Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1[C:9]2C(=C[C:6]([N:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=5)[CH:17]=4)[NH:12][C:11]3=[O:31])=[CH:7][CH:8]=2)C=C1.BrCC1CC1.C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O.C(Cl)Cl.BrC1C=C2N(CC3CC3)C(=O)NC2=NC=1.COC1C=C(B(O)O)C=C(OC)C=1OC.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:7]1([CH2:6][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[CH:17]=3)[NH:12][C:11]2=[O:31])[CH2:9][CH2:8]1
Reactant: COc1cc(-c2cnc3[nH]c(=O)n(-c4ccc5[nH]ccc5c4)c3c2)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: BrCC1CC1
Agent: COc1cc(B(O)O)cc(OC)c1OC
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc(-c2cnc3[nH]c(=O)n(CC4CC4)c3c2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
Intermediate 5 from Example 124 was alkylated with (bromomethyl)cyclopropane using K2CO3 in acetone, after which it was deprotected using TFA/CH2Cl2. To the resulting 6-bromo-1-(cyclopropylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II)dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 3.7 mg of the title compound. HPLC retention time: 1.90 minutes; MS ESI (m/z): 356.2 (M+1)+, calc. 355.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6]CCC.OOS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CC[O:24][C:25]([CH3:27])=[O:26]>CN(C=O)C.O=[Os](=O)(=O)=O>[C:25]([OH:24])(=[O:26])[CH2:27][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCCCCC
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)O
Reaction time: 0.08 h
Yield: 90 %

Procedure:
1-Nonene (100 mg) was dissolved in DMF (5 mL), and OsO4 (0.1 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (1.94 g) was added in one portion and the reaction had a final volume (7 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (600 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (50 mL×3) and brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Octanoic acid was obtained in 90% yield without the need for further purification.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:17][CH3:18])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].I([O-])(=O)(=O)=[O:20].[Na+].I([O-])(=O)=O.[Na+]>CO.O>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH2:14][S:15]([CH2:16][CH2:17][CH3:18])=[O:20])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCCSCc1cc2oc(S(N)(=O)=O)cc2cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: CO
Solvent: O
Product: CCCS(=O)Cc1cc2oc(S(N)(=O)=O)cc2cn1
Yield: 85 %

Procedure:
To a solution of 2-sulfamoyl-6-(propylthiomethyl)furo[3,2-c]pyridine (913 mg, 3.19 mmol) in methanol (23 mL) and water (8 mL) was added sodium metaperiodate (906 mg, 4.24 mmol). This mixture was stirred for 4 hours as sodium iodate precipitated from the solution. This precipitate was filtered off and the methanol was evaporated. Sodium chloride was added to the residual aqueous solution and this was exhaustively extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was triturated with diethyl ether/methylene chloride to give 820 mg of product. This material was crystallized from a large volume of ethyl acetate to give pure product (470 mg, 49% yield), mp: 179°-180.5° C. (dec).
Reaction SMILES: [NH2:1][CH2:2][S:3]([OH:6])(=[O:5])=[O:4].C([O-])(=O)C.[K+:11].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(O)(=O)C>[K+:11].[C:12]1(=[O:17])[N:1]([CH2:2][S:3]([O-:6])(=[O:5])=[O:4])[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: NCS(=O)(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)[O-]

Procedure:
A suspension of 15.1 g. (0.136 mol.) of aminomethanesulfonic acid and 14.2 g. (0.145 mol.) of anhydrous potassium acetate in 48 ml. of acetic acid is refluxed for 10 minutes. Phthalic anhydride (21.4 g., 0.145 mol.) is then added and the resulting mixture is refluxed for 2.5 hours. The product is collected by filtration and washed with acetic acid and ethanol to give phthalimidomethanesulfonic acid potassium salt.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([NH:57][CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:17])=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:2][CH2:3]1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1cnc(N2CCN(CC3CC3)C2=O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid (0.10 g, 0.37 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.17 mL, 1.34 mmol), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.59 mmol). The reaction was stirred at ambient temperature for 0.5 hours, 1-Hydroxybenzotriazole (0.07 g, 0.52 mmol) was added, followed by the addition of pyridin-3-ylmethanamine (0.06 g, 0.56 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was concentrated in vacuo. The residue was diluted with dichloromethane (150 mL), washed with water (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in dichloromethane and hexane to yield the title compound as a colorless solid in 40% yield (0.065 g): mp 190-192° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.98 (t, J=5.8 Hz 1H), 8.49 (m, 1H), 8.43-8.39 (m, 1H), 7.98 (s, 1H), 7.68-7.65 (m, 1H), 7.34-7.30 (m, 1H), 4.40 (d, J=5.8 Hz, 2H), 4.01-3.95 (m, 2H), 3.65-3.59 (m, 2H), 3.07 (d, J=7.1 Hz, 2H), 1.01-0.85 (m, 1H), 0.53-0.39 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.5, 161.3, 155.1, 149.3, 148.6, 140.1, 135.7, 135.3, 127.1, 123.9, 48.2, 42.5, 42.3, 9.31, 3.63; MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][CH:8]2[CH2:11][N:10]([C:12]([CH3:32])([CH3:31])[CH2:13][CH2:14][C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([NH2:18])=[O:17])[CH2:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:11][N:10]([C:12]([CH3:31])([CH3:32])[CH2:13][CH2:14][C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([NH2:18])=[O:17])[CH2:9]2)=[CH:33][CH:34]=1
Reactant: COc1ccc(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2ccc(O)cc2)C1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 27 %

Procedure:
The product of example 106 (53 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL) and the solution was cooled to 0° C. Boron tribromide (1M in dichloromethane, 0.52 mL, 0.52 mmol) was added and the solution was stirred at 0° C. for 35 minutes. Further boron tribromide (1M in dichloromethane, 0.52 mL, 0.52 mmol) was added and stirring continued at 0° C. for 30 minutes. The reaction was then quenched with saturated sodium hydrogen carbonate solution (20 mL) and stirred at room temperature for 18 hours. The aqueous layer was separated, extracted with ethyl acetate (25 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give a gum. The gum was re-dissolved in dichloromethane (5 mL) and the solution was cooled to −10° C. Boron tribromide (1M in dichloromethane, 0.52 mL, 0.52 mmol) was added and the mixture was stirred at −10° C. for 1 hour. The reaction was then quenched with saturated sodium hydrogen carbonate solution (20 mL) and the organic layer was separated and extracted with ethyl acetate (20 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate/methanol/0.88 ammonia (90/10/1), 75:25 to 50:50, to afford the title compound as a colourless foam in 27% yield (14 mg).
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:3][CH2:4][C@@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: Clc1ccc(Cl)nc1
Reactant: OC[C@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 59.3 %

Procedure:
A mixture of 2.5 g (10.3 mmol) of (7S,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihydrochloride, 7.62 g (51.5 mmol) of 2,5-dichloropyridine, 5.45 g (51.5 mmol) of sodium carbonate and 100 mL of isoamyl alcohol was heated at reflux for 72 h. The mixture was cooled, the mixture filtered to remove solids and the solvent evaporated in vacuo. Purification by flash silica gel chromatography using 95:5 chloroform:methanol gave 1.72 g (59%) of the title compound. mp (base) 61-62° C. 13C NMR (base, CDCl3): δ26.6, 27.2, 34.3, 45.4, 50.9, 54.6, 58.4, 60.5, 68.0, 107.7, 120.1, 137.1, 146.2, 157.5. HRMS calcd for C14H20ClN3O: 281.1295, found: 281.1298.
Reaction SMILES: [Na].CN(C)C([S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1)=O.O.Cl>CO>[SH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=1
Reactant: COC(=O)CCC(=O)c1ccc(SC(=O)N(C)C)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(S)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 280 mg, was dissolved in anhydrous methanol, 50 ml, under an N2 atmosphere. To the resulting solution there was added 5.0 g of the compound from Step D. The mixture was stirred at room temperature overnight, then poured into a mixture containing 30 ml of water and 7 ml of concentrated HCl. The resulting yellow solid was collected by filtration, washed with water and dried in air to give the title compound, mp 83°-84°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:42])[C:6]([NH:29][CH:30]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:31][C:32]([O:34]CC)=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)#[N:2].[Li+].[OH-].O.C(OCC)(=O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([F:42])[C:6]([NH:29][CH:30]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:31][C:32]([OH:34])=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)#[N:2]
Reactant: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)c(C#N)cc1F)C(C)(C)CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(CC(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F
Temperature: 70 °C

Procedure:
Ethyl 3-[[5-cyano-3-fluoro-6-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-pyridyl]amino]-4,4-dimethyl-hexanoate, 159a, (0.27 g, 0.45 mmol) was dissolved in THF (7 mL) and treated with LiOH (4.50 mL of 1 M, 4.50 mmol). The reaction mixture was heated to 70° C. for 10 hours. After cooling to room temperature, water (20 mL) and ethyl acetate (20 mL) were added and the layers were separated. The aqueous layer was brought to a neutral pH by addition of 1N HCl, and the resulting precipitate was collected by filtration, washed with water and concentrated in vacuo to provide 77 mg of the desired product: 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 12.12 (s, 1H), 8.75 (d, J=9.9 Hz, 1H), 8.32 (s, 2H), 7.83 (d, J=11.4 Hz, 1H), 7.48 (d, J=9.5 Hz, 1H), 5.00 (t, J=9.1 Hz, 1H), 2.71-2.54 (m, 2H), 1.30 (d, J=7.4 Hz, 2H), 0.80 (t, J=18.7 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.14 minutes (M+H) 414.31.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C3CCCCO3)[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.Cl.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>CO.O1CCCC1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:13]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(N(Cc2cccc(OC3CCCCO3)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCc1ccc(N(Cc2cccc(O)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-{4-[[3-(tetrahydro-pyran-2-yloxy)-benzyl]-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-propionic acid methyl ester in 0.5 mL methanol and 0.3 mL tetrahydrofuran was added HCl (0.52 mL of a 4.0M solution in 1,4-dioxane, 2.09 mmol) and triethylsilane (0.134 mL, 0.84 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was separated, dried (magnesium sulfate), and concentrated. Preparative thin layer chromatography afforded 0.059 g of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-propionic acid methyl ester. 1H NMR (CDCl3) δ 7.03 (t, 1H, J=8.0 Hz), 6.95–6.80 (m, 6H), 6.68–6.62 (m, 2H), 6.48 (bs, 1H), 4.69 (s, 2H), 3.59 (s, 3H), 2.81 (t, 2H, J=7.6 Hz), 2.51 (t, 2H, J=7.6 Hz), 2.41 (s, 6H), 2.24 (s, 3H).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13](=[O:21])[C:14]([C:16]([O:18]CC)=[O:17])=[CH:15][N:9]3[N:8]([CH3:22])[CH2:7][C:6]2(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:12]=1>C(O)(=O)C>[I:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13](=[O:21])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:9]3[N:8]([CH3:22])[CH2:7][CH2:6]2)[CH:12]=1
Reactant: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)CN2C
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCc2cc(I)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of acetic acid (1 mL), 6N HCl (1 mL), and 3,3-di(tert-butyl) 8-ethyl 5-iodo-1-methyl-7-oxo-1,2-dihydro-3H,7H-pyrido[3,2,1-ij]cinnoline-3,3,8-tricarboxylate (Preparation 38, 0.165 g) is heated in an oil bath at 110° C. for 1.5 h. Additional acetic acid (1 mL) and 6N HCl (1 mL) is added and heating continued for 2 h. The reaction vessel is purged with a strong nitrogen stream while heating in the oil bath at 115° C. until dry solid remains. Dimethylsulfoxide (2 mL) is then added and the temperature raised to 150° C. for 1 h. The mixture is allowed to cool slowly overnight. The mixture is diluted with chloroform, treated with 2 g of silica gel, and concentrated at reduced pressure. The residue is chromatographed using 35 g of silica gel, packed and eluted with acetone/chloroform/methanol/acetic acid (3/6.6/0.4/0.5%), to obtain 53 mg (52%) of the title compound as a tan colored solid. Physical characteristics: 1H NMR (DMSO-d6) δ14.88, 8.80, 8.49, 8.18, 3.50, 3.15, 2.88; MS (ESI+) m/z 371 (M+H)+; TLC (silica gel GF): Rf=0.46 acetone/chloroform/methanol/acetic acid (3/6.5/0.5/0.5%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 455 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (m, 2 H), 1.99 (m, 2 H), 2.79 (t, J=7.64 Hz, 2 H), 2.96 (t, J=7.49 Hz, 2 H), 3.06 (m, 2 H), 3.52 (m, 2 H), 3.71 (q, J=5.61 Hz, 2 H), 4.74 (t, J=6.24 Hz, 2 H), 6.95 (m, 4 H), 7.11 (m, 1 H), 7.30 (m, 2 H), 7.37 (m, 3 H), 7.43 (m, 1 H), 7.68 (m, 1 H), 8.31 (s, 1 H), 9.67 (br s, N H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]1[C:38]2[C:33](=[N:34][C:35]([NH:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[CH:36][CH:37]=2)[N:32]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[N:31]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[N:13]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][C:35]([NH:39][CH2:40][C:41]5[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=5)=[CH:36][CH:37]=4)[N:32]([CH2:49][C:50]4[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=4)[N:31]=3)[CH:14]=[CH:15][C:16]=2[C:17]([F:18])([F:19])[F:20])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(C#N)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.150 g, 0.477 mmol) and potassium carbonate (0.066 g, 0.477 mmol) suspended in dimethylformamide (1 mL) was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (0.202 g, 0.477 mmol) as a solution in dimethyl formamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 7.91 (d, J=7.0 Hz, 1H), 7.76-7.74 (m, 1H), 7.72-7.68 (m, 1H), 7.58-7.56 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49-7.47 (m, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.40 (d, J=8.9 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 4.50-4.46 (m, 2H), 3.71 (s, 3H), 3.69 (s, 3H). LRMS (M+1)=700.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[NH:23]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[N:26][CH:25]=[N:24]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([S:28]([C:27]3[NH:23][N:24]=[CH:25][N:26]=3)(=[O:30])=[O:29])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ncn[nH]1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.27 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] were dissolved in 10 ml of THF, and 143 mg (1.27 mmol) of potassium tert-butoxide were added at −78° C. Over a period of 30 min, the reaction mixture was warmed to RT, and the mixture was stirred at this temperature for a further 20 min. The mixture was then once more cooled to −78° C., and 213 mg (1.27 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolved in 5 ml of THF, were added. Over a period of 30 min, the reaction mixture was warmed to RT, and the mixture was stirred at this temperature for a further 20 h. For work-up, 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 136 mg (29% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>Cl.O1CCOCC1>[NH:19]1[CH2:20][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:18]1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Compound 239a (1.0 g, 2.3 mmol) was suspended in 4M HCl/dioxane (10 mL). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure. The residue was basified with aqueous NaOH and the resulting mixture was extracted with dichloromethane. The combined organic layer was washed with brine and concentrated under reduced pressure to afford 239b as a yellow solid (650 mg, 84%). MS-ESI: [M+H]+ 335.
Reaction SMILES: Cl[C:2]1C=C(C#N)C2C=C[N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])[C:9]=2[CH:10]=1.[NH:26]1C=CC=N1>>[CH2:22]([N:12]1[C:11]([N:8]2[CH:9]=[CH:10][CH:2]=[N:26]2)=[C:16]([CH:17]([CH3:19])[CH3:18])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Reactant: c1cn[nH]c1
Product: CCn1c(-n2cccn2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made using a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that pyrazole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 249.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.36 (br, 1H), 7.81 (m, 1H), 7.58 (m, 1H), 6.54 (m, 1H), 3.38 (m, 2H), 2.04 (m, 1H), 1.17 (m, 9H).