Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:22]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12])[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
A stirred solution of 5-methoxyisatin (5.0 g, 28 mmol) in dry DMF (40 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 1.7 g, 42 mmol) slowly, the dark red solution turning quickly black. After stirring for 20 min, BnBr (3.7 mL, 31 mmol) was added to the reaction mixture by syringe and the resulting mixture was stirred for 1 h. Water (150 mL) was added with stirring, and the resulting dark red precipitate collected by filtration and washed with water to give 1-benzyl-5-methoxyindoline-2,3-dione as a dark red solid (6.1 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 7.17 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 4.92 (s, 2H), 3.79 (s, 3H). MS ESI 268.1 [M+H]+, calcd for [C16H13NO3+H]+ 268.09. A solution of 1-benzyl-5-methoxyindoline-2,3-dione (6.1 g, 23 mmol) and hydrazine hydrate (50-60% grade, 2.9 mL, ca. 2 eq) in DMSO (15 mL) is heated to 140° C. in an oil bath. After 3 h, the mixture was cooled, diluted with water and EtOAc, the layers separated and the aqueous extracted with EtOAc three times (30 mL). The combined organic portions were washed with 2M H2SO4, brine, and dried over MgSO4, filtered and concentrated to afford the crude product as a viscous brown oil. The crude product was purified by silica gel chromatography (20-50% EtOAc in hexane) to yield the title compound as a brown oil (5.0 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 6.89 (s, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.62 (s, 2H). MS ESI 254.0 [M+H]+, calcd for [C16H15NO2+H]+ 254.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]#[N:12])[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:11]#[N:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cc2nc(Cl)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2nc(Cl)ccc2n1Cc1ccccc1

Procedure:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonitrile (0.10 g, 0.56 mmol, from Step 2) in DMF (1.3 mL) was treated with K2CO3 (0.12 g, 0.84 mmol) and benzyl bromide (74 μL, 0.62 mmol, Aldrich) overnight. The reaction mixture was diluted with EtOAc and washed three times with water and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded purified product. Yield: (0.12 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[S:18](Cl)(=[O:20])=[O:19])([O:11][CH3:12])=[O:10]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:19])=[O:20]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Product: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 73 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared in the same manner as described in Example 10 from 5-amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thiophene-3-sulfonyl chloride in 73% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 198-200° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH:7]=[CH:8][Sn:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[C@@H:3]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].[CH:31](N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][O:29][C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:3]1[C@H:4]([CH:7]=[CH:8][Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Wang resin bound trans-7-[2-Oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid. A dichloromethane (5 mL) solution of trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl]-heptanoic acid of Step E (6.35 g, 12.05 mmol, 3 eq) was added to the Wang resin (5.66 g, 4.02 mmol, 1 eq) along with diisopropylethylamine (6.23 g, 48.20 mmol, 12 eq). The mixture was allowed to swell for 1 hour, and EDC (2.31 g, 12.05 mmol, 3 eq) was added followed by 4-dimethylaminopyridine (catalytic amount about 20 mg). The mixture was stirred at room temperature overnight. The resin was filtered, washed with dichloromethane (20 mL×2), repeatedly swollen with dichloromethane (20 mL) and shrunk with methanol (20 mL). The resin was washed with diethyl ether (20 mL×3) and dried on a filter funnel attached to a water aspirator for 30 minutes. Further drying under high vacuum for 5 hours provided the title compound as a free-flowing yellow resin.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)CCC>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[N:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(-c2cnccn2)nc1
Yield: 60 %

Procedure:
Obtained (0.310 g, yield 60%) following the procedure described in Intermediate 37, starting with 2,5-dibromopyridine (2.11 mmol, 0.5 g), 2-(tributylstannyl)pyrazine (2.32 mmol, 0.857 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:17]O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: O=C(O)CCCc1nc2ccccc2s1
Agent: Cl
Product: COC(=O)CCCc1nc2ccccc2s1
Yield: 73 %

Procedure:
A solution of 4-(2-benzothiazolyl)butanoic acid (3.75 g, 16.1 mmol, prepared according to the procedure of Example 11 in JP, A, 8-208631 (1996)) in hydrochloric acid-methanol (80 ml) was stirred at room temperature overnight, and evaporated. The residue was dissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and purified through flash column chromatography to give methyl 4-(2-benzothiazolyl)butanoate (2.75 g, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][N:15]([CH3:22])[C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCc2ncc(OCc3ccccc3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2ncc(OCc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
3-(Benzyloxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (10.0 mg, 0.04 mmol) was dissolved in DMF (0.5 mL). NaH (2.0 mg, 0.08 mmol) was added into the solution and stirred at room temperature. After 30 min, MeI (5.0 μL) was added into the mixture and allowed to stir for another hour. Reaction was then quenched with H2O (2.0 mL) and extracted with EtOAc (3.0 mL×3). The organic layers were combined and concentrated to afford pure product as a white solid (9.2 mg, 87%). LC-MS (M+H)=267.1.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:56][CH2:57][CH2:58][C:59]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[NH:61][CH:60]=1>CCOC(C)=O>[NH:61]1[C:62]2[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:59]([CH2:58][CH2:57][NH:56][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])=[CH:60]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.19 g (1.41 mmol) of 1-hydroxybenzotriazole hydrate in 20 mL of anhydrous EtOAc (under a N2 atmosphere) was treated in one portion with 0.34 g (1.65 mmol) of 1,3-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 2 hours, treated with 0.26 g (1.62 mmol) of tryptamine, and stirred for an additional 18 hours. The precipitated solid was filtered, washed with a small amount of fresh EtOAc, and discarded. The filtrate was diluted to 150 mL with EtOAc and washed with 5% aqueous citric acid (3×150 mL), brine (1×150 mL), 5% aqueous NaHCO3 (3×150 mL), and brine again. The organic layer was dried (Na2SO4) and evaporated (vacuum) to a tan solid. The residue was chromatographed (E. Merck prepacked Lobar column, 37×440 mm, eluted with 2% MeOH in CH2Cl2) to yield the purified product as a white foam, 0.32 g (47%); 1H NMR (CDCl3) δ 1.46-1.92 (17H, m), 2.83 (2H, t, J 7 Hz), 3.23 (1H, d, J 15 Hz), 3.40 (1H, d, J 15 Hz), 3.52 (2H, m), 4.78 (1H, m), 6.82 (1H, m), 7.06-7.58 (8H, m), 7.96 (2H, br s).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>N1CCCCC1.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>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])=[CH:3][CH:4]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A mixture of 1-iodo-4-trifluoromethoxy-benzene (5 g, 17 mmol), Pd(PPh3)4 (973 mg, 1 mmol) and cuprous iodide (160 mg, 1 mmol) in piperidine (130 ml) was stirred for 30 min at 50° C. under an argon atmosphere. 4-Pentyn-1-ol (2.13 g, 25 mmol) was added within 60 min at 50° C. The temperature was raised to 80° C. and the mixture was stirred for 3 h at this temperature. The reaction mixture was cooled to ambient temperature, poured into a solution of saturated aqueous 10% KHSO4/ice water 1/1 and extracted two times with tert butyl methyl ether. The combined extracts were washed with water and brine (two times) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 3.4 g (13.9 mmol, 83%) of the title compound as orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:20][N:21]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:22][CH2:23][N:24]1[C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(O)Cc1ccccc1F
Product: COc1ccc(N2CCN(C(=O)Cc3ccccc3F)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 50 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(2-fluorophenyl)acetic acid and (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine as starting materials. Product was obtained as an off-white solid (50%). LC/MS (Method B) 4.53 min, [M+1]+ 503.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)#[CH:21]>>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:21]#[C:20][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CC1CCCCO1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(I)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2CCCCO2)c1

Procedure:
Sonogashira reaction of 106 with 2-ethynyltetrahydro-2H-pyran yielded tert-butyl 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)ethynyl)phenyl)propylcarbamate (107) as dark brown oil. Yield (1.21 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.27-7.35 (m, 3H), 4.87 (bs, 1H), 4.69-4.71 (m, 1H), 4.49-4.51 (m, 1H), 4.02-4.07 (m, 1H), 3.50-3.52 (m, 1H), 3.56-3.61 (m, 1H), 3.13-3.18 (m, 1H), 1.91-1.93 (m, 2H), 1.74-1.86 (m, 4H), 1.51 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11](=[O:35])[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:40]=[N+:41]=[N-:42])(C)C.[N-]=[N+]=[N-].Cl>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11](=[O:35])[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:42][N:41]=[N:40][N:34]=3)=[CH:25][CH:26]=2)[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 96 h

Procedure:
A mixture of 472 mg of 3-tert.-butoxycarbonylaminomethyl-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine, 206 mg of trimethyltin azide and 12 ml of xylene is boiled for 96 hours; a further 0.2 g of azide is added after 48 hours. The mixture is cooled, treated with ethereal hydrochloric acid and evaporated. Chromatography of the residue (silica gel; methylene chloride/methanol 95:5) yields 3-tert.-butoxycarbonylaminomethyl-6-butyl-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]pyridine; m.p. 105°. The corresponding K salt is prepared therefrom in conventional manner.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:13]2[CH:14]=[CH:15][O:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccon1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1cccc(Nc2ccon2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a solution of 3-bromophenylboronic acid (2.00 g, 9.96 mmol) in CH2Cl2 (80 mls) was added Isoxazol-3-ylamine (0.84 g, 19.92 mmol), Cu(OAc)2 (0.9 g, 0.46 mmol) and triethylamine. (14 mls). The reaction mixture was stirred at room temperature for 18 h, filtered and the resulting precipitate purified by silica column chromatography (20-80% EtOAc in hexane) to afford the title compound (0.33 g). MS: [M+H]+=239, 241
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[N:10](C1CCCCO1)[N:9]=[CH:8]2.Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[NH:10][N:9]=[CH:8]2
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2-c2ccncc2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2-c2ccncc2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of 5-(2-fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.8 g, 6.45 mmol) in EtOH (30 mL) is added HCl (concentrated 5.0 mL). The mixture is stirred at 80° C. for 2 hours. Then aqueous NaHCO3 and EtOAc are added. The organic phase is dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (3:1) to give the desired product (1.95 g, 86.0% yield). MS (m/z): 351.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:39])[NH:34][C:35](=[S:38])[NH:36][CH:37]=2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][S:38][C:35]3[NH:36][CH:37]=[C:32]([CH2:31][C:28]4[CH:29]=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[C:33](=[O:39])[N:34]=3)=[CH:10][C:7]=2[C:8]#[N:9])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 33.2 %

Procedure:
The same procedure as E63 from 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl) phenyl]oxy}benzonitrile (198 mg, 0.599 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (150 mg, 0.599 mmol) and K2CO3 (166 mg, 1.199 mmol) in DMF (3 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (108 mg, 33.2% yield). LCMS: rt=3.32 min, [M+H+]=544
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH:17]2[CH2:18][CH2:19][N:20]([C:2]3[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=3)[CH2:21][CH2:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC(c3ccccc3)CC2)nc1

Procedure:
Intermediate B-6 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-phenylpiperidine as starting materials. LCMS (ESI) calcd for [M+1]+ 254.2. found 254.1.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1.[NH2:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1>>[NH2:13][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][NH:3][C:19]2[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([NH2:14])[N:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCCNc1ccnc(N)n1
Agent: Cl
Product: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1

Procedure:
The product of Example 1E (250 mg, 1.11 mmol) and 2-amino-4,6-dichloropyrimidine (201 mg, 1.23 mmol) were treated under the conditions described in Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.31-3.41 (m, 4H) 5.72 (d, J=5.95 Hz, 1H) 5.75 (s, 1H) 5.85 (s, 2H) 6.40 (s, 2H) 6.85 (s, 1H) 7.21 (s, 1H) 7.61 (d, J=5.55 Hz, 1H); MS (ESI+) m/z 280.9 (M+H)+.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35]N[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1>O1CCOCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][N:4]([S:1](=[O:3])(=[O:2])[NH2:5])[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 4 h

Procedure:
Sulfamide (9 mg, 0.093 mmol) was added to solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (25 mg, 0.058 mmol) (Example-32) in 1,4-Dioxane (0.5 mL) and stirring was continued at 110° C. for 4 h. The reaction mixture was concentrated to afford the residue, which was quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude. The crude product was purified by Preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 10% MeOH in DCM as eluent) to afford 8 mg, of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11](S)[NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1>[Ni].CN(C)C=O>[CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CN(C)c1cc(-c2c[nH]c(S)n2)ccn1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2c[nH]cn2)ccn1

Procedure:
A mixture 800 mg. (3.63 mmoles) of 4-(2-dimethylamino-4-pyridyl)imidazole-2-thiol, 2 g. of Raney nickel and 20 ml. of dimethylformamide was heated at 120° C. for 3.5 hours. The catalyst was filtered and the filtrate concentrated to an oil which solidified on treatment with ether. The product was purified by chromatographing on 10 g. of florisil using chloroform-methanol (9:1, v:v) as the eluent, 361 mg., m.p. 173°-173.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (14.99 g) and 4-chlorobenzonitrile (10.35 g) in DMF (100 mL) was treated with sodium hydride (60%, 3.8 g). The resulting dark mixture was then heated to 65 C for 16 h, and allowed to cool to RT. The mixture was poured into water (1 L) and extracted with ether (3×400 mL). The combined organic phases were evaporated and the brown oil dissolved in methanol (500 mL) and treated with concentrated hydrochloric acid (20 mL). After 24 h the methanol was removed, 5% aqueous sodium hydroxide (300 mL) and water (300 mL) were added, and the mixture was extracted with DCM (3×300 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Bulb to bulb distillation of the residue gave the title compound as an off white waxy solid (12.23 g).