Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[F:25])[C:11](=[O:26])[CH:10]=1)C1C=CC=CC=1>[Pd].C(Cl)Cl.CO.C1COCC1>[F:25][C:16]1[CH:17]=[C:18]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:19]=[CH:20][C:15]=1[N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:26]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)c(F)c1
Reaction time: 1.75 h
Yield: 107.8 %

Procedure:
To a 1 liter recovery flask added 10% palladium on carbon (1.75 g, 16.44 mmol), applied vacuum for 5 minutes then vented to nitrogen. Added 20 mL each of CH2Cl2/MeOH/THF to wet solid, then added a suspension of 4-(benzyloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (5.38 g, 14.41 mmol) in ˜80 mL each of CH2Cl2/MeOH/THF (total of 100 mL each solvent), all while keeping a nitrogen flow over mixture. Applied vacuum briefly then placed under an atmosphere of hydrogen for 105 minutes, filtered through a 60×60 mm pad of CELITE® 545 filter aid using an additional 200 mL each of MeOH and CH2Cl2, and concentrated the filtrate to give 4.4 g of crude product as an off-white powder. MS (ESI) 284.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+].O>[OH-].[OH-].[Pd+2].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.CO>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:2]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=2[CH2:4][OH:6])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2CO)CC1
Temperature: 80 °C
Yield: 39.8 %

Procedure:
Methyl 2-bromo-5-fluorobenzoate (1.8 g, 7.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.3 g, 7.5 mmol), THF (69 mL, 850 mmol) and 2 M of sodium carbonate in water (15.0 mL, 30.0 mmol) were combined, and the mixture was degassed and flushed with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (158 mg, 225 μmol) was added, and the mixture was again degassed and flushed with nitrogen. The mixture was heated at 80° C. for 1 hour. The mixture was then cooled and the layers separated, diluted with EtOAc (50 mL), washed with saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc in hexanes). A solution of the crude material and Pearlman's Catalyst (0.1:0.4, Palladium hydroxide:carbon black, 1.1 g, 1.5 mmol) in MeOH (60.8 mL, 150 mmol) was hydrogenated at 1 atm at room temperature overnight. The mixture was then evacuated, purged with nitrogen, filtered through Celite® and concentrated to yield a colorless oil. This oil was dissolved in THF (30 mL, 400 mmol) and treated with borane-dimethyl sulfide complex (1.3 mL, 15.0 mmol) at room temperature. The mixture was heated to reflux for 5 hours. After cooling to room temperature, MeOH (20 mL) was slowly added and removed by rotary evaporation. Another 20 mL of MeOH was added and removed by rotary evaporation. The residue was then dissolved in EtOAc (100 mL) and washed with 1N HCl and sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The material was then purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound (924 mg) as a colorless sticky solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[O:31])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CN(C)CCCNC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCNC(=O)COc1ccc(CCCCN)cc1
Yield: 79.6 %

Procedure:
A suspension of 3 (377 mg, 0.85 mmol) and 10% palladium on carbon (0.30 g, 50% wet) in methanol (15 mL) was stirred at room temperature for 2 h under atmospheric pressure of hydrogen. The mixture was then filtered through a Celite pad and the solvent was evaporated to provide 4 (208 mg, 80%) as a white solid. The crude product was directly used in the next step without purification. 1H NMR (300 MHz, CD3OD) δ 1.61 (m, 6H), 2.11 (s, 6H), 2.32 (m, 2H), 2.65 (m, 4H), 3.28 (m, 2H), 4.45 (s, 2H), 6.90 (d, 2H), 7.19 (d, 2H). m/z (ESI) 308.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C1COCC1.CC#N.O.ClCCl>[CH3:20][C:18]([CH3:19])([CH3:21])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N)c3)nc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(NS(=O)(=O)c4ccccc4)c3)nc12
Temperature: 55 °C
Yield: 38 %

Procedure:
To a flask was added 1-[2-(3-Amino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one 0.027 gm (0.092 mM), 1 ml dichloromethane, diisopropylethylamine 0.040 ml (0.23 mM) and benzenesulfonyl chloride 0.026 ml (0.204 mM). The mixture was stirred over night. Additional benzenesulfonyl chloride 0.0095 ml (0.074 mM) and diisopropylethylamine 0.015 ml (0.086 mM) was added and the mixture stirred overnight. The mixture was concentrated, 10 ml water and a few drops 1 M hydrochloric acid were added and it was extracted with ethyl acetate (3×30 ml). The ethyl acetate was dried over magnesium sulfate, stripped and purified on a preparative TLC plate (35:65 ethyl acetate/hexane) to give the diadduct 0.035 gm (0.061 mM, 66% yield). The diadduct was dissolved in a mixture of 3 ml THF and 6 ml MeCN. To this was added 0.4 ml 3M aqueous sodium hydroxide and the mixture heated to 55° C. for 4 hours. To this was added 50 ml water and concentrated on a rotary evaporator to remove the THF and MeCN. To the mixture was added 1M hydrochloric acid till neutral (solid forms) and extracted with ethyl acetate (3×50 ml). The solution was dried over magnesium sulfate and purified by preparative TLC (50:50 ethyl acetate/hexane) to give N-{3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-benzenesulfonamide 0.015 gm (0.035 mM, 38% overall yield) M+1 435, m.p. 217-219° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.[H-].[Na+].Cl[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23][CH2:22]1>CN(C)C=O>[O:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]([O:1][C:2]2[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=2)[CH2:22][CH2:23]1
Reactant: ClC1CCOc2ccccc21
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)C)cc2n1C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (50 mg, 0.21 mmol, WO 2004054984) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% dispersion in mineral oil, 11 mg, 0.27 mmol) at room temperature. After stirring for 20 minutes, a solution of 4-chlorochromane (71 mg, 0.42 mmol, WO 2000078751) in N,N-dimethylformamide (1 mL) was added at room temperature. The reaction mixture was warmed to 70° C., and stirred for 6 hours at the same temperature. The reaction mixture was quenched with sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate (20 mL×2). The combined extracts were washed with water and brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1 as an eluent) to afford the title compound as a white solid (40 mg, 52%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:34]\[OH:35])=[C:4]([CH3:32])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCCC2=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(N2CCCC2=O)cc1

Procedure:
In analogy to example 151, step 3, 5-{3-(4-chloro-2-methyl-phenyl)-3-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-propionyl}-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=464.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[O:15][CH:14]([O:22]C(=O)C5C=CC=CC=5)[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.C[O-].[Na+]>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[O:15][CH:14]([OH:22])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(OC1Oc2ccccc2-n2cnc(-c3noc(C4CC4)n3)c21)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC1Oc2ccccc2-n2cnc(-c3noc(C4CC4)n3)c21
Reaction time: 3.75 h
Yield: 81 %

Procedure:
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-4-(benzoyloxy)-4H-imidazo(5,1-c)(1,4)benzoxazine, Example compound 3 (0.88 g), was placed in methanol (44 mL). To that solution was added sodium methoxide (0.24 g) and stirring continued for 3.75 hours. The reaction was evaporated to dryness and triturated with water. Recrystallization from methanol afforded 0.53 g (81%) of the title compound. Mp 230°-4° C.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.O.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.[CH3:61][C:62]1[C:66]([CH2:67][NH2:68])=[C:65]([CH3:69])[NH:64][N:63]=1>>[CH3:61][C:62]1[C:66]([CH2:67][NH:68][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:43])=[C:65]([CH3:69])[NH:64][N:63]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1n[nH]c(C)c1CN
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: O=C(O)C(=O)O
Solvent: O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1c(C)n[nH]c1C
Yield: 24 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (3,5-dimethyl-1H-pyrazol-4-yl)methanamine dioxalate monohydrate, the title compound was obtained as a colorless solid in 24% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 2H), 6.08 (s, 1H), 5.61 (t, J=4.6 Hz, 1H), 4.42 (s, 2H), 4.35 (d, J=4.6 Hz, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H), 2.28 (s, 6H): MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]([CH3:20])([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14]([C:15]([NH:19][C:44](=[O:45])[C:43]([CH3:48])([CH3:47])[CH3:42])([CH3:20])[CH:16]([CH3:17])[CH3:18])=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)C(C)(C)C)C(C)C)CC1
Yield: 67.3 %

Procedure:
N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}-2,2-dimethylpropanamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-1,2-dimethylpropyl}-2,2-dimethylpropanamide (0.039 g, 67%) as an oil. ES-LCMS m/z 643 (M+1).
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.N>C(Cl)Cl.O>[NH2:8][C@@H:9]([CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CC#Cc1ccc(NCc2ccccc2F)cc1)NC(=O)OC(C)(C)C
Agent: N
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CC#Cc1ccc(NCc2ccccc2F)cc1
Yield: 89.9 %

Procedure:
A solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]amino}phenyl)-4-pentynoate (D65, 192 mg, 0.450 mmol) in DCM containing 5% TFA (10.5 ml) was stirred at room temperature for 4.5 h. Then 28% NH3 in water was added and the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to afford the title compound (132 mg). The crude product was used unpurified in the next step. UPLC: 0.56 min, MS: (ES/+) m/z: 327 [MH]+, C19H19FN2O2 requires 326.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5](=[O:17])[N:4]2[CH2:18][CH2:19][S:20][C:3]=12.[CH:21]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:24]([CH:21]2[CH2:23][CH2:22]2)(=[O:26])=[O:25])=[C:3]2[S:20][CH2:19][CH2:18][N:4]2[C:5](=[O:17])[CH:6]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1c(Nc2ccc(I)cc2F)cc(=O)n2c1SCC2
Solvent: c1ccncc1
Product: O=c1cc(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n1CCS2
Yield: 19.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.08 g, 0.199 mmol) in pyridine (1 mL) was reacted with cyclopropylsulfonyl chloride (33 mg, 0.238 mmol) to afford the crude product. Purification by preparative HPLC afforded 20 mg of the product (20% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@:7]1([C@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([OH:15])[C@@H:9]([CH2:16][OH:17])[O:8]1)[O:6][CH2:5]2.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C(C)=CC=CC=1C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:17][CH2:16][C@H:9]2[O:8][C@@:7]3([C:18]4[C:4](=[CH:3][C:2]([Cl:1])=[C:20]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=5)[CH:19]=4)[CH2:5][O:6]3)[C@H:12]([OH:13])[C@@H:11]([OH:14])[C@@H:10]2[OH:15])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: Cc1cccc(C)n1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 65.9 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (0.15 g, 0.356 mmol) in 3.5 mL of 2,6-lutidine was added p-toluenesulfonyl chloride (0.34 g, 1.78 mmol). After stirring for 21 h at ambient temperature, the solvent was distilled off. The residue was taken up with 30 mL of ethyl acetate, washed with 1 M hydrochloric acid and brine prior to drying over Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 135 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.61 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.21 (s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 4H), 5.02 (d, J=12.8 Hz, 1H), 4.97 (d, J=12.8 Hz, 1H), 4.22-4.08 (m, 4H), 3.90-3.86 (m, 1H), 3.71-3.65 (m, 2H), 3.39-3.34 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 2.33 (s, 3H), 1.18 (t, J=7.6 Hz, 3H); LC-MS (m/z) 575 [(M+1)+], 619 [(M+45)−].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:11]/[O:12][C:13]1([C:18](=[O:22])[NH:19][O:20][CH3:21])[CH2:17][CH2:16][CH2:15][CH2:14]1)/[C:7]([O:9]C)=[O:8].[Na]>CS(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:11]/[O:12][C:13]1([C:18](=[O:22])[NH:19][O:20][CH3:21])[CH2:17][CH2:16][CH2:15][CH2:14]1)/[C:7]([OH:9])=[O:8]
Reactant: CONC(=O)C1(O/N=C(\C(=O)OC)c2ccco2)CCCC1
Agent: [Na]
Solvent: CS(C)=O
Product: CONC(=O)C1(O/N=C(\C(=O)O)c2ccco2)CCCC1
Yield: 87 %

Procedure:
This compound was prepared from methyl Z-2-(fur-2-yl)-2-(methoxycarbamoylcyclopent-1-yloxyimino)acetate as described in Preparation 7(d). It was obtained as a pale brown foam, of which part was the sodium salt, νmax (Nujol) 3220 (--NH--), 3700-1800 (bonded OH), 1740, 1707 (--CO2H), 1625, 1512 cm-1 (--CONH--, --CO2θ), τ(DMSO d6) 6.4 (--OCH3), 7.7-8.6 (cyclopentyl), 2.18, 3.20, 3.38 (furyl). Yield 87%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][OH:35]>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:33][CH2:34][OH:35])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 85 °C
Yield: 51.4 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.255 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (234 mg, 2.55 mmol) and 2-bromoethanol (0.090 mL, 1.27 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil (50 mg, 52% yield).
Reaction SMILES: [CH3:1][N:2]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:25]([O-])=O)[CH:22]=2)[CH2:17]1)[CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:7]=2[CH:8]=1>C(O)C.[Pd]>[NH2:25][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH:16]([N:2]([CH2:3][C:4]1[O:5][C:6]3[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:7]=3[CH:8]=1)[CH3:1])[CH2:24]2
Reactant: CN(Cc1cc2cc([N+](=O)[O-])ccc2o1)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CN(Cc1cc2cc(N)ccc2o1)C1Cc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-[N-methyl-N-(5-nitrobenzofur-2-ylmethyl)amino]-5-nitroindane (0.33 g) in ethanol (25 ml) containing 5% Pd/C (0.03 g) was stirred under a hydrogen atmosphere [206.8 kPa (30 p.s.i.)] for 3 hours at room temperature. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to afford the title compound as a gum, yield 0.3 g, which was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[CH:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]4[CH:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=4[CH:24]=3)[CH:16]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)CC1COc2cc(OCc3cccc(-c4ccc(OC5CCCCO5)cc4C)c3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CC1COc2cc(OCc3cccc(-c4ccc(O)cc4C)c3)ccc21
Yield: 86.4 %

Procedure:
A solution of methyl (6-{[2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetate (4.49 g, 9.19 mmol) and p-toluenesulfonic acid monohydrate (0.175 g, 0.919 mmol) in methanol (50 mL) was stirred at room temperature for 30 hr. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (3.21 g, yield 86%) as a colorless viscous oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[N:5]1.[Cl-].[NH4+]>[Zn].O1CCOCC1.O>[F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:6]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[NH2:21])=[N:5]1
Reactant: O=[N+]([O-])c1cccc(-c2nn(CCF)cc2-c2ccncc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(-c2nn(CCF)cc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 4-[1-(2-fluoroethyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine in a solution of dioxane/water (5:1) ammonium chloride (144 mg, 2.7 mmol) and zinc (70 mg, 1.08 mmol) were added. The reaction was stirred at 80° C. After two hours the reaction was allowed to cool to room temperature and it was poured into Na2HPO4 (pH=8) solution and extracted with ethyl acetate. The organic layer was washed with brine (1×50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and it was used in the next step without further purification.