]−); HRMS calcd for C34H36N3O3: 534.2757; found (ESI+): 534.2745; Anal. calcd for C34H35N3O3.0.65 H2O: C, 74.88; H, 6.71; N, 7.70. Found: C, 74.55; H, 6.31; N, 7.68.
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH2:25][CH2:26][O:27][CH3:28])[CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1.C(O)(C(F)(F)F)=[O:30]>C(Cl)Cl.N>[O-:24][N+:13]1[C:14]2[CH:23]=[C:22]3[C:18](=[CH:17][C:15]=2[N+:16]([O-:30])=[C:11]([CH2:10][CH2:9][CH2:8][N:7]([CH2:25][CH2:26][O:27][CH3:28])[CH2:6][CH2:5][O:4][CH3:3])[N:12]=1)[CH2:19][CH2:20][CH2:21]3
Reactant: O=C(O)C(F)(F)F
Reactant: COCCN(CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3)CCOC
Agent: N
Agent: OO
Solvent: ClCCl
Product: COCCN(CCCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3)CCOC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFM (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 80 (1.50 g, 4.2 mmol) and TFA (1.5 mL, 1.95 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (36 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 81 (533 mg, 35%) as a red gum: 1H NMR δ 8.28 (s, 1H, H-9), 8.24 (s, 1H, H-5), 3.78 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.40-3.45 (m, 6H, 3×CH2), 3.33 [s, 6H, 2×OCH3), 3.19-3.23 (m, 2H, CH2), 3.12-3.17 (m, 4H, H-6, H-8), 2.34-2.38 (m, 2H, CH2), 2.22-2.28 (m, 2H, H-7); 13C NMR δ 155.5, 152.5, 151.1, 139.0, 134.0, 115.8, 113.8, 67.2 (2), 58.9 (2), 52.9 (3), 33.4, 32.9, 27.2, 25.5, 18.8; HRMS (FAB+) calcd for C19H29N4O4 (MH+) m/z 377.2189, found 377.2185.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[CH:14][C:13]=2Cl)[O:9][N:8]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[C:13]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][N:15]=[CH:16][C:17]=2[O:18][CH3:19])[O:9][N:8]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
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
Solvent: ClCCl
Product: COc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1
Yield: 4.1 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-chloro-5-methoxy-pyrid-4-yl)-1,2,4-oxadiazole (75 mg, 0.260 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 40% ethyl acetate in hexane and 100% ethyl acetate afforded 3.5 mg (4.1%) 3-(2-pyridyl)-5-[3-methoxy-5-(3-pyridyl)-pyrid-4-yl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.39 (s, 1H), 8.91 (d, 1H), 8.72 (d, 1H), 8.42 (d, 1H), 8.25 (d, 1H), 8.20 (s, 1H), 7.92 (dt, 1H), 7.63 (dd, 1H), 7.50 (m, 2H), 4.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[O:24])=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CSC(=O)N1CC(C)(C)SCc1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]L-cysteine methyl ester (0.6 g) in dimethylformamide (DMF,10 ml), carbonyldiimidazole (0.34 g) was added and the mixture was stirred for 2.5 hr at 110°-120° C. After the addition of hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.35 g of (4R)-3-[2-(4-methoxybenzylthio)-2-methylpropyl]-4-methoxycarbonylthiazolidine-2-one.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:14]([CH3:20])([CH3:19])[C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(c1cc(Cl)ccc1O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Boron tribromide (1 M in dichloromethane, 16.8 mL, 16.8 mmol) was added drop-wise over 10 minutes to a −78° C. solution of 4-chloro-1-methoxy-2-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (C47) (850 mg, 3.36 mmol) in dichloromethane (10 mL). After stirring at −78° C. for 30 minutes, the reaction mixture was heated to 40° C. and held at that temperature for 24 hours. The reaction mixture was then cooled to −78° C. and quenched with saturated aqueous sodium bicarbonate solution (10 mL). The pH was adjusted to approximately 5 with aqueous hydrochloric acid, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 515 mg, 2.16 mmol, 64%. GCMS m/z 238 (M+). 1H NMR (400 MHz, CDCl3) δ 1.67 (br s, 6H), 5.37 (br s, 1H), 6.71 (d, J=8.6 Hz, 1H), 7.14 (dd, J=8.6, 2.5 Hz, 1H), 7.33-7.36 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[NH3:12].CO>C1COCC1>[CH3:1][C:2]1[C:6]([S:7]([NH2:12])(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: N
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(C)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
3,5-Dimethylisoxazole-4-sulfonyl chloride (4.3 g; 21.8 mmol; 1 eq) is dissolved in THF (10 mL), ammonia in MeOH (55 mL; 2 M; 109 mmol; 5 eq) is added and the reaction is stirred for 1 h at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is taken up in 100 mL of EtOAc. The organic phase is washed with a saturated aqueous solution of NH4Cl (100 mL) then dried over MgSO4. The solvent is removed under reduced pressure, affording 2.6 g (67%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.59 (s, 2H), 2.56 (s, 3H), 2.34 (s, 3H). HPLC (max plot) 96.5%; Rt 1.22 min.
Reaction SMILES: [SH:1][C:2]([SH:7])=[CH:3][C:4](=[O:6])[CH3:5].[N+:8]([CH2:11][CH2:12]OC(=O)C)([O-])=[O:9]>C(O)C>[O:6]=[C:4]([CH3:5])[CH:3]=[C:2]1[S:7][C:11](=[N:8][OH:9])[CH2:12][S:1]1
Reactant: CC(=O)C=C(S)S
Reactant: CC(=O)OCC[N+](=O)[O-]
Solvent: CCO
Product: CC(=O)C=C1SCC(=NO)S1

Procedure:
To a solution of 6.8 grams (0.5m) of 4,4-dimercapto-3-buten-2-one in ethanol cooled to 10° C. was added 2.0 grams (0.5m) of sodium hydroxide dissolved in 30 ml of ethanol followed by dropwise addition at 0°-10° C. of 6.7 grams (0.5m) of nitroethylacetate dissolved in ethanol.
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2n1C1=CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(F)c(F)cc2n1C1CCNCC1
Reaction time: 8 h

Procedure:
A solution of 5,6-difluoro-1-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (D88) (0.7 mmol, 240 mg) in ethanol (10 mL) and acetic acid (2 mL) was treated under argon with 10% palladium on charcoal (50 mg, ˜0.25 eq wt) and the mixture was stirred overnight under 25-30 PSI, then 8 h under 50 PSI of hydrogen at room temperature. The mixture was concentrated under reduced pressure to give a yellow/orange oil which crystallized with a touch of methanol (from evaporation of the methanol). The residue was dissolved again in 10 mL ethanol and 2 mL of acetic acid, then 50 mg of palladium on charcoal was added again under argon and the mixture was stirred under 50 PSI of hydrogen for 9 days, until completion of the reaction. The mixture was concentrated under reduced pressure to give the title compound as the acetate salt. M+H 254.2, M−H 252.2
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:11][C:10]1[CH:12]=[CH:13][C:5]([CH:4]=[O:3])=[CH:6][C:7]=1[O:8][CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCc1ccccc1

Procedure:
Sodium hydroxide (2.4 g) is dissolved in water (50 mL) by stirring. Vanillin (7.60 g, 0.05 mol) and α-chloro-toluene (7.60 g, 0.06 mol) are added and the reaction mixture is heated at reflux with stirring for 16 hours. The product is extracted from the aqueous mixture using methylene chloride (10 mL). When the solvent is removed under vacuum an oil results which crystallizes when treated with isopropyl alcohol and stirred. Mass spectrometry supports the following structure: ##STR17##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F-].[Cs+]>O1CCOCC1.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>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:3]=1
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1nn(-c2cccc(-c3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 90 °C

Procedure:
1-(3-Bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg, 0.20 mmol), phenylboronic acid (37 mg, 0.31 mmol), cesium fluoride (124 mg, 0.82 mmol) are taken in dioxane-water (2:1) and bubbled with nitrogen for 5 min. Then bis(triphenyl phosphine)dichloro palladium(II) (21 g, 0.03 mmol) is added to reaction mass and heated under microwave irradiation for 1 h at 90° C. The reaction mixture is filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography to afford the title compound as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.03-8.01 (m,1H), 7.95-7.93 (d, J=8.0 Hz, 1H),7.83 (s, 1H), 7.72-7.70 (m, 4H), 7.68-7.60 (m, 2H), 7.59-7.47 (m, 3H), 7.45-7.40 (m, 1H), 4.91 (s, 2H), 3.96 (m, 4H), 3.62-3.61 (m, 2H). MS (ESI+): 486.0. HPLC (max plot) 98.53%; Rt 4.84 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)CCCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 1-(3-chlorophenyl)piperazine hydrochloride (12 g, 0.051 mol) in anhydrous toluene (250 ml) was added triethylamine (TEA) (15.6 ml, 0.112 mol) and ethyl 6-bromohexanoate (13.6 g, 0.061 mol) and the mixture heated at reflux for 4 hours. The mixture was then cooled to room temperature, washed with water (2×100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel using ethyl acetate/hexane (1/1) to give ethyl 6-[N′-(3-chlorophenyl)-N-piperazinyl]hexanoate (10.3 g) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:25][CH2:24][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Yield: 96.3 %

Procedure:
A solution of [3-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (2) (2.0 g, 0.007 mol) and 2,2-diphenylethylamine (2.5 g, 0.013 mol) in DMSO (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 2.72 g in 96% yield. 1H NMR (CDCl3) δ 7.24 (m, 7H), 7.19 (t, 3H), 6.85 (d, 1H), 6.74 (s, 1H), 6.72 (d, 2H), 5.26 (s, 1H), 4.22 (t, 1H), 3.96 (t, 2H), 3.68 (s, 3H), 3.57 (d, 2H), 3.26 (d, 2H), 2.84 (t, 2H), 1.92 (m, 2H). 13C NMR (CDCl3) δ 173.3, 160.5, 144.4, 136.7, 130.9, 130.1, 129.5, 129.4, 127.9, 122.9, 116.9, 114.6, 67.6, 56.0, 53.5, 52.6, 48.3, 42.6, 31.0.