Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C1CCCCC1
Yield: 46.8 %

Procedure:
Using the general method of Example 195 except that the acid chloride was added in a dropwise fashion, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with cyclohexanecarbonyl chloride (1.14 g, 7.83 mmol) to provide 1.34 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanecarboxamide as a white powder, m.p. 234.4-235.4° C. Analysis: Calculated for C21H27N5O: % C, 69.01; % H, 7.45; % N, 19.16; Found: % C, 68.70; % H, 7.39; % N, 19.24.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[S:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[N:32]=4)[CH:23]=[CH:22][N:12]3[C:13](=[O:21])[C:14]=2[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH2:4]1)=[O:2].O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[S:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[N:32]=4)[CH:23]=[CH:22][N:12]3[C:13](=[O:21])[C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:4]1)=[O:2]
Reactant: COC(=O)CCc1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(CCC(=O)O)c(N4CCCC(C=O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
The methyl 3-{2-(3-formylpiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}propanoate (23.1 mg, 0.0451 mmol) obtained in (B) was dissolved in a mixed solution of methanol, tetrahydrofuran and water (1:1:1, 3 ml), added with lithium hydroxide monohydrate (3.8 mg, 0.0901 mmol), and stirred overnight at room temperature. The reaction mixture was added with 1 N hydrochloric acid (0.091 ml) to neutralize the system, and then the solvent was evaporated. The resulting residue was purified by preparative TLC (chloroform:methanol=10:1) to obtain the title compound (15.0 mg, 71%) as lyophilized product.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[C:27]2[C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[O:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:11]12[O:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][N:9]([C:4]1[C:3]([CH2:2][O:17][C:18]3[C:27]4[C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[O:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:10]2
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Reactant: ClCc1cccnc1N1CC2CCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2c(OCc3cccnc3N3CC4CCC(C3)O4)cccc2O1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.080 g, 0.35 mmol) and 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (0.061 g, 0.31 mmol) in DMF was added cesium carbonate (0.307 g, 0.94 mmol) and the reaction mixture was heated (60° C.). After 30 minutes, the reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the aqueous layer was extracted two times with EtOAc. Combined organic layers were washed with brine, dried over MGSO4 and concentrated in vacuo. Purification by silica gel chromatography yielded 5-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methoxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (112 mg, 90% yield). MS (ES) for C22H24N2O5: 397 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7](Cl)[N:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C>O1CCCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ncc(N)nc1N
Temperature: 125 °C
Reaction time: 12 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid methyl ester (8.00 g, 39.5 mmol) in tetrahydrofuran (150 mL) were added tetrakis(triphenylphosphine)palladium(0) (2.28 g, 1.98 mmol), formic acid (2.24 mL, 59.3 mmol) and triethylamine (16.5 mL, 119 mmol) at 0° C. under nitrogen atmosphere, then, the solution was stirred at 125° C. for 12 hours. The reaction solution was cooled to room temperature, and a solid precipitated. This solid was collected by filtration, and the title compound (10.7 g, quantitatively) was obtained as a crude product of a white solid.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Na].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cn1ccnc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 2.2 g (0.010 mol) of chloromethyl(4-chlorophenyl)dimethylsilane and 1.1 g (0.012 mol) of imidazole sodium salt in 5 ml of dimethylformamide was stirred at 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.0 g (81%) of the title compound as a yellow liquid: nD20 1.5472; ir (neat) 1560, 1495, 1480, 1375, 1250, 1105, 1080, 905, 830, 810, 740 cm-1 ; nmr (CDCl3) 0.3 (6H, s), 3.6 (2H, s), 6.6 (1H, broad s), 6.9 (1H, broad s), 7.1 (1H, broad s), 7.3 (4H, s).
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8]>O.CO>[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[Mg+2:2]
Reactant: NCCS(=O)(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCS(=O)(=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of magnesium hydroxide (433 mg, 7.46 mmol; Aldrich) and taurine (1.87 g, 14.9 mmol) in 20 ml water was heated under reflux for seven hours. The resulting milky mixture was allowed to cool, diluted with 40 ml methanol and allowed to stand overnight at room temperature. A white powder, consisting mostly of magnesium taurate complex, was removed by filtration. The clear filtrate was concentrated under vacuum to a pasty slurry, then diluted slowly with 10 ml methanol. After 2 hours, crystalline magnesium taurate salt was obtained by filtration. The yield was 940 mg (41% ). The melting point (decomposition) was about 300° C. This salt was identical to that obtained in Example 2.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[OH:28][CH2:27][C@H:23]1[N:24]([CH2:3][CH:2]([OH:1])[C:4]2[CH:13]=[CH:12][C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[CH:5]=2)[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: O=C1OCc2cc(C3CO3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3c(c2)COC3=O)[C@H](CO)C1
Temperature: 150 °C

Procedure:
5-(Oxiran-2-yl)-2-benzofuran-1(3H)-one (1.5 g, 8.5 mmol) and commercially available (S)-4-N-BOC-2-hydroxymethyl piperazine (2.394 g, 11.07 mmol) were combined in ethanol (10 mL) in a microwave tube. The mixture was degassed then heated for 60 min at 150° C. LC-MS showed the product peak. The reaction was worked up by adding ethyl acetate and washing once with brine. The organic layer was separated, dried, and concentrated to dryness. The crude product was purified by MPLC using an 80 g Redi-sep column and eluted with 50%-100% EtOAc/hexane yielding the title compound.
Reaction SMILES: [CH:1]([NH:14][C:15]1[C:20]([Cl:21])=[C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[C:37](=[O:38])[C:36]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)=[CH:35][NH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[F:46])[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:53]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62]Cl)=[O:60])[CH2:55][CH2:54]1>CN(C=O)C.C(Cl)Cl>[N:53]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:54][CH2:55][CH:56]([C:59]([O:61][CH2:62][N:34]2[CH:35]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37](=[O:38])[C:32]([C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:19]4[CH:18]=[CH:17][N:16]=[C:15]([NH:14][CH:1]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:20]=4[Cl:21])=[C:24]([F:46])[CH:25]=3)=[CH:33]2)=[O:60])[CH2:57][CH2:58]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCn2cc(C(=O)Nc3ccc(Oc4ccnc(NC(c5ccccc5)c5ccccc5)c4Cl)c(F)c3)c(=O)c(-c3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A mixture of N-(4-(2-(benzhydrylamino)-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (120 mg, 0.189 mmol), K2CO3 (104 mg, 0.756 mmol) and 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate (157 mg, 0.567 mmol) in DMF (2 mL) was stirred at rt for 3 h. The reaction mixture was then diluted with DCM and the solid that formed was filtered off. The residue was washed with sat. aq. KH2PO4 solution. The organic layer was dried over MgSO4 and the desired product was purified by flash column chromatography (SiO2, eluting with a DCM/EtOAc gradient) to give the desired compound (145 mg) as a white solid. MS (ESI+) m/z 876 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])[CH:3]=1.[Li+].[Br-].P(Br)(Br)[Br:27]>CN(C=O)C>[Br:27][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(Cl)cc1Nc1ccc(CO)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(CBr)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of Example 569B (0.336 g, 1.0 mmol) and LiBr (0.1 g) in 3 mL of DMF was treated with PBr3 (0.1 mL) at 0° C. The solution was stirred for additional two hours, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to give 0.38 g of the title compound (97%). MS (DCI) m/e 401 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 10.94 (s, 1H), 8.29 (d, J=2.03 Hz, 1H), 7.98 (d, J=8.82 Hz, 1H,) 7.70-7.75 (m, 2H), 7.54 (d, J=2.03 Hz, 1H), 7.18 (dd, J=8.48, 2.03 Hz, 1H), 4.80 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26]>O1CCOCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 37 g (0.1 mol) of p-nitrophenyl ester of benzyloxycarbonylproline in 360 ml of dioxane there is added a solution of 16 g (0.09 mol) of arginine in 160 ml of water under vigorous stirring. Two hours thereafter the solvent is evaporated and the precipitate is dissolved in 100 ml of dimethylformamide. The solution is stirred at room temperature for 72 hours and poured into 1 liter of ethylacetate. The resulting residue is filtered-off, washed on the filter with ethylacetate and reprecipitated from a mixture ethanol-ethylacetate. The yield of product (I) is 35 g (96%); the product has the following properties: M.p. 190° C., [α]D20 -46.6°; (c 1.0; H2O); Rf =0.53 (A, "Silufol") 0.66 (B, "Eastman"); EHis =0.56 (pH=2.4).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C1COCC1.CCN(CC)CC>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of the compound (28.8 mg) obtained in Example 26 in THF (2.0 ml), Et3N (25.1 μl) was added, methylsulfonyl chloride (9.3 μl) was added at 0° C., and the reaction mixture was reacted at room temperature 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[N:21]1[CH2:27][CH2:28][CH2:29][NH2:30].Cl.[CH3:32]N(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[N:21]1[CH2:27][CH2:28][CH2:29][NH:30][C:16]([C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][C:8]([CH3:32])=[CH:9][C:4]=2[N:3]=1)=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2oc(N3CCCC[C@H]3C(=O)NCCCN3[C@H](C)CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.5 %

Procedure:
(2S)-1-(1,3-Benzoxazol-2-yl)-2-piperidinecarboxylic acid (270 mg) [see Preparation 3] and 3-[(cis)-2,6-dimethyl-1-piperidinyl]propylamine (180 mg) [J. Am. Chem. Soc. (1971), 71, 3839 and references citied therein] were dissolved in dichloromethane (20 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg) and a catalytic amount of 4-dimethylaminopyridine were then added to the reaction mixture. The reaction mixture was then stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 20:1, by volume, dichloromethane:methanol to afford (2S)-N2-3-[(cis)-2,6-dimethyl-1-piperidinyl]propyl-1-(5-methyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (37 mg) as a solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:4].[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:6]2[C:5]([C:3]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:38][CH:37]=3)=[O:4])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[S:8][C:7]=2[CH:18]=1
Reactant: COC(=O)c1c(-c2ccc(OC)cc2)sc2cc(OC)ccc12
Reactant: Br[Mg]c1ccc(OCCN2CCCCC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (202 mg, 0.615 mmol) in tetrahydrofuran (5 ml) under nitrogen at 5° C. is added, dropwise over 2 min via syringe a solution of 4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (1.0 ml of 0.76 M solution, 0.76 mmol). Cooling is removed, and the reaction is allowed to stir at room temperature for 48 hours. It is then quenched by addition of saturated aqueous ammonium chloride (2 ml), and partitioned between methylene chloride and water. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated to an oil, which is chromatographed on silica (5:1:1 hexanes:dichloromethane:triethylamine) to afford recovered starting material (46.0 mg, 23%) and title compound. The latter is further purified by dissolution in methylene chloride, followed by washing with 1 N hydrochloric acid, then 1 N sodium hydroxide. Drying over magnesium sulfate, filtration and concentration furnished 97.4 mg of title compound (0.194 mmol, 32%, 41% based on recovered starting material). IR (CHCl3): 2932, 1647, 1597, 1475, 1252, 1163, 1029, 828 cm-1 ; 1H NMR (CDCl3) δ7.75 (d, 2H, J=8.7), 7.51 (d, 1H, J=8.7), 7.31 (m, 3H), 6.94 (dd, 1H, J=9.0, 2.4), 6.74 (m, 4 H), 4.07 (t, 2H, J=6.0), 3.87 (s, 3H), 3.73 (s, 3H), 2.72 (t, 2H, J=6.0), 2.47 (m, 4 H), 1.58 (m, 4 H), 1.42 (m, 2H); 13C NMR (CDCl3) d 193.2, 163.1, 159.8, 157.7, 142.5, 140.1, 134.1, 132.4, 130.7, 130. 5, 130.3, 126.1, 124.1, 114.8, 114.3, 114.1, 104.6, 66.3, 57.8, 55.7, 55.3, 55.2, 26.0, 24.2. Anal. Calcd. for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found: C, 71.56; H, 6.27; N, 2.82; S, 6.26.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[C:21](=[O:24])([O-])[O-].[Na+].[Na+].O.CO[CH2:30][CH2:31][O:32][CH3:33]>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>[CH3:33][O:32][C:31]1[CH:9]=[CH:10][C:2]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)=[CH:3][C:30]=1[CH:21]=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C=O
Yield: 96.4 %

Procedure:
In a tube was placed boronate ester 35 (131 mg, 500 μmol), and 3 (175 mg, 500 μmol), with sodium carbonate (114 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (22 mg, 19 μmol). Water (0.9 g) and Ethylene glycol dimethyl ether (2.1 g) were added and the mixture was deoxygenated. The tube was sealed and heated to 110 C overnight, with magnetic stirring. The crude product was extracted with ethyl acetate and water. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. The crude was purified via flash chromatography and eluted with a gradient from 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7N ammonia in methanol to give 36 (98 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl.C(O[Cu]OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[N:7]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[N:6]=[CH:5]2
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc2[nH]ncc2cc1Br
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1Br
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 5-bromo-6-methyl-1H-indazole (2.89 g, 13.69 mmol,) in DCM (137 mL) was added 4-fluorophenylboronic acid (3.83 g, 27.4 mmol), diacetoxycopper (2.48 g, 13.7 mmol), pyridine (2.2 mL, 27.4 mmol) and 4 Å molecular sieves. The reaction was stirred open to air for about 4 h. The reaction mixture was filtered through a pad of Celite® rinsing with EtOAc (80 mL) and then concentrated to about (60 mL) under reduced pressure. Water was added (40 mL) and the layers were separated. The aqueous layer was back extracted with EtOAc (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:20) to afford 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (2.68 g, 8.78 mmol, 64%). LC-MS (Table 1, Method g) Rt=2.75 min, m/z 305, 307 (M+H)+. 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.98 (s, 1H), 7.69-7.59 (m, 2H), 7.52 (s, 1H), 7.28-7.18 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C1COCC1.O>CO.[Fe]>[NH2:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(Br)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(Sc2ccc(Br)cc2N)cc1
Yield: 91.2 %

Procedure:
A solution of the product of Example 106a (1.4 g, 3.9 mmol), iron powder (0.874 g, 15.6 mmol) and ammonium chloride (0.253 g, 4.68 mmol) in a methanol (6 mL), THF (6 mL), and water (2 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate. The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.2 g, 92%).