Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][N:14]=1)[CH2:5][C:6](=O)[CH2:7][C:8](=O)C.Cl.[F:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.[OH-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=3)[N:24]=[C:7]([CH3:8])[CH:6]=2)[CH:12]=[CH:13][N:14]=1
Reactant: NNc1cccc(F)c1
Reactant: CC(=O)CC(=O)Cc1ccnc(Cl)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccnc(Cl)c2)n(-c2cccc(F)c2)n1
Yield: 65.3 %

Procedure:
To a mixture of 1-(2-chloroisonicotinyl)-1,3-butanedione (1.35 g, 0.068 mol) and 3-fluorophenylhydrazine hydrochloride (1.33 g, 0.0082 mol) in ethanol (40 mL) was added ammonium hydroxide (0.96 mL, 0.0082 mol) dropwise. The reaction mixture was heated at reflux overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 1.54 g (79% yield) of product as a yellow oil: Anal. Calcd. for C15H11ClFN3: C, 62.62; H, 3.85; N, 14.60. Found: C, 62.34; H, 3.88; N, 14.30.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10](CC2C=C3C(C=CN=C3N)=CC=2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[C:33]2[CH:34]=[C:35]([CH2:37][NH2:38])[O:36][C:32]=2[CH:31]=[CH:30][N:29]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([NH:38][CH2:37][C:35]2[O:36][C:32]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:27])[C:33]=3[CH:34]=2)[C:9]1=[O:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cc2c(N)nccc2o1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(N)c3c2)C1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(NCc2cc3c(N)nccc3o2)C1=O

Procedure:
Using the procedure described in example 85i 166 mg of 4-amino-2-(aminomethyl)furo[3,2-c]pyridine was transformed into 150 mg of the title compound. MS ESI+: 347 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][CH3:12])[CH:8]=2)[CH2:3]1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][CH:2]([NH:1][C:14]1[C:15]3[C:22]([CH3:23])=[CH:21][S:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: COc1ccc2c(c1)CC(N)C2
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(Nc1ncnc3scc(C)c13)C2
Yield: 12.8 %

Procedure:
Using 2-amino-5-methoxyindan (90 mg) synthesized in b) in the above Preparation Example 1, 4-chloro-5-methylthieno[2,3-d]pyrimidine (90 mg, 0.50 mmol), triethylamine (0.23 ml, 1.7 mmol) and ethanol (1 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (20 mg, 0.064 mmol) having the following physical properties:
Reaction SMILES: [S:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)[C:2]#[N:3].O.S(=O)(=O)(O)[OH:15]>C(O)(=O)C>[OH:15][C:2]1[S:1][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#CSCC(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc(-c2ccccc2)cs1
Reaction time: 8 h

Procedure:
Following the known process [Bull. Soc. Chem. France, 11, 2498 (1963)], 8.85 g (50 mmol) of α-thiocyanoacetophenone, 5 ml, of water and 1.3 ml of concentrated sulfuric acid were added to 40 ml of acetic acid and the resultant mixture was refluxed for 2 hours. The reaction mixture was then allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration and then washed with water, whereby the title compound was obtained a colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1Cl
Reactant: O=C(C=Cc1ccc(Br)cn1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cn2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
1-(5-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (936.0 mg, 2.8 mmol) prepared in Step 3, 2-chlorophenylhydrazine hydrochloride (508.0 mg, 2.8 mmol), and piperidine (560.0 uL, 5.7 mmol) were added to ethanol (28.4 mL). The reaction mixture was stirred at 60° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 450.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.N1C=CC=CC=1.[CH3:33][C:34]1([CH3:42])[O:38][C@H:37]([C:39](Cl)=[O:40])[CH2:36][O:35]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:33][C:34]1([CH3:42])[O:38][C@H:37]([C:39]([N:2]2[CH2:7][CH2:6][C:5]([C:8]3[C:13]([F:14])=[CH:12][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:10][C:9]=3[F:26])=[CH:4][CH2:3]2)=[O:40])[CH2:36][O:35]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: CC(=O)OC[C@H]1CN(c2cc(F)c(C3=CCNCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-acetoxymethyloxazolidin-2-one hydrochloride (14.5 g, 37.3 mM) was suspended in dry dichloromethane (300 ml) under nitrogen at 0°, and treated with pyridine (9.78 g, 0.12 M). A solution of 2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl chloride (9.59 g, 75.6 mM) in dichloromethane (100 ml) was added dropwise, and stirring continued for 3 hours, allowing the temperature to rise to ambient. Aqueous sodium bicarbonate (5%, 300 ml) was added, and stirring continued for 30 minutes. The organic phase was separated, dried (magnesium sulfate), filtered, and evaporated to dryness after the addition of toluene (20 ml). The solid residue was triturated with a mixture of diethyl ether (250 ml) and isohexane (150 ml), and solid filtered to give the title compound (17.5 g). NMR (DMSO-d6) δ: 1.30 (2×s, 6H); 2.02 (s, 3H); 2.28 (br, 1H); 2.39 (br, 1H); 3.67 (t overlapping m, 2H); 3.83 (dd, 1H); 4.00-4.32 (overlapping m, 7H); 4.90 (overlapping m, 2H); 5.86 (s, 1H); 7.34 (d, 2H). MS (ESP): 481 (MH+) for C23H26F2N2O7
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:30][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a suspension of methoxymethyltriphenylphosphonium chloride (6.366 g, 18.5 mmol) in dry tetrahydrofuran (50 ml) under argon atmosphere at −78° C. slowly (ca. for 5 minutes) a 2.46 N solution of potassium tert-butoxide in tetrahydrofuran (8.2 ml, 20.2 mmol) was added and the reaction mixture was stirred at this temperature for 1 hour. A solution of methyl 4-formylbenzoate (6a) (2.531 g, 15.4 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture and the resultant suspension was stirred at −78° C. for 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 30 minutes allowing warming up to room temperature. The mixture was partitioned between benzene (150 ml) and water (150 ml), and the organic layer was washed successively with water (150 ml), brine (50 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (100 g) with toluene-triethylamine (100:0.25) as eluent to give the title compound (2.696 g, 91%) as a mixture of E and Z isomers (ca. 95:5). (E)-(7a): 1H NMR (CDCl3, HMDSO) δ: 3.67 (3H, s); 3.86 (3H, s); 5.81 (1H, d, J=13.5 Hz); 7.14 (1H, d, J=13.5 Hz); 7.25 (2H, d, J=8.5 Hz); 7.89 (2H, d, J=8.5 Hz). A small additional singlet at 3.80 ppm and 2 doublets at 5.23 (d, J=7.6 Hz); 6.22 ppm (d, J=7.6 Hz) in the 1H NMR spectrum of 7a was attributed to minor amounts (ca. 5%) of (Z)-(7a) isomer present in the product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][CH2:16][C:17]2[C:18]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:11]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[N:10]=1)#[N:2].Cl>CO.O1CCOCC1>[NH2:24][CH2:23][C:18]1[C:17]([CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:32]=[CH:33][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[N:10][C:11]=2[NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccnc2CN)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl (3-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (737 mg, 1.27 mmol) in methanol (6 mL) at 0° C. was added a solution of 4M HCl in 1,4-dioxane (3 mL). The mixture was warmed to room temperature and stirred for 2 hrs. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave N-((2-(aminomethyl)pyridin-3-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide as a pale yellow solid (545 mg, 89%). LRMS (M+H+) m/z 481.2.
Reaction SMILES: [F:1][CH:2]([F:23])[N:3]1[C:7]2[C:8](=[O:22])[NH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:11][C:6]=2[N:5]=[CH:4]1.O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[F:23][CH:2]([F:1])[N:3]1[C:7]2[C:8]([O:22][C@@H:25]([C@H:27]3[CH2:31][N:30]([C@@H:32]([C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)[CH3:33])[C:29](=[O:42])[CH2:28]3)[CH3:26])=[N:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: COc1ccc(-c2cc3ncn(C(F)F)c3c(=O)[nH]2)cc1OC
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C(F)F)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.29 (49 mg, 0.153 mmol), lactam alcohol 1.05 (60 mg, 0.23 mmol), and PPh3 (60 mg, 0.23 mmol) were taken up in THF (2 mL). To the resulting suspension was added DEAD (38 μL, 0.24 mmol) dropwise. The resulting clear colorless solution was heated to 40° C. and stirred 15 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography gave (R)-4-((R)-1-(3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.30 that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33F2N4O5: 567.2; found 567.4.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(S)cc1
Reactant: CCOC(=O)c1cc(Cl)nc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1cc(Sc2ccc(N)cc2)nc2ccccc12
Yield: 36 %

Procedure:
2-Chloro-4-ethoxycarbonylquinoline (0.024 moles, 5.56 g), 4-aminothiophenol (0.024 moles, 3.0 g) and 4-dimethylaminopyridine (0.024 moles, 2.9 g) were stirred in 250 ml ethanol for 3 days. The reaction mixture was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 25% ethyl acetate/hexane to yield 2-(4-aminophenylthio)-4-ethoxycarbonylquinoline 2.8 g, 36%. Mass Spec (FD) 324. Calculated for C18H16N2O2S: C, 66.64; H, 4.97; N, 8.63. Found: C, 66.50; H, 5.00 N, 8.54.
Reaction SMILES: O[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(O)n(C)n1
Product: CC(C)c1cc(Cl)n(C)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
The 5-hydroxy-3-isopropyl-1-methylpyrazole (20.5 g) was added in small portions over five minutes to 60 ml of phosphorus oxychloride cooled at 10° C. No significant exotherm resulted and after five minutes the cooling bath was removed. After stirring for one hour, the reaction was heated to 70° C. overnight and then 90° C. for four hours. The cooled reaction was cautiously added to 500 g of ice. The desired product was extracted with two 200 ml portions of ethyl acetate and the combined extracts were concentrated under reduced pressure to yield 13.7 g of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C1([Si:16]2([CH2:31][CH2:32][CH2:33][CH:34]([F:36])[CH3:35])[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)C=CC=CC=1>>[F:36][CH:34]([CH3:35])[CH2:33][CH2:32][CH2:31][Si@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[O:27])=[CH:29][CH:30]=2)[CH2:18][CH2:17]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Product: CC(F)CCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4-difluorophenol and 4-(4-phenyl-4-(4-fluoropentyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[O:9][CH2:10][C:11]#[CH:12])=[CH:4][CH:3]=1.[C-:14]#[N:15].[Na+].O.[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:9][CH2:10][C:11]#[CH:12])[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: C#CCOC(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
1-Chloro-4-(chloro-prop-2-ynyloxy-methyl)-benzene (13.0 g) is added to sodium cyanide (3.1 g) in N,N-dimethylformamide (40 ml) over 2 hours at room temperature. The reaction mixture is stirred at room temperature for 3 hours and then poured into water (200 ml), which contained sodium hydroxide (4 g). The aqueous phase is extracted with tert butyl methyl ether (2×200 ml). The organic phases are washed with water (2×50 ml), combined, dried (sodium sulfate) and evaporated. (4-Chloro-phenyl)-prop-2-ynyloxy-acetonitrile (9.2 g) is obtained which is purified by flash column chromatography on silica gel using ethyl acetate/hexane as eluant.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:15]=1[NH2:16].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][C:19]([F:21])=[CH:18][C:17]=2[F:22])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cc(F)cc2F)n1
Temperature: 50 °C
Yield: 87 %

Procedure:
A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] (1.0 g, 4.48 mmol) in CHCl3 (20 mL) was added 2,4,6-trifluoroaniline (0.735 mg, 5 mmol) followed by Et3N (0.94 mL, 6.72 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to 50° C. for 8 h, 1 M aq Na2CO3 (50 mL) was added and the layers were separated. The organic layer was washed with 50 mL satd aq NaCl solution, dried through anhydrous MgSO4 and evaporated. The crude product was purified by flash chromatography to afford 1.3 g (87%) of pure 4-chloro-6-(2,4,6-trifluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. LC MS (m/e)=334.0 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17]Br)[C:13]=2[CH:19]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[C:13]=2[CH:19]=1
Reactant: Clc1ccc2onc(CBr)c2c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2onc(Cn3ccnc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 276.6 g, 6.92 moles) is added in portions to a solution of imidazole (471 g, 6.92 moles) in dimethylformamide (4 L) over a period of 1 hour. After the addition is complete, the resulting suspension is stirred for 1 hour at ambient temperature. A solution of 5-chloro-3-bromomethyl-1,2-benzisoxazole (1.57 kg, 6.37 moles) in dimethylformamide (3 L) is then added over a period of 30 minutes, during which time there is an exotherm from 24° C. to 68° C. On completion of this addition, the reaction mixture is stirred and heated at 90° C. for 2 hours. The solvent is then removed in vacuo and the residue is taken up in methylene chloride (4 L). The resulting suspension is washed with water (2×2 L), which dissolves the solid material, and the organic solution is then dried over anhydrous sodium sulfate (1 kg), filtered and evaporated to give 5-chloro-3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole, m.p. 100°-102° C.; hydrochloride salt, m.p. 201°-203° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[CH2:29]([N:36]([CH3:37])[C:23]([C:20]1[N:19]=[C:18]([C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[O:22][N:21]=1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CNCc1ccccc1
Solvent: CCO
Product: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Yield: 82.9 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with N-benzyl-N-methylamine (0.98 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (100:0) gradually changing to dichloromethane:ethyl acetate (95:5) to afford the title compound (296 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22](COCC[Si](C)(C)C)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:38])([CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:25][C:24]([C:26]([F:28])([F:27])[F:29])=[CH:23][N:22]=3)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
In trifluoroacetic acid (2.9 mL) and water (0.3 mL) was dissolved methyl 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (144 mg) under ice-cooling, and the mixture was stirred at room temperature overnight. To the residue obtained by concentrating the reaction mixture under reduced pressure were added chloroform and a saturated aqueous sodium bicarbonate solution. The formed insoluble material was dissolved in methanol and combined with the organic layer. The organic layer was washed with water, and concentrated under reduced pressure. The obtained residue was pulverized by cooled ether, collected by filtration and dried to obtain methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-propanoate (85.9 mg).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:36])[NH:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]3[N:32]=[C:33]([CH3:35])[CH:34]=[C:22]3[N:21]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][C:5](=[O:10])[C:6]([O:8]C)=[O:7].[OH-].[Li+].Cl>CO>[CH3:11][C:2]([C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:36])[NH:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:23]3[N:32]=[C:33]([CH3:35])[CH:34]=[C:22]3[N:21]=2)=[CH:16][CH:17]=1)([CH3:1])[CH2:3][NH:4][C:5](=[O:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=O)NCC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nc(C)cc3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CNC(=O)C(=O)O)cc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Methyl 2-(2-methyl-2-(4-(2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-ylcarbamoyl)phenyl)propylamino)-2-oxoacetate was dissolved in MeOH (1 ml). Lithium hydroxide (2 N aqueous solution, 1 ml) was then added. The mixture was stirred for 30 minutes at room temperature. Hydrochloric acid (2N aqueous solution) was added to acidify the mixture to pH 3. The reaction mixture was partitioned between brine and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by preparatory HPLC (55-65% MeCN/H2O gradient+0.01% TFA). Combined fractions were concentrated in vacuo to give a suspension. The precipitate was collected on a small fritted funnel, washed with water, and then dried under a stream of nitrogen to give the titled product (16 mg, 38% yield) as a white powder. 1H NMR (DMSO-d6) δ: 11.22 (s, 1H), 8.47 (br. s., 1H), 8.00-8.16 (m, 4H), 7.96 (s, 1H), 7.64 (d, J=2.5 Hz, 3H), 7.55 (d, J=8.6 Hz, 2H), 6.40 (s, 1H), 2.40 (s, 3H), 1.30 (s, 6H); ESI-MS: m/z 400.4 (M+H)+.