Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([N:22]1[C:26]2[CH:27]=[C:28]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]3)[C:29]3[N:30]([C:31]([CH3:34])=[N:32][N:33]=3)[C:25]=2[CH:24]=[C:23]1[CH3:43])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C=O>C(Cl)Cl>[CH2:15]([N:22]1[C:26]2[CH:27]=[C:28]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([NH:42][CH3:1])[CH2:38][CH2:37]3)[C:29]3[N:30]([C:31]([CH3:34])=[N:32][N:33]=3)[C:25]=2[CH:24]=[C:23]1[CH3:43])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2c(cc(N[C@H]3CC[C@H](N)CC3)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (11 mg, 0.053 mmol) was added to a mixture of trans-N-(6-benzyl-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-yl)cyclohexane-1,4-diamine (10. mg, 0.027 mmol, from Example 217) and formaldehyde solution (37 wt % in water, 3.2 mg, 0.040 mmol, Aldrich) in DCM (0.5 mL). After 30 minutes, both monomethylated and dimethylated products were observed by LCMS. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded monomethylated product. (Yield: 0.8 mg, 7%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[CH:36][C:35]([F:46])=[CH:34][N:33]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:47]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O>[Si:13]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:39][C@H:40]([CH3:45])[O:41][C@H:42]([CH3:44])[CH2:43]2)=[C:36]([Cl:47])[C:35]([F:46])=[CH:34][N:33]=1)([C:26]([CH3:27])([CH3:29])[CH3:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H]1CN(c2cc(F)cnc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H](C)O1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of diisopropylamine (3.51 ml, 24.65 mmol) in THF (30 ml) was cooled in a dry ice-acetone bath. A solution of n-butyllithium (2.5 M in hexanes, 9.28 ml, 23.20 mmol) was added and the mixture was warmed to 0° C. and recooled in a dry ice-acetone bath. The solution was added to a second solution of (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 44, 6.94 g, 14.50 mmol) in THF (30 ml) cooled in a dry ice-acetone bath. The mixture was stirred for 45 minutes before the solution was transferred via cannula to a solution of hexachloroethane (2.79 ml, 24.65 mmol) in 60 ml THF also cooled in a dry ice-acetone bath. The mixture was allowed to warm to room temperature before being diluted with EtOAc and washed with water and brine. The combined aqueous layers were extracted again with EtOAc, which was washed with brine. Drying (MgSO4) of the combined EtOAc extracts and removal of solvent gave a gummy solid that was chromatographed on silica gel (50% hexanes in CH2Cl2 followed by gradient elution to 100% CH2Cl2) to afford product as an oil that slowly solidified (5.26 g yield). MS (ES) MH+: 513 for C28H34ClFN2O2Si.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:22])[NH:17][C:16](=[O:18])[C:15]([C:19]#[N:20])=[C:14](O)[CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:25].CCN(C(C)C)C(C)C>C(Cl)CCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:22])[NH:17][C:16](=[O:18])[C:15]([C:19]#[N:20])=[C:14]([Cl:25])[CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2(C)CC(O)=C(C#N)C(=O)N2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(C2(C)CC(Cl)=C(C#N)C(=O)N2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a stirred solution of Intermediate 107E (130 mg, 0.433 mmol) in ClCH2CH2Cl (3 mL) was added POCl3 (0.056 mL, 0.606 mmol) and Hunig's base (0.113 mL, 0.649 mmol). The reaction was stirred at rt for 30 min and then heated to 85° C. for 3 h. The reaction mixture was concentrated and the residue was diluted with EtOAc. The organic layer was washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (102 mg, 74%) as a white solid. LCMS Anal. Calc'd for C17H19ClN2O2 318.11, found [M+H] 319.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J=8.80 Hz, 2H), 6.90 (d, J=8.80 Hz, 2H), 3.97 (t, J=6.60 Hz, 2H), 2.05 (s, 2H), 1.74-1.82 (m, 2H), 1.69 (s, 3H), 1.46-1.55 (m, 2H), 0.99 (t, J=7.43 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1)#[CH:27].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:27]#[C:26][C:28]2([OH:36])[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOC(=O)C1CCN(c2ccc(I)c(Cc3ccccc3)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)CC1
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A mixture of 1.42 g of 2-benzyl-3-iodo-6-(4-ethoxycarbonylpiperidino)pyridine, 520 mg of 3-ethynyl-3-quinuclidinol, 110 mg of tetrakis(triphenylphosphine)palladium(0), 3 mg of cuprous iodide, 1.3 ml of triethylamine and 6 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 80° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 700 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=O.[CH2:7]([NH:10]C=O)[CH:8]=[CH2:9].C(=O)=O>>[ClH:1].[CH2:5]([O:4][CH:2]=[N:10][CH2:7][CH:8]=[CH2:9])[CH3:6]
Reactant: C=CCNC=O
Reactant: CCOC(=O)Cl
Agent: O=C=O
Product: C=CCN=COCC
Product: Cl
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (2.66 g., 24.47 mmole) is added by syringe to N-allylformamide (2.08 g., 24.47 mmole) in a dry flask under N2. The resulting mixture is then stirred at 25° C., for 2 hours during which time CO2 is rapidly evolved. The reaction mixture is then heated to 45° C. until no further evolution of gas is evident (2 hours). The viscous product is then cooled and held at a vacuum of 0.2 mm for 2 hours to remove all volatiles.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[H][H]>C(O)C.[Pd]>[CH2:19]([O:18][C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:17])[CH3:20]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 59.6 %

Procedure:
A mixture of 0.814 g of L-alanyl-L-proline, 0.206 g of ethyl 2-oxo-4-phenylbutyrate, and 1.6 g of molecular sieves in 10 ml ethanol is hydrogenated at room temperature under 40 pounds pressure with 0.1 g of 10% Pd on carbon as catalyst. After uptake of hydrogen ceases the crude product obtained by filtration and concentration is absorbed on ion exchange resin, (Dowex 50, H+) and eluted with 2% pyridine in water to yield 0.224 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline. HPLC indicates a 55:45 isomer ratio.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40]>C(OCC)C>[CH:39]([NH:42][C:43]([C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1)=[O:44])([CH3:41])[CH3:40]
Reactant: CC(C)N=C=O
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)NC(=O)c1cc(N(C)Cc2ccccc2)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
2.22 g (0.0051 mol) of 2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 3.4 ml of a 1.65M-hexane solution of BuLi (0.0051×1.1 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After 0.86 g (0.0051×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2]1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>>[CH:18]([NH:21][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: c1ccc(-c2ccccc2CCC2CO2)cc1
Reactant: CC(C)N
Product: CC(C)NCC(O)CCc1ccccc1-c1ccccc1

Procedure:
Following a precedure similar to that of Example 32, 1,2-epoxy-4-(1,1'-biphenyl-2-yl)butane was reacted with isopropylamine to provide N-isopropyl-2-hydroxy-4-(1,1'-biphenyl-2-yl)butylamine. The amine base so formed was reacted with hydrogen chloride to provide N-isopropyl-2-hydroxy-4-(1,1'-biphenyl-2-yl)butylaminium chloride. M.P. 153°-154° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>C(O)(=O)C>[Cl:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([N:1]2[C:14](=[O:15])[C:13]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]3[C:11]2=[O:16])=[CH:7][C:6]=1[OH:8]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)c(Cl)cc1F
Yield: 92.9 %

Procedure:
5-Amino-2-chloro-4-fluorophenol (3.0 g, 18.6 mmol) and phthalic anhydride (3.3 g, 22.3 mmol) were dissolved in glacial acetic acid (60 ml) and the solution refluxed for 2 hr. Water was added and the resultant precipitate was separated by filtration. The residue was washed with water and dried to afford the title compound (5.04 g); 1H NMR (CDCl3+CD3OD, 300 MHz) 3.68 (1H, s), 6.93 (1H, d, J=6.6 Hz), 7.27 (1H, d, J=9.1 Hz), 7.84 (2H, dd, J=3.0, 5.5 Hz), 7.97 (2H, dd, J=3.0, 5.5 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CS(O)(=O)=O>C(Cl)Cl>[C:11]12([C:7]3[CH:6]=[C:5]([OH:8])[CH:4]=[C:3]([O:9][CH3:10])[C:2]=3[Br:1])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[C:11]12([C:6]3[CH:7]=[C:2]([Br:1])[C:3]([O:9][CH3:10])=[CH:4][C:5]=3[OH:8])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: COc1cc(O)ccc1Br
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Product: COc1cc(O)cc(C23CC4CC(CC(C4)C2)C3)c1Br
Temperature: 54 °C
Yield: 55 %
Yield: 26 %

Procedure:
A mixture of 4-bromo-3-methoxyphenol (6.33 g, 31.18 mmol), 1-adamantanol (4.75 g, 31.18 mmol) and MeSO3H (1.3 mL) in CH2Cl2 (22 mL) was stirred with heating at 54° C. (oil-bath) for 29 h. The resulting solution was quenched with H2O (30 mL) and extracted with EtOAc (140 mL). The extract was washed with H2O, 5% NaHCO3, and brine and dried. The residue obtained on concentration was purified on silica gel (0% to 15% EtOAc/hexane) to give 5.77 g (55%) of 3-(1-adamantyl)-4-bromo-5-methoxyphenol as a white solid, mp 151-153° C. and 2.71 g (26%) of 2-(1-adamantyl)-4-bromo-5-methoxyphenol as a white solid, mp 182-185° C. 3-(1-Adamantyl)-4-bromo-5-methoxyphenol: IR 3515, 2902, 2848, 1312, 1216 cm−1; 1H NMR δ (CDCl3) 1.75 (bs, 6H, AdCH2), 2.04 (bs, 9H, AdCH and AdCH2), 3.79 (s, 311, OCH3), 5.29 (s, 1H, OH), 6.57 (s, 1H, 6-ArH), 7.19 ppm (s, 1H, 2-ArH). 2-(1-Adamantyl)-4-bromo-5-methoxyphenol: IR 3513, 2902, 2848, 1389, 1207 cm−1; 1H NMR δ (CDCl3) 1.77 (bs, 6H, AdCH2), 2.06 (bs, 9H, AdCH and AdCH2), 3.83 (s, 3H, OCH3), 4.83 (s, 1H, OH), 6.29 (s, 1H, 6-ArH), 7.31 ppm (s, 1H, 3-ArH).
Reaction SMILES: [C:1](=[O:44])([O:3][CH2:4][CH2:5][O:6][C@@H:7]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:36])[NH:15][C@H:16]([CH2:24][NH:25][CH2:26]C(OCC[Si](C)(C)C)=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9]1)[NH2:2].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[C:1](=[O:44])([O:3][CH2:4][CH2:5][O:6][C@@H:7]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:36])[NH:15][C@H:16]([CH2:24][NH:25][CH3:26])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9]1)[NH2:2].[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: C[Si](C)(C)CCOC(=O)CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCOC(N)=O)c2cccc(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCOC(N)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(2-(trimethylsilyl)ethoxycarbonylmethylamino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethyl carbamate (0.0250 g, 0.038 mmol) and trifluoroacetic acid (1 mL) in CH2Cl2 (5 mL) was stirred at rt for 3 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 13 min, flow rate 25 mL/min) to give 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethyl carbamate as its TFA salt (0.0205 g, 86%). LC-MS (3 min) tR=1.49 min, m/z 511, 509 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.28-7.12 (m, 4H), 4.20 (d, J=13.2 Hz, 1H), 4.11-3.99 (m, 3H), 3.95 (d, J=8.8 Hz, 1H), 3.87 (d, J=13.2 Hz, 1H), 3.40-3.28 (m, 2H), 2.96 (dd, J=12.6, 3.2 Hz, 1H), 2.84 (dd, J=12.6, 10.2 Hz, 1H), 2.73-2.63 (m, 2H), 2.61 (s, 3H), 1.71-0.75 (m, 18H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH:15]3[CH2:17][CH:16]3[C:18](O)=O)[CH:9]=2)[N:3]=1.[CH3:21][NH:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(O)(=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH:15]3[CH2:17][CH:16]3[C:18]3[N:22]([CH3:21])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[N:29]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1nc(C2CC2C(=O)O)cc(-n2nc(C)nc2C)n1
Reactant: CNc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C2CC2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A slurry of 2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylic acid (2-5, 1.50 g, 5.49 mmol, 1.0 eq.), n-methyl-2-phenylenediamine (1.006 g, 8.23 mmol, 1.0 eq.), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.473 g, 7.68 mmol, 1.3 eq.), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (1.046 g, 7.68 mmol) and diisopropylethyl amine (2.88 mL, 16.47 mmol) in tetrahydrofuran (20 mL) was allowed to stir for 16 hours. The solvent was removed by roto-evaporation to afford a dark brown oil. The oil was dissolved in acetic acid (3 mL) and heated at 90° C. for 30 minutes. The solvent was removed by roto-evaporation and the resulting yellow oil was purified by reverse phase liquid chromatography (H2OCH3CN gradient w/ 0.1% NR4OH present) to afford 2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (2-6) as a white powder. 1H NMR (500 MHz, CDCl3) δ 7.69 (m, 2H), 7.28 (m, 3H), 3.82 (s, 3H), 2.90 (s, 3H), 2.83 (m, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 2.19 (m, 2H). HRMS m/z (M+H) 360.1937 found, 360.1931 required.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][S:11][C:12]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][S:11][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Temperature: 100 °C

Procedure:
Starting material 9 (1.12 g) is dissolved in DME (12 ml) and to this are added 439 mg of 10, water (5 ml) and 954 mg of Na2CO3. The mixture is degassed with argon for 5 min. Pd(dppf)Cl2 (121 mg) is added, the tube is sealed and the reaction mixture is heated at 100° C. in the microwave for 15 min. TLC (Hep/EtOAc, 80/20) shows a good conversion into a slower moving spot. The reaction mixture is diluted with EtOAc and washed with water and brine. The organic layer is dried and concentrated. The residue is purified by flash column chromatography using 5% diisopropyl ether in heptane as eluent. Isothiazole 11 is obtained in good yield as a white crystalline solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][S-:14].[K+]>>[CH3:13][S:14][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: C[S-]
Agent: [K+]
Product: CSc1cccc(CC(=O)O)c1
Yield: 17.2 %

Procedure:
Prepared in an essentially similar fashion from methyl 3-aminophenylacetate (111 g, 0.67 mole) and potassium methanethiolate (2.68 mole) to give 3-methylthiophenylacetic acid (21.0 g). Mp=76°-77° C., 1H NMR (DMSO-d6, 200 MHz) δ: 2.44 (s, 3H, SCH3), 3.53 (s, 2H, ArCH2), 7.02-7.28 (m, 4H, Ar), 12.30 (br s, 1H, CO2H). Mass spectrum (CI-CH4): 183 (M+1, 100%). (Lit. ref.: Plant Physiol 42(11) 2596-1600 (1967).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)=[O:6])=[CH:26][CH:25]=1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide (45 mg, 0.13 mmol), 4-methoxy benzaldehyde (16 uL, 0.13 mmol), and glacial acetic acid (8 uL, 0.13 mmol) in methanol (1 mL) was added sodium triacetoxy borohydride (84 mg, 0.4 mmol) portionwise. The solution was stirred at 50° C. for 18 h. The solution was absorbed onto Celite and purified by ISCO Companion (silica 0-10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide (56 mg, 75%) LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (1H, br. s.) 7.98-8.07 (2H, m) 7.77 (1H, d, J=5.47 Hz) 7.46 (1H, d, J=5.47 Hz) 7.30 (1H, d, J=3.32 Hz) 7.19 (2H, d, J=8.59 Hz) 6.76-6.84 (2H, m) 6.43 (1H, d, J=3.51 Hz) 3.69 (3H, s) 3.60 (2H, s) 3.33 (2H, q, J=6.25 Hz) 2.61 (2H, t, J=6.64 Hz)
Reaction SMILES: C([O:4][C:5]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[C:11]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[S:8])(=O)C.C1COCC1.CO.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:11]2[C:10]([NH:9][C:7](=[S:8])[C:6]3[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:5]=3[OH:4])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:17])=[N:20][CH:21]=1
Reactant: CC(=O)Oc1cc(C)ccc1C(=S)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a mixture of 3-[2-acetoxy-4-methylthiobenzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (13 g, 28.4 mmol), THF (100 mL) and MeOH (50 mL) was added Na2CO3 (5.75 g, 54.3 mmol), and the mixture was stirred for 18 h. The resulting yellow suspension was diluted with dichloro-methane (100 mL), and 1 N HCl (about 55 mL) was slowly added. The mixture was partitioned and the white organic suspension was concentrated. The residue was triturated with dichloromethane (200 mL) and filtered to give the title compound as a white solid (9.5 g, 22.9 mmol, 80%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)[CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:10][CH2:11][C:12]2[N:13]=[CH:14][N:15]([C:17]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cn(-c2ccc(I)cc2)cn1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-chlorothiophene-2-carboxylic acid 1-5 (0.346 g, 2.13 mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole I-2 prepared above (0.578 g, 1.93 mmol) and TEA (0.670 mL, 4.82 mmol) in DMF (10 mL), BOP (1.03 g, 2.33 mmol) was added. The mixture was then stirred at room temperature overnight. Water and EtOAc were added. The organic layer was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 as a solid (0.832 g), which was found to be pure enough for next reaction. MS 443.9 and 445.9 (M+H, Cl pattern).