Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:24]3[CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])[CH:21]=[CH:20][CH:25]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1cnn2c(I)cnc2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of 7-chloro-3-iodoimidazo[1,2-b]pyridazine (1.40 g, 5.01 mmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (1.76 g, 5.11 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (DCM) (1:1) (164 mg, 0.200 mmol), and potassium carbonate (2.08 g, 15.0 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was degassed and recharged with nitrogen three times. The mixture was then heated and stirred at 60° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (3 mL) and acetonitrile (3 mL). The precipitate was collected by filtration and washed with acetonitrile, dried under vacuum to afford the desired product (0.988 g). The filtrate (mother liquid) was concentrated. The residue was purified by flash chromatography on a silica gel column with methanol in DCM (0-10%) to afford the additional product 0.17 g. The total product is 1.158 g (62.5%). LCMS (M+H)+: m/z=370.0/372.0.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH:14]=2)[C:9](=[NH:13])OCC)[CH2:3][CH2:2]1.C(O)(=O)C.C(N(CC)CC)C.Cl.Cl.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:36]2[CH2:41][CH2:40][CH2:39][C@@H:38]([C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH2:37]2)=[N:33][C:34]=1N>C(O)C>[CH:1]1([C:4]2[CH:14]=[C:8]([C:9]3[NH:13][C:34]4=[N:33][C:32]([N:36]5[CH2:41][CH2:40][CH2:39][C@@H:38]([C:42]([N:44]6[CH2:48][CH2:47][CH2:46][CH2:45]6)=[O:43])[CH2:37]5)=[CH:31][CH:30]=[C:29]4[N:28]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=N)c1cncc(C2CC2)c1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cncc(C5CC5)c4)[nH]c3n2)C1)N1CCCC1
Yield: 5.8 %

Procedure:
To a solution of ethyl 5-cyclopropylnicotinimidate (0.2 g, 1.04 mmol) in ethanol was added acetic acid (0.1 mL), triethylamine (0.1 mL) and a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride salt (0.4 g, 1.1 mmol) in ethanol. The reaction mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure and to the resulting residue was added a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (0.025 g). 1H NMR (400 MHz, DMSO-d6) δ 0.85 (br s, 2H), 1.07 (d, 2H), 1.47-1.74 (m, 4H), 1.74-1.96 (m, 5H), 1.98-2.10 (m, 1H), 2.61 (br s, 2H), 2.92 (d, 2H), 3.41-3.59 (m, 2H), 4.33 (d, 1H), 4.39 (d, 1H), 6.86 (d, 1H), 7.81 (d, 1H), 8.00 (br s, 1H), 8.47 (br s, 1H), 9.05 (br s, 1H), 13.07 (br s, 1H). MS (ES+) (M+H) 417.36; LCMS retention time 3.03 min (Method S).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[N:10]=[CH:11][S:12][CH:13]=1>Cl>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[N:10]=[CH:11][S:12][CH:13]=2)[CH2:7]1
Reactant: Brc1cscn1
Reactant: C[C@@H]1CNCCN1
Agent: Cl
Product: C[C@@H]1CN(c2cscn2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
10.0 g (100 mmol) (R)-2-methylpiperazine were fused at 100° C. 2.7 g (16.8 mmol) 4-bromothiazol was added in portions to this fusion over a period of 2 h. Stirring was subsequently performed for 18 h at 100° C. After cooling to RT, the residue was received in 10% aq. hydrochloric acid and washed with AE. Alkalic adjustment was subsequently performed with a 10% aq. NaOH sol. (pH>12) and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in a vacuum. CC (SiO2, DCM/MeOH 9:1) was performed with the residue, whereby 277 mg (1.5 mmol, 9%) (R)-4-(3-methylpiperazine-1-yl)thiazol was obtained.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:18]([OH:21])[C:19]#[CH:20].[H-].[Na+].O>CN(C)C=O>[CH2:18]([O:21][C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2)[S:7][N:6]=1)[C:19]#[CH:20]
Reactant: CC1CC(C)CN(c2nc(S(C)(=O)=O)ns2)C1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1nsc(N2CC(C)CC(C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
In 3 ml of N,N-dimethylformamide were dissolved 373 mg of 3-methylsulfonyl-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole and 84 mg of 2-propyn-1-ol, and 71 mg of sodium hydride (oil suspension; content: 60 weight %) was added under ice-cooling. The mixture was stirred for 15 minutes and at room temperature for 1.5 hour. The reaction mixture was poured to water, and extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 326 mg of 3-(2-propynyloxy)-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole (hereinafter, referred to as the present compound (20)).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=CC([O:30][C:31]([F:34])([F:33])[F:32])=CC=1C=O>>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:7][C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1ccc(OC(F)(F)F)cc1C(O)C#Cc1ccccc1
Yield: 99 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-5-trifluoromethoxy-benzaldehyde was reacted to give the title compound as a pale yellow oil (642 mg, 99%). LCMS (Method B): RT=4.55 min, [M−H2O+H]+=305.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[S:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][S:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncsc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[Cl:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[C:13]([F:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>CO.O>[CH3:3][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([F:20])[C:14]([CH3:19])=[C:15]([N+:16]([O-:18])=[O:17])[C:7]=1[Cl:6]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1c(F)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(F)c(C)c([N+](=O)[O-])c1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of chlorotrimethylsilane (200 mL) in methanol (300 mL) was treated with 2-chloro-5-fluoro-4-methyl-3-nitrobenzoic acid (Example 252c, 65.5 g) portionwise under nitrogen. The resulting solution was stirred at 20° C. for 16 h. Further chlorotrimethylsilane (100 mL) was added and the reaction heated at 50° C. for 6 h. The reaction mixture was evaporated to afford crude product which was diluted with water and extracted with ethyl acetate (300 mL). The organic extract was dried (MgSO4), filtered and evaporated to afford the subtitle compound (53.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4](I)[C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24]>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([Cl:17])[CH:19]=2)[C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Cc1ccc(B(O)O)cc1Cl
Reactant: OCc1cc(I)c(OCC(F)(F)F)c(Cl)n1
Product: Cc1ccc(-c2cc(CO)nc(Cl)c2OCC(F)(F)F)cc1Cl

Procedure:
The title compound was synthesized in analogy to Example B using [4-iodo-6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol (example A) and B-(3-chloro-4-methylphenyl)-boronic acid, (CAN 175883-63-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 366.0269 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][CH2:8][N:9]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([C:26](=[O:39])[NH:27][C:28]2[S:29][C:30]3[C:35]([N:36]=2)=[CH:34][CH:33]=[C:32]([O:37][CH3:38])[N:31]=3)[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.[OH-].[Na+]>CO.O>[CH2:40]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([C@H:19]([C:26](=[O:39])[NH:27][C:28]2[S:29][C:30]3[C:35]([N:36]=2)=[CH:34][CH:33]=[C:32]([O:37][CH3:38])[N:31]=3)[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH2:8][CH2:7][C:6]([OH:47])=[O:5])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)OC(C)(C)C)Cc4ccccc4)cc3)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)O)Cc4ccccc4)cc3)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title I compound, 3-(benzyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid tert-butyl ester (0.064 g, 0.0942 mmol) is dissolved in methanol (5 mL), to which a solution of sodium hydroxide (0.004 g, 0.0942 mmol) in water (2 mL) is added. The reaction mixture is stirred at RT overnight. The reaction mixture is then concentrated and the residue is partitioned between 1 M HCl/ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated to afford 3-(benzyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid as a white foam: 1H NMR (400 MHz-CDCl3) δ 1.17 (m, 2H) 1.50 (m, 2H) 1.66 (m, 4H) 1.78 (m, 1H) 2.28 (m, 1H) 2.43 (m, 2H) 3.23 (m, 1H) 3.50 (m, 1H) 3.85 (m, 2H) 4.00 (s, 3H) 4.37 (m, 1H) 4.77 (m, 1H) 6.79 (m, 1H) 7.36 (m, 5H) 7.52 (m, 2H) 7.67 (m, 1H) 7.95 (m, 2H); LC/MS 623.3 (M+1), 621.4 (M−1). EC50 in primary enzyme assay 0.27 μM
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34]([NH:37][CH2:38][CH2:39][NH2:40])(=[O:36])[CH3:35]>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:15][CH:16]=2)[C:12](=[O:14])[N:40]([CH2:39][CH2:38][NH:37][C:34](=[O:36])[CH3:35])[C:17]3=[O:19])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Reactant: CC(=O)NCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: CC(=O)NCCN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid (185 mg, 0.64 mmol) and carbonyldiimidazole (109 mg, 0.67 mmol) in N,N-dimethylacetamide (3 mL) was stirred at room temperature for 10 min and then heated at 50° C. for 15 min. To this mixture was added N-acetylethylenediamine (78 mg, 0.76 mmol) and the resulting mixture heated under reflux for 20 min. After cooling to room temperature, the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3/MeOH 98:2 to 9:1) to afford the title compound (139 mg, 62%) as an off-white solid. MS: m/e=357.3. (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)[nH]c2cc(N)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(C)c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 7-amino-4-methyl-1H-quinolin-2-one (87 mg, 0.5 mmol) in dry DMF (2 ml) was added sodium hydride (24 mg, 60% disp. in oil, 0.6 mmol) followed by methyl iodide (38 μl, 0.6 mmol) and the reaction stirred at room temperature for 1.5 h. After quenching with water the mixture was extracted with EtOAc and the combined extracts were dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by SPE column chromatography, eluting with 0-10% MeOH/EtOAc gradient gave title compound (64 mg) which was used in the next step without further purification. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.47 (d, 1H), 6.59 (m, 2H), 6.55 (d, 1H), 4.45 (br, 2H), 3.61 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.C(N(CC)CC)C.CN(C=O)C.[C:51]([O:55][CH3:56])(=[O:54])[CH:52]=[CH2:53]>CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:56][O:55][C:51](=[O:54])/[CH:52]=[CH:53]/[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1nn(Cc2ccc(OC)cc2)c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A 50 mL round bottom flask charged with tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (500 mg, 0.8 mmol), tri(o-tolyl)phosphine (18.25 mg, 0.06 mmol), Pd2dba3 (18.3 mg, 0.02 mmol), triethylamine (334 μL, 2.4 mmol), and DMF (7 mL) was purged under N2 (3 cycles). Next, methyl acrylate (216 μL, 2.4 mmol) was added, and the mixture was stirred at 100° C. under N2 atmosphere for 18 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and water (100 mL) was added. The phases were separated, and the organic layer was washed with water (3×30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was crystallized from CH3CN to provide (E)-tert-butyl 4-(3-(3-methoxy-3-oxoprop-1-enyl)-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (390 mg, 84% yield) as a solid. LCMS (APCI+) m/z 584.2 (M+H)+, Retention time=4.96 minutes.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16]>CCOCC.CCCCCC.CO>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
5 mg (0.125 mmol) of sodium hydride, at 60% in mineral oil, in suspension in 2.5 cm3 of anhydrous ether are placed, under an argon atmosphere, in a 10 cm3 round-bottomed flask equipped with a magnetic stirrer system. 156 μl (172.8 mg, 1.251 mmol) of pure 4-methoxybenzyl alcohol are then added. The resulting homogeneous solution is stirred (evolution of gas) for 30 minutes at a temperature in the region of 20° C. and it is then cooled to 0° C. 125 μl (180 mg, 1.20 mmol) of trichloroacetonitrile are then added. The reaction mixture is allowed to react for 4 hours while allowing the temperature to slowly rise to the region of 20° C. The reaction mixture is concentrated under reduced pressure until an orange-yellow oil is obtained which is redissolved in 1.7 cm3 of hexane containing 5.5 μl of dry methanol. The suspension is filtered through Celite under reduced pressure. The solids obtained are washed once with 5 cm3 of hexane and the solvents are then removed under reduced pressure. The yellow oil obtained (4-methoxybenzyl trichloroacetimidate) is dissolved in 2 cm3 of cyclohexane. 240 mg (0.81 mmol) of methyl (2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxy-propionate, 1.0 cm3 of dry dichloromethane and 4 μl of boron trifluoride etherate are then added. The reaction mixture is allowed to react at a temperature in the region of 20° C. for 13 hours. The reaction mixture is filtered through Celite and the solids are washed 3 times with 10 cm3 of a dichloromethane/cyclohexane (1/2 by volume) mixture. The resulting organic phase is washed twice with 5 cm3 of a saturated aqueous sodium hydrogencarbonate solution, 3 times with 5 cm3 of water and once with 5 cm3 of a saturated aqueous sodium chloride solution. It is dried over anhydrous magnesium sulphate. After filtration and evaporation of the solvents under reduced pressure, the residue obtained (547 mg) is purified by chromatography on a column of silica gel, the eluent being a hexane/ethyl acetate (70/30 by volume) mixture. There are obtained 282 mg of a solid which is recrystallized from the dichloromethane/hexane mixture at 0° C. After separation of the crystals obtained (impurities), the liquid phase ("mother liquors") is evaporated under reduced pressure. There are obtained, with a yield of 68%, 228 mg (0.55 mmol) of methyl (2R,3S)-3-t-butoxy-carbonylamino-3-phenyl-2-[(4-methoxybenzyl)oxy]-propionate, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2SC=C(C(OC)=O)N=2)[CH2:18][CH2:17]1)=[O:13].ClCC1[O:38][C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]2[O:38][C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:35]=2)[CH2:20][CH2:21]1)=[O:13]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)o1

Procedure:
Ethyl 5-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl) piperidin-1-yl]methyl}furan-2-carboxylate 23 was prepared, according to the procedure described for compound 7, starting from ethyl 5-(chloromethyl)furan-2-carboxylate. Yield: 290 mg, 71%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH2:27]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 85.4 %

Procedure:
4-Hydroxybenzaldehyde (5.0 g, 41 mmol, 1.0 equiv.), potassium carbonate (8.5 g, 61 mmol, 1.5 equiv.), dodecyl bromide (12.3 g, 49.2 mmol, 1.20 equiv.), and 18-crown-6 (1.0 g, 4.1 mmol, 0.10 equiv.) were placed in a flask with a magnetic stirring bar and a cooling column, and dissolved in 50 ml of acetone. The mixture was refluxed for 24 h. After cooling down, the mixture was filtered and concentrated in vacuo. The crude product was subjected to a column chromatography using CH2Cl2 to afford the product as pale yellow solid (10.3 g, 35.0 mmol, 87% yield). 1H NMR (400 MHz, CDCl3) δ: 9.85 (s, 1H), 7.83 (d, 2H, J=8.6 Hz), 7.00 (d, 2H, J=8.6 Hz), 4.05 (t, 2H, J=6.4 Hz), 1.80 (m, 2H), 1.27 (m, 18H), 0.89 (t, 3H, J=6.7 Hz); 13C NMR (500 MHz, CDCl3) δ: 191.0, 164.5, 132.2, 130.0, 115.0, 68.7, 32.2, 29.9, 29.8, 29.6, 29.3, 26.2, 22.9, 14.4; APCI-MS m/z 291.3 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([I:11])[C:3]=12.C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:9]=[C:10]([I:11])[C:3]=12
Reactant: Clc1ccnc2[nH]nc(I)c12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (1.31 g, 4.688 mmol) in DMF (40 mL) was added K2CO3 (1.30 g, 9.38 mmol) and 1-(chloromethyl)-4-methoxybenzene (0.766 ml, 5.63 mmol). The reaction mixture was stirred at room temperature overnight to yield two regioisomeric products is a 5.5:1 ratio by LC-MS. The mixture was partitioned between EtOAc and H2O. The phases were separated and the organic layer washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark yellow solid. The crude product was purified by flash column chromatography, eluting with 3:1 hexanes/EtOAc and loaded with 10:1:1 CH2Cl2/MeOH/THF due to poor solubility. The desired N1-regioisomeric product (1.256 g, 67%) was obtained as a white crystalline solid. LRMS (APCI pos) m/e 400, 402 (M+, Cl pattern). The undesired N2-regioisomer, 4-chloro-3-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine, was not isolated.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:35][C:33]([F:34])([F:36])[CH2:32][N:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:37])=[O:3])=[CH:10][CH:11]=2)=[CH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3CC(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 1 f], {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as off-white crystals.