Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: COCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 46.7 %

Procedure:
A solution of the product of Example 48 (150 mg, 0.34 mmol) and 2-methoxy-ethylamine (0.09 mL, 1.01 mmol) in DMF (2 mL) was stirred 23° for 16 h. The mixture was diluted with EtOAc and washed with H2O to give the crude material, which was purified as described in Example 198 to give the desired product 70 mg (47%). LC-MS: 441.2 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:33]4[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=4)[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]=3[CH:10]=[N:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCC2)c(=O)[nH]1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 6-bromo-1-cyclobutyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (80% yield). LCMS: 489.30 (M+1)+; HPLC: 95.97% (@ 254 nm) (Rt;5.425); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.89 (t, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 6.81 (s, 1H), 5.89 (s, 1H), 5.52-5.44 (m, 1H), 4.37 (d, 2H, J=4.8 Hz), 2.73-2.63 (m, 2H), 2.43 (m, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.94-1.88 (m, 2H), 1.24 (d, 6H, J=6 Hz), 1.15 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[S:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (intermediate 179.1) (9.6 g, 34.49 mmol, 1.00 equiv) in anhydrous pyridine (12 mL). The mixture was cooled to 0° C. and 4-methylbenzene-1-sulfonyl chloride (7.9 g, 41.44 mmol, 1.20 equiv) was added slowly in several portions. The resulting solution was stirred at 0° C. for 1-2 h and then the flask containing the reaction mixture was sealed and placed in a refrigerator at 0° C. overnight. The mixture was poured into 120 mL of water/ice, and the aqueous layer was extracted with 3×50 mL of DCM. The combined organic layers were washed with 2×50 mL of cold 1.0 N hydrogen chloride and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to yield 13.4 g (90%) of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCC1CC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NCC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorphenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hours. Aminomethylcyclopropane hydrochloride (3.01 g, 0.028 mole) and triethylamine (2.83 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol with cooling. The crystalline precipitate was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 60° C. overnight to give 3.92 g (82%) of crystals, mp 228°-229° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[N:18][C:19]2[C:20]3[N:28]([CH2:29][CH2:30][CH2:31][OH:32])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:21]=3[CH:22]=[N:23][C:24]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:17]=[N:18][C:19]2[C:20]3[N:28]([CH2:29][CH2:30][CH2:31][O:32][N:57]4[C:61](=[O:62])[C:60]5[C:59](=[CH:66][CH:65]=[CH:64][CH:63]=5)[C:58]4=[O:67])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:21]=3[CH:22]=[N:23][C:24]=2[CH:25]=1
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Diisopropyl azodicarboxylate (6.47 mL, 32.9 mmol) was added dropwise over ten minutes to a stirred solution of 3-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propan-1-ol (10.0 g, 27.4 mmol), triphenylphosphine (8.62 g, 32.9 mmol), and N-hydroxyphthalimide (5.36 g, 32.9 mmol) in DMF (110 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford a solid that was slurried in ethyl acetate, isolated by filtration, washed with ethyl acetate, and dried under vacuum to yield 11.45 g of 2-{3-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propoxy}-1H-isoindole-1,3(2H)-dione as a pink solid.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:9])=[CH:14][CH:13]=1)[CH3:11]
Reactant: Oc1ccccc1
Reactant: CCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2ccccc2O)cc1
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A 60% dispersion of NaH/mineral oil (144 mg, 3.6 mmol) under Ar was added dropwise to a stirred solution of phenol (284 mg, 3 mmol) in PhMe (15 mL). After 10 min, p-ethylbenzyl chloride (1.23 g, 5.3 mmol) in PhMe (2 mL) was added prior to heating the reaction for 6 hr at 80°. After cooling, the volatiles were removed using a rotary evaporator and the residue dissolved in 15 mL of MeOH. The MeOH solution was extracted 4× with hexane prior to concentration. The resulting residue was dissolved in 1:1 EtOAc/H2O (100 mL), the pH adjusted to 5 and the two phases separated. After drying over Na2SO4 and removal of the EtOAc, 390 mg of crude title 2-(4′-ethylbenzyl)phenol was obtained. Prep HPLC yielded 275 mg of clean 2-(4′-ethylbenzyl)phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:27]1([N:33]=[C:34]=[S:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:35])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(N)cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(NC(=S)Nc4ccccc4)cc3)C2)cc1

Procedure:
3.4 g of 5-(4-aminophenyl)-3-(4-methoxyphenyl)-1-phenyl-2-pyrazoline and 1.5 g of phenyl isothiocyanate were reacted with each other in acetonitrile, and the product was reprecipitated from dimethylformamidemethanol to obtain 2.7 g of the desired end compound.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([F:37])[C:28]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:44](=[O:45])[C:42]2[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:28]3[C:29]([F:37])=[CH:30][C:31]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:32][C:27]=3[F:26])[N:43]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-hydroxypropan-2-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 200. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.28 (dd, J=8.7, 4.0 Hz, 1H), 8.14 (t, J=8.9 Hz, 1H), 7.89 (s, 1H), 7.34 (d, J=9.8 Hz, 2H), 5.36 (br, 1H), 4.80 (dd, J=10.4, 3.7 Hz, 1H), 4.37-4.06 (m, 1H), 4.02-3.87 (m, 2H), 3.75 (s, 3H), 3.13-3.00 (m, 1H), 2.10-1.99 (m, 1H), 1.85-1.57 (m, 3H), 1.47 (s, 6H). LCMS (ES+) m/z 522 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.9 %

Procedure:
To a solution of 3-amino-5-bromopyridine (1.0 g, 5.78 mmol) and pyridine (1.3 mL, 12.9 mmol) in DCM (5 mL) is added acetic anhydride (0.6 mL, 6.358 mmol) dropwise. The mixture is stirred at room temperature for 17 h. The mixture is concentrated and the resulting crude product is purified by normal phase using 0-75% EtOAc in heptane as the gradient to afford N-(5-bromo-pyridin-3-yl)-acetamide (1.18 g, 95% yield).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:30])[CH2:22][CH2:21][CH2:20][CH:19]2[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=1>>[OH:30][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:13][CH:14]=2)[CH2:22][CH2:21][CH2:20][CH:19]1[NH:23][S:24]([CH:27]([CH3:28])[CH3:29])(=[O:26])=[O:25]
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)NCCOc1ccc(C2(O)CCCC2NS(=O)(=O)C(C)C)cc1

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in example 51 from 2-propanesulfonyl chloride and {2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9](O)[C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[CH:16]1[C:21](O)=[CH:20][CH:19]=[C:18]([CH3:23])[CH:17]=1>O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]2[C:16]3[CH:17]=[C:18]([CH3:23])[CH:19]=[CH:20][C:21]=3[O:12][C:10]2=[O:11])=[CH:7][CH:6]=1
Reactant: O=C(O)C(O)c1ccc(OCCO)cc1
Reactant: Cc1ccc(O)cc1
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccc(OCCO)cc1)C(=O)O2
Yield: 58 %

Procedure:
A suspension of 8.5 g (40.0 mmol) of 4-(2-hydroxyethoxy)mandelic acid (compound (201), Example 10, Table 2) and 12.0 g (110 mmol) of p-cresol is maintained at 180° C. under a nitrogen atmosphere for 75 minutes, during which the water formed distils off. Excess p-cresol is then distilled off in a vacuum rotary evaporator. Chromatography of the residue on silica gel using the eluent system 9:1 dichloromethane/ethyl acetate gives 6.6 g (58%) of 3-[4-(2-hydroxyethoxy)phenyl]-5-methylbenzofuran-2-one, a yellowish resin (compound (119), Table 1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 1% to 5% methanol in ethyl acetate. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.006 g, 11%); 1H-NMR (500 MHz, DMSO-d6) 1H-NMR (500 MHz, DMSO-d6) 2.66 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.65 (br s, 4H, piperazine N(CH2)2), 3.70 (s, 2H, NCH2), 6.82 (d, J=9.00 Hz, 2H) and 8.01 (d, J=8.76 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.28 (dd, J=4.00, 5.86 Hz, 1H), 7.53 (d, J=9.00 Hz, 1H), 7.80 (td, J=1.70, 9.09 Hz, 1H), and 8.52 (d, J=4.96 Hz, 1H) (pyrid-2-yl protons), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.13 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C1C=C([O:21]O)C(C(O)=O)=C(C(O)=O)C=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[C:6](=[O:12])[O:11][C:7](=[O:21])[NH:8][C:9]=2[CH:10]=1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CCc1cc(Br)cc2c1C(=O)C(=O)N2
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(Br)cc2[nH]c(=O)oc(=O)c12

Procedure:
A stirred solution of 6-bromo-4-ethyl-1H-indole-2,3-dione (2.64 g, 10.4 mM) and the hexahydrate magnesium salt of monoperoxyphthalic acid (80% pure, 3.54 g, 5.73 mM) in glacial acetic acid (30 mL) was stirred at 60° C. for 1 hr during which time a precipitate formed. The cooled reaction mixture was then poured into cold water and the resulting mixture was filtered to separate (2.04 g, 73%) the title compound as a tan solid. Recrystallization of a portion of this material from ethyl acetate/hexane provided an analytical sample of the title compound as off white crystals, mp 208.5°-210.5° C.; MS(CI): 270 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH2:13])=[O:12])[C:5]=2[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.ClCCl.C([BH3-])#N.[Na+]>CO>[CH:5]1([N:18]2[CH2:19][CH2:20][CH:15]([N:3]3[C:4](=[O:14])[C:5]4[C:6]([C:11]([NH2:13])=[O:12])=[CH:7][CH:8]=[CH:9][C:10]=4[CH:2]3[CH3:1])[CH2:16][CH2:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxamide (60 mg, 0.19 mmol) in dichloromethane (2 mL) cyclohexanone (147 mg, 0.28 mmol) sodium acetate (32 mg, 0.38 mmol) and methanol (0.3 mL) were added. The resulted solution was stirred at room temperature for 5 hours. Then sodium cyanoborohydride was added and the mixture was stirred overnight. The solvents were removed under reduce pressure and the residue was dissolved in dichloromethane and washed twice with water. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane/methanol: 95:5) to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][S:8]([CH2:11][CH:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13]([OH:15])=O)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH:25]([CH2:39][CH3:40])[C@@H:26]([C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][N:29]=1)[OH:27]>>[C:1]1([CH2:7][S:8]([CH2:11][CH:12]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13]([NH:24][C@H:25]([C:26]([C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][N:29]=2)=[O:27])[CH2:39][CH3:40])=[O:15])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Reactant: O=C(O)C(COC1CCOCC1)CS(=O)(=O)Cc1ccccc1
Product: CC[C@H](NC(=O)C(COC1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
It is similarly prepared according to general procedure given for Example 1 above but using 2-Phenylmethanesulfonylmethyl-3-(tetrahydro-pyran-4-yloxy)-propionic acid and (S)-2-amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38](Cl)=[O:39]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:38]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][N:32]=4)=[O:39])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C(Cl)c1cnccn1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine was diluted to 0.40 M with anhydrous dichloromethane, then delivered to an 8 mL vial via pipette (0.2 mmol). To the amine solution was added base (0.4 M triethylamine in dichloromethane, 0.20 mmol). Pyrazine-2-carbonyl chloride was diluted to 0.40 M with dichloromethane, and added at rt (0.2 mmol). The reaction was shaken overnight at rt, then evaluated by MS. The reaction was concentrated using an HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). Pyrazine-2-carboxylic acid {4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated in 88% purity @ 254 nm, LCMS (APCI): 445 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>C1COCC1.[Ni]>[CH2:1]([O:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(N)c(OCc2ccccc2)n1
Yield: 54.7 %

Procedure:
2-Benzyloxy-6-methoxy-3 nitro-pyridine (3.41 g, 13.1 mmol) was shaken with 1 g Rainey nickel in 100 mL THF in a Parr hydrogenation apparatus at 48 psi H2 for 20 h. TLC analysis (silica, CH2Cl2) indicated complete consumption of starting material. The reaction mixture was filtered and concentrated. The crude product was purified by gradient elution flash chromatography (SiO2, 1:1 CH2Cl2/hexanes to 3:1 CH2Cl2/hexanes to 100% CH2Cl2) to give 1.65 g (7.17 mmol, 55%) of 2-benzyloxy-6-methoxy-pyridin-3-ylamine. MS (APCI) m/z 231.2 (M+1). 1H NMR (300 MHz) CDCl3 7.29-7.48 (m, 5H), 6.98 (d, J=8.1 Hz, 1H), 6.19 (d, J=8.1 Hz, 1H), 5.42 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN)cc1OC
Solvent: ClCCl
Product: COc1ccc(CNS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Aminomethyl)-3,4-dimethoxybenzene (18 ml., 120 mmole, 2 eq.) was added to a solution of methanesulfonyl chloride (4.64 ml., 60 mmole, 1 eq.) in dichloromethane (30 ml., 2.0M) at 0°. Additional dichloromethane (90 ml., final concentration of 0.5M) was then added. The reaction was allowed to warm to room temperature and stirred 2 days. The solid which had precipitated was filtered off and washed with additional dichloromethane. The filtrate was washed with 0.5N HCl (2×200 ml.) and water (200 ml.), dried (MgSO4), filtered, and concentrated to give 13.93 g. of yellow solid. This material was recrystallized from ethyl acetate:hexane (1:1, 75 ml.). The crystalline product was washed with ethyl acetate:hexane (1:1) and ether and dried to give 12.41 g. of N-[(3,4-dimethoxy)methyl]methanesulfonamide; m.p. 78°-81°.