Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH:1][S:35]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:10]3)[CH:16]=1
Reactant: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Reactant: O=S(=O)(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=S(=O)(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
(R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.08 mmol, 25 mg) was dissolved in tetrahydrofuran (1 mL) and triethylamine (0.25 mmol, 35 μL, 25 mg) followed by furan-2-sulfonyl chloride (0.084 mmol, 14.05 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl. (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (R)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)furan-2-sulfonamide (13.1 mg, 0.03 mmol, 37.1%) MS (ESI): m/z [M+H]+ 442.2
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36](=[O:35])[CH2:37][OH:38])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CO)sc5c4)c3)c2)CC1
Yield: 26.4 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (310 mg, 726 μmol) produced in Example A15(iii), pyridine (10 mL), 2-chloro-2-oxoethyl acetate (269 mg, 1.97 mmol) and N,N-dimethylpyridine-4-amine (62.1 mg, 508 μmol) as starting materials, and in the same manner as in Example A14, the title compound (93 mg, 26%) was obtained as colorless crystals. In this Example, the purification operation was performed using silica gel column chromatography (hexane/ethyl acetate=5/95→20/80).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])=[C:13]([CH2:36][O:37][CH3:38])[NH:12][C:11](=[O:39])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>C(O)C.[Pd]>[NH2:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:15]([C:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[NH:10][C:11](=[O:39])[NH:12][C:13]=3[CH2:36][O:37][CH3:38])=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1
Reactant: COCC1=C(C(=O)NCCCN2CC=C(c3cccc([N+](=O)[O-])c3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: COCC1=C(C(=O)NCCCN2CCC(c3cccc(N)c3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
A mixture of (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide, 10% Pd/C in ethanol was hydrogenated (balloon method) for 2 days. The reaction mixture was filtered through Celite 545, washed with ethanol and concentrated to give the desired product.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([CH:9]([CH2:20][CH:21]=[CH2:22])[CH2:10][O:11][SiH2:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1)[CH:7]=[CH2:8].C(C(CC=C)[CH2:27][O:28][SiH2]C1C=CC([Mg]Cl)=CC=1)C=C.CN(C=O)C.Cl>C1COCC1>[CH2:6]([CH:9]([CH2:20][CH:21]=[CH2:22])[CH2:10][O:11][SiH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:27]=[O:28])=[CH:15][CH:14]=1)[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc([Mg]Cl)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCC(CC=C)CO[SiH2]c1ccc(C=O)cc1
Yield: 85 %

Procedure:
Firstly, i-PrMgCl (0.71 mL, 2 M in THF, 1.42 mmol) was added dropwise to a THF solution (2 mL) of 4-(diallylethoxysilyl)iodobenzene (255 mg, 0.71 mmol) obtained in Synthesis example 7 at −30° C. The resultant mixture was stirred under a nitrogen atmosphere at −30° C. for 1.5 hours to obtain a solution containing 4-(diallylethoxysilyl)phenylmagnesium chloride (Grignard solution). Then, DMF (110 μL, 1.42 mmol) was added dropwise to the obtained solution at −30° C., and the resultant mixture was stirred under a nitrogen atmosphere at room temperature for 13 hours to obtain a reaction mixture. Subsequently, an aqueous solution of HCl of 10% by mass was added to the reaction mixture to cease the reaction. After that, an organic layer was separated from the reaction mixture, and an aqueous layer was extracted with ether. The organic layer thus collected was washed with sat. NaHCO3 and sat. NaCl, and dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=20/1) to obtain 4-(diallylethoxysilyl)benzaldehyde (158 mg, 85% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=1[C:49]1[C:53]([CH2:54]O)=[C:52]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[C:43]=1[C:49]1[C:53]([CH2:54][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:52]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[O:51][N:50]=1
Reactant: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Temperature: 90 °C
Yield: 42 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (154 mg, 0.550 mmol), triphenylphosphine (144 mg, 0.550 mmol) and {3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methanol (150 mg, 0.500 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.550 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution). A second purification was done by chromatography (silica gel, 2% methanol in dichloromethane) to afford methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate as a white solid (118 mg, 42%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=8 Hz, 2H), 7.63-7.51 (m, 3H), 6.92 (d, J=8 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.94 (s, 3H), 3.27-3.22 (m, 1H), 1.73-1.66 (m, 2H), 1.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10](C(OC(C)(C)C)=O)[NH:11]C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:26]>CO.O1CCOCC1>[ClH:26].[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][NH2:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCC(NN)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
32 g (0.09 mol) of di-tert-butyl 1-(1-acetylpiperidin-4-yl)hydrazine-1,2-dicarboxylate were dissolved in 300 mL of methanol and 30 mL of HCl 4 M in dioxane were added. The mixture was stirred at room temperature overnight. The solvent was then evaporated and the residue crystallized from ethanol, giving 14 g (77% yield) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:56])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][N:17]([CH2:30][C:31]2[N:32]([CH2:36][C:37]([N:39]([CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:38])[CH:33]=[CH:34][N:35]=2)[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:56])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][N:17]([CH2:30][C:31]2[N:32]([CH2:36][C:37]([N:39]([CH2:48][C:49]([OH:51])=[O:50])[CH2:40][C:41]([OH:43])=[O:42])=[O:38])[CH:33]=[CH:34][N:35]=2)[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([S:26](=[O:28])(=[O:29])[NH2:27])=[CH:24][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccn1CC(=O)Nc1cccc(I)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CCN(Cc2nccn2CC(=O)Nc2cccc(I)c2)Cc2nccn2CC(=O)N(CC(=O)O)CC(=O)O)cc1
Yield: 73.6 %

Procedure:
A solution of di-tert-butyl 2,2′-((2-(2-((((1-(2-((3-iodophenyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (45 mg, 0.0497 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 5 hrs. Solvent was removed under a stream of nitrogen to give a residue, which was purified by HPLC to give compound (18) as a white solid (29 mg, 74%). 1H NMR (400 MHz, DMSO-d6) 10.69 (s, 0.66H), 10.61 (s, 0.34H), 8.10 (s, 0.66H), 8.07 (s, 0.34H), 7.69-7.62 (m, 3H), 7.54 (s, 1H), 7.48-7.44 (m, 2H), 7.27 (s, 2H), 7.30-7.26 (m, 3H), 7.13 (t, J=8.0 Hz, 1H), 5.31 (s, 1.32H), 5.15 (s, 1.32H), 5.12 (s, 0.68H), 4.75 (s, 0.68H), 4.33 (s, 2H), 4.16 (s, 2H), 4.05 (s, 4H), 2.72-2.68 (m, 4H); MS (ESI), 793.1 (M+H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].C(O)(=O)C.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1c(F)cc([N+](=O)[O-])cc1F
Yield: 96.7 %

Procedure:
A solution of the obtained diethyl 2,6-difluoro-4-nitrophenylmalonate (42 g) in a mixed solvent of acetic acid (200 mL), water (150 mL) and conc. sulfuric acid (50 mL) was heated under reflux for 18 hr, and the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate (×2). The organic layer was back-extracted with 10% sodium carbonate aqueous solution, and the aqueous layer was acidified with 2N hydrochloric acid. The precipitate was collected by filtration to give 2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128 mmol, 92.0%) as white crystals.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[CH3:10][O:11][C:12](=[O:21])[CH:13](Br)[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[CH3:10][O:11][C:12](=[O:21])[CH:13]([N:2]1[C:3](=[O:7])[CH:4]=[CH:5][CH:6]=[N:1]1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=c1cccn[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A solution of 2H-pyridazin-3-one (2.0 g, 20.81 mmol) in tetrahydrofuran (104 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (839 mg, 24.97 mmol). The reaction was stirred at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 5.38 g, 22.89 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., was poured into water (150 mL) and was extracted into ethyl acetate (3×100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 30% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (3.0 g, 57%) as a tan oil; ES+-HRMS m/e calcd for C13H18N2O3 [M+H+] 251.1390 found 251.1389.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](Cl)(=O)C(Cl)=O.C(OCC)(=O)CC(OCC)=O.[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[CH3:14])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
To a solution of 4-chloro-2-nitrobenzoic acid (30.0 g, 0.15 mol) in THF (400 mL) was added oxalyl chloride (26 mL, 0.3 mol) at 0° C., followed by DMF (2 drops). After stirring for 10 min at 0° C., the ice bath was removed and the reaction mixture was heated at reflux for 3 h. The resulting mixture was then cooled and evaporated under reduced pressure. A second 1 L round bottom flask was loaded with diethyl malonate (22.8 mL, 0.15 mol) and THF (150 mL): sodium hydride (60% dispersion in mineral oil, 7.2 g, 0.18 mol) was then added at 0° C., portionwise over a period of 30 minutes. The ice bath was then removed, and the mixture was heated at reflux for 3 h. The acyl chloride, dissolved in 2 portions of THF, was added and the resulting mixture was heated at reflux for 3 h and then stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc; the organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. A mixture of glacial AcOH (50 mL) and sulfuric acid (20% in water, 50 mL) was added to the residue, and the resulting mixture was heated at reflux for 6 h and then stirred at 80° C. overnight. The reaction mixture was basified to pH 10 by adding NaOH (aq) and then was extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to give 7.1 g of 1-(4-chloro-2-nitro-phenyl)-ethanone.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH:7]1([O:12][C:13]2[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][N:16]=[C:15]([CH2:23][OH:24])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[K+].C([OH:30])(C)C>O>[CH:7]1([O:12][C:13]2[C:18]([O:19][CH:20]([F:21])[F:22])=[CH:17][N:16]=[C:15]([C:23]([OH:30])=[O:24])[CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)O
Reactant: OCc1cc(OC2CCCC2)c(OC(F)F)cn1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(OC2CCCC2)c(OC(F)F)cn1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Solid potassium permanganate (306 mg) is added portionwise to a stirred suspension of 4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine (250 mg) in water (10 mL) while heating at 50±5° C. The resulting mixture is heated for 1.5 hours at this temperature, then at 70° C. for minutes. A solution of potassium hydroxide (150 mg) in water (1 mL) is added followed by the addition of isopropanol until the excess potassium permanganate is consumed. After 15 minutes, the mixture is cooled and filtered through a pad of diatomaceous earth and the filtrate adjusted to pH 5 with glacial acetic acid. The white precipitate is collected, washed with water and dried in vacuo to give 4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxylic acid (240 mg) as a white solid, m.p. 215-6° C. decomp. [Elemental analysis: C, 52.57; H, 4.67; N, 5.18%, calculated: 52.75; H, 4.80; N, 5.13%].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])/[CH:5]=[C:6](/[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)\[C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1)[CH3:2]>C(OCC)C.CC(O)=O.CCOC(C)=O.[Zn]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(/c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)CC(c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Reaction time: 8 h
Yield: 94 %

Procedure:
18 g (46.55 mmol) of (Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylic acid ethyl ester are dissolved in 250 ml Diethylether and 80 ml AcOH. 3 Eq (140 mmol) of zinc dust are added over a period of 60 minutes. The resulting mixture is allowed to stir overnight, diluted with 100 ml EtOAc and filtrated over a pad of Celite. The solvent is removed in vacuo, the residue taken up in EtOAc, washed with brine and dried over MgSO4. After evaporation of the solvent 17 g (Yield=99%) of crude product are obtained, which are used in the last step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(Cl)Cl>O.C1COCC1>[C:23]([O:22][C:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:3][CH2:2]1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1ccccc1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Temperature: 25 °C

Procedure:
A solution of the hydrobromide salt of 2-piperidin-4-yl-phenol Compound 3a (5.00 g, 19.37 mmol) in water (400 mL) was made basic to pH 8 by the addition of NaHCO3. A solution of O(Boc)2 (4.22 g, 19.36 mmol) in THF (80 mL) was added and the mixture was stirred at r.t. over night. CH2Cl2 (500 mL) was added and the organic layer was isolated and dried. The crude product was purified by chromatography to provide 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester Compound 2a (4.56 g, 85%) as a white powder 1H NMR δ 1.50 (s, 9H), 1.60 (m, 2H), 1.85 (bd, J=19.5 Hz, 2H), 2.82 (bm, 2H), 3.04 (m, 1H), 4.23 (bs, 2H), 6.7˜7.2 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=2)=[O:7])=[C:4]([F:21])[CH:3]=1.[H][H]>C1COCC1.[Ni]>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=2)=[O:7])=[C:4]([F:21])[CH:3]=1
Reactant: [H][H]
Reactant: Nc1cc(F)c(C(=O)Nc2cc(Cl)ccn2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)c(C(=O)Nc2cc(Cl)ccn2)cc1N

Procedure:
A solution of the product obtained at 142f (320 mg, 1.0 mmol) in 20 mL THF was combined with Raney nickel (70 mg) and hydrogenated in a Parr apparatus at ambient temperature for 1.5 days at 3 bar hydrogen pressure. Then the mixture is filtered and concentrated i.vac. The residue is purified by chromatography on RP-HPLC (stable bond C18, 5 μm). The mixture was concentrated i.vac., taken up in water and treated with K2CO3. The aq. phase is diluted with ethyl acetate. The organic phase is dried, filtered and concentrated i.vac.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 62A. mp 149-150° C.; IR (KBr) cm−1: 3089, 1734, 1512, 1473, 1295, 1234; 400 MHz 1H NMR (DMSO-d6): δ 13.11 (br(s), 1H), 7.40-7.71 (m, 3H), 6.88-7.19 (m, 5H), 6.58 (d, 1H, J=8.5 Hz), 5.07 (s, 2H), 4.61 (s, 2H), 3.96 (s, 2H), 2.77 (t, 2H, t, J=7.4 Hz), 2.69 (t, 2H, J=7.4 Hz), 1.91 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53. found: C, 60.95; H, 4.41.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.I[CH2:31][CH3:32].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH3:32])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (400 mg, 0.96 mmol), iodoethane (92.5 μL, 1.2 mmol) and triethylamine (201.5 μL, 1.4 mmol) in 4 mL of DMF was heated at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2 SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH/DCM: 1/9) to afford 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 1HNMR (DMSO-d6) δ 8.01 (s, 1H), 7.35 (m, 1H), 7.02 (d, 1H), 6.22 (s, 1H), 2.97 (d, 2H), 2.62 (m, 1H), 2.34 (q, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (t, 2H), 1.64 (m, 4H), 1.01 (t, 3H); ESMS m/z 444.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=1
Reactant: CCc1cnccc1C
Reactant: FC(F)(F)c1cccc(CCCBr)c1
Product: CCc1cnccc1CCCCc1cccc(C(F)(F)F)c1
Yield: 80.4 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 4.03 g (15.1 mmol) of 1-bromo-3-(3-trifluoromethylphenyl) propane were reacted in the same manner as in Example 26. The reaction compound was purified to obtain 3.73 g of the desired compound (yield: 80.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.B.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)cn1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Fluoro-phenyl)-1H-imidazole-4-carboxylic acid (18 g, 87 mmol) was dissolved in 90 mL dry THF. Borane tetrahydrofuran complex (174 mL, 1M in THF, 174 mmol) was added dropwise. The reaction was refluxed for 2 h and stirred at RT overnight. The reaction mixture was cooled to 0° C. and 100 mL methanol were added dropwise. The solvents were evaporated. The residue was taken up in 100 mL 2N HCl and refluxed for 2 h. The reaction mixture was then cooled to 0° C. and 120 mL 2N sodium hydroxide solution were added dropwise. The solid material was filtered off and dried at 50° C. and 15 mbar. The desired compound was obtained as a white solid (13 g, 78%), MS: m/e=193.2 (M+H)+.