Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:15][CH2:14]1)=S.[S]>O=[Hg].C(O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:15][CH2:14]1
Reactant: Nc1ccccc1NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: CCO
Product: Clc1ccc(CN2CCC(CNc3nc4ccccc4[nH]3)CC2)cc1Cl

Procedure:
After adding ethanol (1 ml) to 1-(2-amino-phenyl-3-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-thiourea (11 mg, 0.025 mmol), mercury (II) oxide red (16 mg, 0.074 mmol) and sulfur (0.3 mg, 0.0094 mmol) were added at room temperature, and the mixture was refluxed for 7 hours. The mercury was filtered with celite, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/dichloromethane/methanol/triethylamine=40/25/20/10/5) to obtain (1H-benzoimidazol-2-yl)-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amine. The compound was identified by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Cl)c(Cl)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.16 (d, J 8.4, 1H), 7.31 (s, 1H), 7.52 (d, J 8.4, 1H), 7.77 (t, J 7.8, 1H), 7.89 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.22 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.49 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:16](Br)[CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:8]([CH2:16][CH2:17][CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCCBr
Reactant: COc1cccc2nc(C(F)(F)F)[nH]c12
Product: CCCn1c(C(F)(F)F)nc2c(OC)cccc21

Procedure:
Prepared from 4-methoxy-2-trifluoromethylbenzimidazole (2.4 g) and propyl bromide (3.02 ml). Purification by flash chromatography on silica eluting with 15% ethyl acetate in hexane gave the title compound as a white solid (2.03 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[O:8]1[CH2:12][CH2:11][O:10][CH:9]1[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:35]1[CH2:38][N:37]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:36]1>CCOCC>[O:10]1[CH2:11][CH2:12][O:8][CH:9]1[CH2:13][CH:14]=[C:35]1[CH2:36][N:37]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:38]1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC(=CCC2OCCO2)C1
Temperature: 35 °C
Reaction time: 6 h
Yield: 15.2 %

Procedure:
Potassium tert-butoxide (1.393 g, 12.4 mmol) and [2-(1,3-dioxolan-2-yl)ethyl]-triphenylphosphonium bromide (5.51 g, 12.4 mmol) were stirred in ether (30 mL) at ambient for 1 h. Phenylmethyl 3-oxoazetidine-1-carboxylate (1.025 g, 5.0 mmol), prepared using procedures similar to those described in Reference 3, was added and the mixture was stirred at 35° C. for 6 h and then at ambient for 4 days. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave phenylmethyl 3-[2-(1,3-dioxolan-2-yl)ethylidene]azetidine-1-carboxylate (220 mg, 0.761 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 7.39-7.28 (m, 5H), 5.43-5.35 (m, 1H), 5.11 (s, 2H), 4.89 (t, 1H), 4.56 (br d, 4H), 4.00-3.92 (m, 2H), 3.91-3.83 (m, 2H), 2.27 (br t, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].CCOP(O)N(C(C)C)C(C)C>O1CCOCC1>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][NH:14][C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1nc(Br)sc1NC
Agent: CCOP(O)N(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(NCCNC(=O)OC(C)(C)C)sc1NC
Temperature: 100 °C

Procedure:
Ethyl 2-bromo-5-methylamino-thiazole-4-carboxylate (546 mg, 2.059 mmol) and tert-butyl N-(2-aminoethyl)carbamate (1.3 g, 8.11 mmol) were combined in anhydrous 1,4-dioxane (15 ml). EDIPA (3 ml, 17.2 mmol) was added and the mixture was heated in a sealed tube for 23 hours at 100° C. The mixture was cooled to room temperature and partitioned between DCM and a saturated solution of sodium bicarbonate. Layers were separated, the aqueous phase was extracted twice with DCM and the combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica, gradient of 30 to 100% ethyl acetate in heptane) to yield 185 mg (0.537 mmol, 26%) MS(ESI) m/z=345.2 [M+1]+.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (330 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (291 mg, 94%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:10].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[O:10]
Reactant: OB(O)c1ccncc1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc(I)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: O=C(c1cccc([N+](=O)[O-])c1)c1cc(-c2ccncc2)ccc1F
Yield: 56.5 %

Procedure:
A 20 mL microwave tube was charged with (2-fluoro-5-iodophenyl)(3-nitrophenyl)methanone (1.1 g), 4-pyridylboronic acid (730 mg), dichlorobis(triphenylphosphine)palladium(II) (420 mg), dimethoxyethane (8 mL), ethanol (4 mL) and a saturated solution of sodium carbonate (2 mL) then heated to 110° C. for 360 s using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water then extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying salts were removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography to provide [2-fluoro-5-(4-pyridinyl)phenyl](3-nitrophenyl)methanone (540 mg) as a solid. H1 NMR (d6-dmso): 8.63 (d, 2H), 8.52 (dd, 1H), 8.48 (s, 1H), 8.21 (d, 1H), 8.15 (m, 1H), 8.06 (dd, 1H), 7.85 (dd, 1H), 7.74 (d, 2H), 7.58 (dd, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10]2[N:9]=[CH:8][NH:7][C:6]3=[N:5][CH:4]=[C:3]([CH3:2])[C:11]=23)[CH2:13][CH2:14]1)=[O:34]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(C(=O)NC2CCN(c3nc[nH]c4ncc(C)c3-4)CC2)c1
Reaction time: 18 h

Procedure:
To a mixture of 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (70 mg) and DIPEA (0.159 mL, 0.908 mmol) in DCM (1 mL) was added 3-(methyloxy)benzoyl chloride (56.8 mg, 0.333 mmol) and the reaction stirred for 18 hours. The mixture was partitioned between DCM (4 mL) and aqueous sodium bicarbonate (4 mL). The organic phase was then washed with 2M HCl (4 mL) before it was dried (phase separator) and concentrated. The crude product was purified by MDAP but the product was not clean, so it was then purified by silica chromatography eluting 2-10% MeOH in DCM to give E24 (17 mg) as a white solid, 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.33 (1H, d), 8.22 (1H, s), 7.45 (1H, d), 7.41 (1H, s), 7.37 (1H, t), 7.08 (1H, d), 7.07 (1H, s), 4.12-3.99 (3H, m), 3.81 (3H, s), 3.04 (2H, t), 2.37 (3H, s), 1.94 (2H, d), 1.74 (2H, ddd), MS(ES+) 366 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)cn2)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 2-amino-5-fluoropyridine instead of 2-chloro-4-aminopyridine to yield [2-(5-Fluoro-pyridin-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester as a white solid. MS (ISP): m/e=347.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide as a light yellow solid, MS (ISP): m/e=247.3 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a light yellow solid, MS (ISP): m/e=324.3 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH2:44]([C:48]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:49]=1[CH2:50][NH:51][CH:52]1[CH2:54][CH2:53]1)[CH2:45][CH:46]=[CH2:47]>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]([CH2:50][C:49]4[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:48]=4[CH2:44][CH2:45][CH:46]=[CH2:47])[CH:52]4[CH2:54][CH2:53]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCCc1cc(F)ccc1CNC1CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCc1cc(F)ccc1CN(Cc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (53.3 mg, 0.091 mmol) in acetonitrile (2 mL) at 0° C. was added Hunig's Base (0.016 mL, 0.091 mmol) and N-(2-(but-3-en-1-yl)-4-fluorobenzyl)cyclopropanamine (20 mg, 0.091 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)(cyclopropyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (45 mg, 0.067 mmol, 73.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.3, 6.1 Hz, 1H), 6.89-6.78 (m, 2H), 6.41 (s, 1H), 6.06-5.95 (m, 2H), 5.80 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.17 (d, J=11.0 Hz, 1H), 5.03-4.92 (m, 2H), 4.30-4.13 (m, 2H), 4.01 (d, J=4.9 Hz, 2H), 3.88 (s, 2H), 3.80 (s, 2H), 2.76-2.69 (m, 2H), 2.63 (s, 3H), 2.33-2.22 (m, 2H), 2.10-1.87 (m, 4H), 1.72 (br. s., 1H), 1.36 (br. s., 3H), 1.27-1.21 (m, 12H), 0.48-0.31 (m, 4H), 4 protons from piperidine were missing. LCMS (M+1)=676.5.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH:13]([CH3:15])[CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23]>O1CCCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:13]([CH3:14])[CH3:15])([CH2:23][CH2:22][C:24](=[O:25])[CH3:26])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CC(C)=O
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C(C)C)C2
Solvent: C1CCOC1
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCC(C)=O)(C(C)C)C2
Temperature: 25 °C

Procedure:
Methyl [(6,7-dichloro-2-isopropyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetate (16.5 gm., 0.05 mole) is suspended in dry tetrahydrofuran (100 ml.) containing triton-B (1 ml.). The suspension is stirred at ambient temperature and methyl vinyl ketone (5.02 gm., 0.072 mole) is added. The solution which becomes warm initially, is stirred at ambient temperature for 4 hours. Then, the stirring solution is treated with methyl vinyl ketone (0.3 ml.) and triton-B (0.6 ml.) every 4 hours for the next twenty hours.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Cl

Procedure:
In a similar manner as described for example A5, 2.60 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(1R)-1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate and 92 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[O:16][CH2:15][S:14][C:13]=2[C:17]=1[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH3:19])[C:12]2[O:16][CH2:15][S:14](=[O:29])[C:13]=2[C:17]=1[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)S(=O)CO2
Reaction time: 1 h

Procedure:
The whole of the 5-t-butyldimethylsilyloxy-4,6,7-trimethyl-1,3-benzoxathiole obtained as described in Example 92 was dissolved in 100 ml of methylene chloride, and 0.99 g of m-chloroperbenzoic acid was added, with ice cooling, to the resulting solution. The reaction mixture was then stirred for 1 hour at the same temperature, after which it was poured into a saturated aqueous solution of sodium bicarbonate, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off, whereupon the residue crystallized. The crystals were washed with carbon tetrachloride, yielding 1.30 g of the title compound, melting at 100°-101° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]([CH3:29])[C:25](OC)=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH:24]([CH3:29])[CH:25]=[O:26])=[CH:30][CH:31]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C=O)Oc1ccc(OCc2ccccc2)cc1
Temperature: -65 °C
Reaction time: 5 h
Yield: 42.5 %

Procedure:
A 1.5 molar solution of diisobutylaluminum hydride in toluene (138 mL, 0.207 mol) is added dropwise to a mixture of methyl 2-[p-(benzyloxy)phenoxy]propionate (56.4 g, 0.197 mol) in toluene at -65° C. under a nitrogen atmosphere. The reaction mixture is stirred at -65° C. for 5 hours. Acetic acid (70 mL) is added dropwise and the reaction mixture is warmed to room temperature, diluted with hexanes, washed with 10% hydrochloric acid solution and water, dried and concentrated in vacuo to obtain an oil. Flash chromatography of the oil using silica gel and eluting with a 1:1 methylene chloride/hexanes solution gives the title product as a white solid (21.44 g, mp 50°-51° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([CH3:26])=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:25][C:23]1[CH:24]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:20]=[CH:21][C:22]=1[CH3:26]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)c(O)c3)c2cc1OC
Yield: 81.4 %

Procedure:
A mixture of 2.98 g of 4chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.85 g of 5-amino-o-cresol, 1.39 g of pyridine hydrochloride, and 200 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 h. The mixture was cooled and added to 1000 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 3.27 g of 4-(3-hydroxy-4-methyl-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 222-224° C.; mass spectrum (EI, m/e): M 335.1269.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([CH3:20])=[CH:13][N:12]=1.O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>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>[Cl:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:15][C:14]([CH3:20])=[CH:13][N:12]=1
Reactant: Cc1cnc(Cl)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Temperature: 90 °C
Yield: 44.6 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-6-methyl-1,3,5-triazin-2-amine (0.350 g, 2 mmol), 2-chloro-5-methylpyridin-3-ylboronic acid (combi-blocks catalog number BB-3511) (0.6 g, 3 mmol), sodium carbonate, monohydrate, crystal (J.T. Baker catalog number 3600-01) (0.450 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0) (Strem chemicals catalog number 46-Z150) (0.3 g, 0.2 mmol). Degassed 1,2-dimethoxyethane (Aldrich catalog #255527) (11 mL, 109 mmol) and water (1 mL, 2 mmol) were added to the mixture. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 90° C. for 30 min. The mixture was filtered through Celite® (diatomaceous earth) and washed with ethyl acetate. The crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3/MeOH in dichloromethane, to provide 4-(2-chloro-5-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.210 g, 36% yield).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.FC(F)(F)C(O)=O>CC#N>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7]1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Reactant: C1=COCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Yield: 0 %

Procedure:
A mixture of methyl 5-nitro-1H-pyrazole-3-carboxylate (7.5 g, 43.8 mmol), 3,4-dihydro-2H-pyran (8 mL, 87.7 mmol) and trifluoroacetic acid (65 μL, 0.9 mmol) in anhydrous MeCN (100 mL) was refluxed for 16 hrs. The solvent was evaporated and the residue was resuspended in CH2Cl2 (50 mL) and washed with H2O and brine. After drying with Na2SO4, solvent evaporation and silica gel column chromatography (PE-EtOAc, 9:1) methyl 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylate (3.71 mg, 33%) was obtained.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:21][CH2:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(C(=O)NCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Sulfamoylbenzoic acid (201 mg), (tetrahydro-2H-pyran-4-yl)methanamine (144 mg), 1-hydroxybenzotriazole hydrate (230 mg), and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (288 mg) were combined in acetonitrile. The mixture was stirred at room temperature overnight. The solids were filtered off and reaction mixture was concentrated. The crude material was purified by flash chromatography eluting with a gradient of 2% methanol/dichloromethane to 10% methanol/dichloromethane.