Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:22])[C:14]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:15].[N+:23]([O-])([OH:25])=[O:24]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:23]([O-:25])=[O:24])=[CH:9][C:8]=1[C:13](=[O:22])[C:14]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)C(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
To concentrated sulfuric acid (15.0 ml) at 5° C. is added 2′-chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol) followed by dropwise addition of concentrated nitric acid (90%, 0.740 ml, 0.0204 mol). After stirring 5 minutes, the mixture is poured onto ice and extracted with ethyl acetate. The organic layers are washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%) which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][C:22]=2[O:28][CH2:29][C@@H:30]1[CH2:32][O:31]1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:32][C@H:30]([OH:31])[CH2:29][O:28][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:21]=4[NH:20][C:19]([CH3:18])=[CH:27]5)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Reactant: Cc1cc2cccc(OC[C@@H]3CO3)c2[nH]1
Solvent: CCO
Product: Cc1cc2cccc(OC[C@@H](O)CN3CCC(n4c(=O)[nH]c5cc(F)ccc54)CC3)c2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
A mixture of 5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (13.7 mg, 0.058 mmol), 2-methyl-7-[(2S)-oxiranylmethoxy]-1H-indole (12 mg, 0.058 mmol) in ethanol (2 mL) was kept on stirring at 80° C. for 5 h. The volatiles were removed in vacuo and residue purified by silica gel flash chromatography to give titled compound (18 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[N:6][CH:7]=1.C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]([OH:10])[C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=1
Reactant: CC(C)(C=O)c1ccc(Br)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cn1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(5-bromopyridin-2-yl)-2-methylpropanal (1.0 g, 4.4 mmol) and trimethyl(trifluoromethyl)silane (1.1 g, 7.5 mmol) in tetrahydrofuran (10 mL) under nitrogen was added the solution of TBAF (230 mg, 0.88 mmol) in tetrahydrofuran (5 mL) dropwise at −30° C. The resulting solution was stirred at −30° C. for 1 hour and at ambient temperature for an additional 1 hour before the addition of a second batch of TBAF (1.1 g, 4.4 mmol) at ambient temperature. After stirred at ambient temperature for 20 minutes, the reaction solution was diluted with water (10 mL), and then extracted with ethyl acetate (3×15 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 2-5% ethyl acetate in hexane to afford the title compound as a yellow oil. MS ESI: [M+H]+ m/z 298, 300; 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 4.01 (q, J=7.8 Hz, 1H), 1.51 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:15])=[C:4]([Cl:11])[N:3]=1
Reactant: CI
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2c(Cl)nc(N)nc21
Reaction time: 0.75 h
Yield: 77 %

Procedure:
The 2-amino-6-chloropurine (1.08 g, 6.4 mmol) was suspended in dry DMF (75 ml) and treated with sodium hydride, 60% dispersion (0.28 g, 7 mmol). The suspension was stirred for 15 min before iodomethane (0.44 ml, 7.06 mmol) was added and the resulting yellow solution stirred for 1 hr 45 min. The solid was filtered and the filtrate evaporated before addition of water for 10 min. The resulting solid was filtered and dried overnight to give the product as a mixture of N-7 and N-9 alkylation products. The residual liquor was left overnight and more crystals were collected the next day and dried. Yield=77%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@@H:5]([CH3:34])[CH2:6][CH:7]([NH:22][C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH3:34])[CH2:6][C@H:7]([NH:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)O

Procedure:
Next, a solution of (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester (261 mg, 59.1 mmol) in 8 mL of methylene chloride/TFA (1:1) is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) and the product is further purified by chiral HPLC on a Chirapak OD-H column using heptane/ethanol (90:10) (0.1% TFA) to elute the title compound; HPLC Retention time 1.48 minutes (condition C): MS 447.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 1.03-1.05 (d, J=7.07 Hz, 3H), 1.08-1.12 (t, J=7.33 Hz, 3H), 1.27-1.34 (m, 1H), 1.70-1.76 (m, 1H), 2.62-2.67 (m, 1H), 2.71-2.76 (m, 2H), 3.66-3.68 (d, J=5.81 Hz, 2H), 3.71-3.78 (m, 1H), 3.95-4.00 (q, J=7.07 Hz, 14.40 Hz, 2H), 5.94-5.97 (t, J=5.56 Hz, 1H), 6.07-6.09 (d, J=8.34 Hz, 1H), 7.25-7.28 (m, 2H), 7.38-7.41 (m, 1H), 7.45-7.49 (t, J=7.83 Hz, 1H), 7.60-7.63 (m, 3H), 7.69-7.70 (t, J=1.77 Hz, 1H), 12.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccco1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mNol) 2-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 413(M+1)
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH3:24])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH3:24])[C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1c(F)cccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(F)cccc1F)C2
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A stirred solution, cooled in ice, of 0.7 ml (1.3 mmol) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution of 210 mg (0.71 mmol) of 5-(2,6-difluorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 1 hour. To the mixture were added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 200 mg (87%) of 3-(2,6-difluorophenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =323].
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C1COCC1.CO>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=1)[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27]
Reactant: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3c(C)cccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc12
Temperature: 50 °C
Yield: 79.6 %

Procedure:
A mixture of 4-[3-Methyl-1-(8-methyl-quinoline-3-ylamino)-butyl]-benzoic acid ethyl ester (62 mg, 0.16 mM) and 1N aqueous NaOH solution (0.413 mL, 0.413 mM) in THF-MeOH (1:1, 3.3 mL) was heated to 50° C. for 4 h. The reaction was cooled, concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (5×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (45.7 mg, 79%). 1H NMR (400 MHz, CD3OD) δ ppm 0.98 (d, J=6.44 Hz, 3 H) 1.03 (d, J=6.25 Hz, 3 H) 1.56-1.68 (m, 1 H) 1.73-1.93 (m, 2 H) 2.68 (d, 3 H) 4.60-4.68 (m, 1 H) 7.23-7.35 (m, 2 H) 7.38 (d, 1 H) 7.44 (d, 1 H) 7.48-7.61 (m, 2 H) 7.96 (d, 2 H) 8.53 (dd, 1 H), two protons (COOH and NH) were exchanged. This material will be used for the next step reaction without further work-up.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[O:4][N:3]=1.[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(Br)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)no1
Yield: 80.7 %

Procedure:
A solution of 442 mg (2.0 mmol) of ethyl 3-bromoisoxazole-5-carboxylate (Intermediate 119) and 5.0 ml of 1 N sodium hydroxide in 10 ml of MeOH was stirred at ambient temperature for 5 h, then acidified with 6.0 ml of 1 N hydrochloric acid, diluted with 25 ml of water and extracted with EtOAc (3×25 ml). The combined organic extract was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (310 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].N1C=CC=CC=1>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C1CCCN1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
p-Toluenesulfonylchloride (1 g) is added portionwise to a solution of 1-(2-hydroxyethyl)pyrrolidin-2-one (500 μL) and pyridine (1.5 mL) in dichloromethane (8 mL) chilled in an ice bath. The mixture is stirred at room temperature for 12 hours and partitioned between 1 M hydrochloric acid and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (ethyl acetate) to give the title compound. Yield: 390 mg; Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:19]=2>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:19]=3)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1cnc2cc(CCN3CCCC3)cnc2c1
Product: COc1ncc(-c2cnc3cc(CCN4CCCC4)cnc3c2)c(OC)n1

Procedure:
The title compound was prepared by the method described in Example 156, using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product from Example 153E in place of 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and the product from Example 154. 1H NMR (CDCl3, 300 MHz) δ 1.55 (m, 2H), 1.65 (m, 2H), 2.50 (m, 4H), 2.60-2.65 (m, 4H), 3.80 (s, 3H), 3.85 (s, 3H), 8.35 (m, 1H), 8.70 (m, 1H), 8.85 (s, 1H), 8.90 (m, 1H), 9.20 (m, 1H). MS (ESI) [M+H]+ at 366.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1)[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(O)ccc1-c1nc2ncncc2[nH]1
Product: CCc1cc(OS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 1 from 8-(2'-ethyl-4'-hydroxyphenyl)-purine and methanesulfonic acid chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]([CH:21]1[CH2:23][CH2:22]1)[C:32]1[C:31]2[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=2)[NH:34][CH:33]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(C(F)(F)F)cc1Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3Cl)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.6 ml (33.8 mmol) of trifluoroacetic acid were added to 7.07 g (28.2 mmol) of the compound from Example 150A and 5.00 g (28.2 mmol) of the compound from Example 8A in 620 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 960 mg (7% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:5]2[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:4]2[NH:3]1.[ClH:26]>O1CCOCC1>[ClH:26].[F:15][C:12]([F:13])([F:14])[C:10]1[C:11]2[C:2](=[O:1])[NH:3][C@H:4]3[CH2:18][NH:17][CH2:16][C@@H:5]3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N[C@H]2CNC[C@@H]2c2cccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the first eluting peak, (3aR,9bS)-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (50 mg, 0.14 mmol) in 4 mL of dioxane was added 1 mL of 12 N HCl. The resulting solution was stirred at ambient temperature for 1 h and then was concentrated. The residue was azeotroped with toluene and dried in vacuo to afford a foam. This foam was triturated 3× with ether and dried in vacuo to afford 25 mg (61%) of the title compound of Example 13 as an off-white powder. 1H NMR (DMSO-D6): δ 9.8 (broad s, 1H), 9.6 (broad s, 1H), 9.00 (s, 1H), 7.83 (d, 1H, J=8.2 Hz), 7.73 (t, 1H, J=7.7 Hz), 7.58 (d, 1H, J=7.7 Hz), 3.94-3.90 (m, 1H), 3.67-3.60 (m, 1H), 3.55-3.50 (m, 1H), 3.37-3.32 (m, 1H), 3.20-3.10 (m, 2H). LRMS (ESI): 257.16 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:5]
Reactant: COC(=O)C(OC)OC
Reactant: Cc1ccc(CN)cc1
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1ccc(C)cc1
Temperature: 140 °C

Procedure:
A mixture of methyl dimethoxyacetate (1.35 g, 9.96 mmol) and 4-methylbenzylamine (1.21 g, 9.98 mmol) in a sealable tube was heated in a microwave reactor to 140° C. for 50 min. The reaction mixture was diluted with EtOAc (≈60 mL), washed with diluted aq. HCl, water, sat. NaHCO3 solution, and brine, and dried over MgSO4. The EtOAc extract was filtered, concentrated, and dried in vacuo overnight to give the title compound as pale yellow oil. It was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=7.20-7.13 (AA′BB′, 4H), 6.82 (brs, 1H), 4.75 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.40 (s, 6H), 2.34 (s, 3H). MS(ES+): m/z=246.10 (43) [MNa+], 224.11 (91) [MH+], 192.14 (8) [MH+-MeOH], 160.06 (80) [MH+-2 MeOH]. HPLC: tR=2.84 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][CH:34]([F:37])[CH2:35]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:35][CH:34]([F:37])[F:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCC(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC(F)F)C1
Yield: 57 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2,2-difluoroethylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as a glass (100 mg, 57%). LCMS (method B): RT=3.81 min, M+H+=510.
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[C:16]3[CH3:21])=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[C:16]3[CH:21]=[O:2])=[CH:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: Cc1ccnc2c(OCc3ccc(Cl)cc3)cccc12
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2c(OCc3ccc(Cl)cc3)cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Selenium dioxide (620 mg, 5.6 mmol) was suspended in dioxane (5 mL); a few drops of water was added until a clear solution was obtained. The mixture was heated to 100° C. and 8-(4-chlorobenzyloxy)-4-methyl quinoline (1.6 g, 5.6 mmol) in dioxane (20 mL) was added dropwise during a period of 2 hours. The mixture kept at 100° C. for 4 hours, filtered hot and concentrated. The residue was treated with 1N HCl (200 ml), and filtered. The filtrate was neutralized with 3N NaOH, and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), and concentrated. Recrystallization from toluene provided 1.02 g (62%) yellow needles.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:1][C:28]3[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1ccccc1-c1cccn2nc(N)nc12)S(C)(=O)=O
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5ccccc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a white solid (1.01 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9 Hz, 1H), 7.35-7.30 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H). MS=334 (M+Na)+. 130b) N-[2-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (625.0 mg, 2.934 mmol) and N-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1000.0 mg, 3.2133 mmol) in a manner analogous to Example 2c. Product was isolated as white solid (0.479 g, 51%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.52 (d, J=6.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.35 (d, J=7.2 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 5.94 (s, 2H), 3.10 (s, 3H), 2.85 (s, 3H). MP=209-211° C. MS=318 (MH)+. 130c) N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[C:18](O)=[CH:17][C:16](=[O:20])[N:15]([CH3:21])[CH:14]=1)=[O:12])[CH3:9].O=P(Cl)(Cl)[Cl:24]>>[CH2:8]([O:10][C:11]([C:13]1[C:18]([Cl:24])=[CH:17][C:16](=[O:20])[N:15]([CH3:21])[CH:14]=1)=[O:12])[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn(C)c(=O)cc1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C)c(=O)cc1Cl
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Triethyl amine (7.07 mL, 50.7 mmol) was added to a suspension of 4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (10.0 g, 50.7 mmol) and POCl3 (27.85 mL, 304.3 mmol). After stirring 16 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was poured onto ice, carefully neutralized with saturated K2CO3 solution, and diluted with EtOAc. The layers were separated and the aqueous phase further extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield 7.3 g (67%) clean desired product.