Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](Br)[CH:41]=1)[CH3:36]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:35]([O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:41]=[C:42]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)[CH:43]=[CH:44][CH:45]=1)[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1cccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, (3-bromo-phenyl)-acetic acid ethyl ester, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{4-[1-(2-Chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-3-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH2:22])[C:20]([CH2:23][O:24][CH2:25][CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:29](OC)([CH3:31])[CH3:30].C(O)(=O)C>C(#N)C.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([N:22]=[C:29]([CH3:31])[CH3:30])[C:20]([CH2:23][O:24][CH2:25][CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N=C(C)C
Temperature: 100 °C
Reaction time: 22 h
Yield: 100 %

Procedure:
A suspension of 7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (6.91 g, 19.8 mmol) in 55 mL of acetonitrile was treated with 2,2-dimethoxypropane (12.2 mL, 99.2 mmol) and 14 mL of glacial acetic acid. The reaction mixture was heated to 100° C. under an atmosphere of nitrogen. After 22 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown oil. The oil was dissolved in 125 mL of CHCl3 and washed with saturated NaHCO3 solution (2×30 mL) and water (30 mL). The combined aqueous washes were back-extracted with CHCl3 (25 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 7.69 g of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine as a brown solid.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]>C1C=CC=CC=1>[CH3:3][C:4]1[S:5][C:6]([I:1])=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: Cc1csc(C)c1CO
Reactant: II
Solvent: c1ccccc1
Product: Cc1sc(I)c(C)c1CO
Temperature: -50 °C

Procedure:
10.0 G. (46 mmol) of mercuric oxide and 14.7 g. (58 mmol) of iodine were added alternately over a period of 11/4 hrs. to a vigorously stirred solution of 8.2 g. (57.7 mmol) of 2,4-dimethyl-3-hydroxymethylthiophene in 300 ml. of benzene. The reaction mixture was kept at room temperature by cooling with an ice bath and stirring was continued for an additional hour. The mercuric iodide which precipitated was filtered and washed well with warm ethyl ether. The combined organic solutions were washed with 10% sodium thiosulfate and saturated sodium chloride solution, dried and evaporated. The resulting residue was dissolved in a minimum amount of hot ether, an equal amount of hexane was added and the solution cooled to -50° C. The crystals which precipitated were filtered and washed with cold hexane to yield after drying 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene, m.p. 118.5°-120.5° C.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:34][C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: O=Cc1ccncc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2Cc2ccncc2)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with pyridine-4-carbaldehyde in analogy to experiment L3 to give (2S,4R)-1-pyridin-4-ylmethyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 479.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[O:17][C:16]([C@@H:18]([NH:28]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[N:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>CCOC(C)=O.CO.[Pd]>[NH2:28][C@H:18]([C:16]1[O:17][C:13]([C:12]2[C:3]([O:2][CH3:1])=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:14][N:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2cc3ccccc3nc2OC)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
F6 was dissolved in EtOAc/MeOH (1:1, 0.025 M) and treated with Pd/C (10% w/w). Mixture was purged with N2 and stirred under H2 atmosphere at room temperature for 48 h. Then, reaction mixture was filtered through a pad of Solka-Floc® and filtrate was concentrated under vacuum to give the title compound as pale yellow solid which was used as such in the next step. MS (ES+) C21H26N4O3: 383 (M+H)+.
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([Br:13])[CH:12]=1)=O)C.S(O)(O)(=O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([NH2:28])=[NH:27])[CH2:22][CH2:21]1.CC([O-])(C)C.[K+]>O1CCOCC1>[Br:13][C:11]1[CH:12]=[C:8]([C:6]2[N:28]=[C:26]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[N:27]=[CH:4][N:5]=2)[S:9][CH:10]=1
Reactant: CN1CCN(C(=N)N)CC1
Reactant: CN(C)C=NC(=O)c1cc(Br)cs1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2ncnc(-c3cc(Br)cs3)n2)CC1

Procedure:
To a solution of 4-bromo-thiophene-2-carboxylic acid dimethylamino-methyleneamide (261 mg, 1.0 mmol) in anhydrous 1,4-dioxane (8 mL) was added 4-methyl-piperazine-1-carboxamidine sulfate (95.6 mg, 0.25 mmol) and KOtBu (56.1 mg, 0.5 mmol). The resulting suspension was heated at reflux overnight under argon. After cooling, the reaction mixture was passed through a pad of diatomaceous earth, the filtrate was concentrated and the residue was purified by preparative TLC (2 M NH3 in MeOH/CH2Cl2) to yield the title compound as a yellowish solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O:31]C)=[O:30])[C@H:26]([CH3:33])[C:25]([C:34]([F:37])([F:36])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:38])[CH2:11]2)[CH:9]=1)[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([OH:31])=[O:30])[C@H:26]([CH3:33])[C:25]([C:34]([F:36])([F:37])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:38])[CH2:11]2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)OC)cc3)[C@H](C)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(F)c(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3)[C@H](C)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (2.57 g, 4.66 mmol) in THF (85 mL) and water (8.5 mL) was added a 1 M aqueous solution of LiOH (58.2 mL, 23.3 mmol) and the reaction mixture was stirred at rt until complete for 1 h. The reaction mixture was concentrated to remove the THF and hexanes were added. An emulsion formed. The layers were separated as much as possible. Brine was added to the emulsion and the layers separated completely. The combined aqueous layer and brine aqueous layer was acidified to pH 2 with 1 M aqueous HCl. The product was extracted with CH2Cl2 (3×) and the combined organic layers were dried (MgSO4) and concentrated to provide 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (2.4720 g, 4.60 mmol, 99% yield) as a white foam. To a solution of 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (7.72 g, 14.4 mmol) in acetonitrile (50 mL) was added 3 N aqueous HCl (9.57 mL, 28.7 mmol). The solution was concentrated. 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid, HCl (8.08 g, 14.0 mmol, 97% yield) was isolated as an off-white solid. LC-MS Anal. Calc'd for C27H31F4N3O4: 537.55. found [M+H] 538.3. 1H NMR (400 MHz, CD3CN) δ 7.99 (br. s., 1H), 7.24 (ddd, J=12.0, 9.3, 1.2 Hz, 1H), 7.12-7.04 (m, 2H), 7.02-6.93 (m, 3H), 4.47-4.38 (m, 1H), 4.18 (td, J=10.0, 4.1 Hz, 1H), 4.04 (q, J=6.9 Hz, 2H), 3.78-3.65 (m, 2H), 3.62 (dd, J=12.4, 4.1 Hz, 1H), 3.42 (td, J=11.8, 4.4 Hz, 1H), 3.37-3.27 (m, 1H), 2.83 (br. s., 1H), 2.73 (dd, J=16.5, 3.0 Hz, 1H), 2.54-2.38 (m, 2H), 2.36-2.28 (m, 1H), 1.37 (t, J=7.0 Hz, 3H), 1.30 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H). Analytical HPLC (Orthogonal method) RT=13.3 min, HI: 97%. hGPR40 EC50=154 nM. hGPR40 IP1 EC50=11 nM. Acute oral glucose tolerance: −52% @ 0.3 mg/kg (average of two experiments).
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:5]([O-:7])=[O:6].[Na+].[CH3:18]I.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[O:3]=[C:4]([C:8]([CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: CI
Reactant: CCC(C(=O)C(=O)[O-])c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(C)(C(=O)C(=O)[O-])c1ccccc1
Yield: 46 %

Procedure:
A 3N aqueous solution (0.84 ml) of sodium hydroxide and 3.0 ml of tetrahydrofuran were added to 0.30 g (1.39 mmoles) of sodium 2-oxo-3-phenylpentanoate, and the mixture was stirred until a completely uniform solution formed. Then, 0.23 mg (2.8 mmoles) of methyl iodide and 36 mg (0.16 mmole) of triethylbenzylammonium chloride were added, and the mixture reacted at room temperature for 7 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ether. The ether layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated. The NMR spectral analysis of the resulting oily product led to the determination that the desired 2-oxo-3-methyl-3-phenylpentanoic acid formed in a yield of 62 %. Then, 1.2 ml of a 1N aqueous solution of sodium hydroxide was added to this product, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated white solid was isolated by filtration to give 0.15 g (0.63 mmole) of sodium 2-oxo-3-methyl-3-phenylpentanoate in a yield of 46 %.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH:11]2[CH2:14][N:13]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>[Pt].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH:11]2[CH2:12][N:13]([CH:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:14]2)=[CH:23][CH:24]=1
Reactant: CC(c1ccccc1)N1CC(CCOc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pt]
Solvent: CCO
Product: CC(c1ccccc1)N1CC(CCOc2ccc(N)cc2)C1

Procedure:
The title compound is prepared by catalytic reduction at room temperature in the presence of platinum on carbon catalyst in ethanol solution using standard laboratory procedures from 3-[2-(4-nitrophenoxy)ethyl]-1-(1-phenylethyl)azetidine.
Reaction SMILES: [C:1]([C:9]([OH:11])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][N:17]([C:9](=[O:11])[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])[CH2:16][CH2:15]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
Benzoylformic acid (1.0 g, 6.7 mmol), dimethylpiperidin-4-ylamine (854 mg, 6.7 mmol), DIPEA (3.5 mL, 20.0 mmol), and 1-hydroxybenzotriazole (1.4 g, 10 mmol) were dissolved in 20 mL of methylene chloride, then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.53 g, 7.99 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with a 1.0 N NaOH solution, then the organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (10-30% MeOH in methylene chloride gradient) to give intermediate (5a) (501 mg).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH3:20])=[C:12]2[C:17]=1[O:16][CH2:15][CH:14]([OH:18])[CH2:13]2.C(OC(=O)C)(=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH3:20])=[C:12]2[C:17]=1[O:16][CH2:15][C:14](=[O:18])[CH2:13]2
Reactant: COc1ccc(Br)c2c1CC(O)CO2
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Br)c2c1CC(=O)CO2
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
To a solution consisting of dry pyridine and CH2Cl2 (120 ml, dried over P2O5) CrO3 (435 mg, 4.35 mmol) was added. The mixture was stirred for 15 min and 8-bromo-5-methoxy-3-chromanol (293 mg, 1.13 mmol) was dissolved in 10 ml dry CH2Cl2 was added and immediately thereafter acetic acid anhydride (0.41 ml, 4.35 mmol) was added to the solution. The mixture was stirred for 10 min and then sucked through a short silica column (13 g SiO2) with vacuum. The column was washed with CH2Cl2 and the solvent evaporated yielding 237 mg (81%) of the product. An analytic sample was obtained from recrystallization in light petroleum-ether, m.p. 97°-100° C. 1H NMR (CHCl3) δ 3.55 (s,2H), 3.80 (s,3H), 4.45 (s,2H), 6.5 (d,1H), 7.4 (d,1H). GC/M (HP-5970A) m/e=258 (64) M+1, 256 (57) M-1, 134 (100), 50 (11), 76 (11).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12].C([O:15][C:16]([N:18]=[C:19]=[S:20])=O)C.[OH-].[NH4+]>CCOC(C)=O>[OH:15][C:16]1[N:6]2[N:5]=[CH:4][C:3]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[C:2]2[N:1]=[C:19]([SH:20])[N:18]=1
Reactant: N#CCCCCc1cn[nH]c1N
Reactant: CCOC(=O)N=C=S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CCCCCc1cnn2c(O)nc(S)nc12
Temperature: 25 °C

Procedure:
To a solution of compound (2) (4.6 g. 14 mmol) in EtOAc (50 mL) was added Ethoxycarbonyli-sothiocyanate (1.69 mL, 15 mmol) drop wise with stirring at ambient temperature. The reaction mixture was refluxed for 2 h, and cooled to room temperature. Ammonium hydroxide (10 mL) was added and the reaction mixture stirred at room temperature for 20 h. The reaction mixture was extracted twice with 1 M NaOH and the aqueous extractions were combined, acidified with concentrate HCl, and extracted twice with EtOAc. The combined organic extracts were dried with anhydrous Na2SO4 and concentrated to give 5-(4-hydroxy-2-mercapto-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (3), as a white solid (2.5 g, 67%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH3:12][C:13](=[CH2:16])[CH2:14][NH2:15]>>[CH3:16][C:13](=[CH2:12])[CH2:14][NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12
Reactant: C=C(C)CN
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Product: C=C(C)CNc1cc(C)nc2cn[nH]c12

Procedure:
The title compound was prepared from 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) and 2-methylallylamine as a pale yellow solid, m.p. 161°-164°, by the method given in Example 1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11]>C(Cl)Cl>[N:12]1([C:10]([O:9][C:6]([CH3:8])([CH3:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(=O)OCC(C)(C)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)OC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of 2-hydroxy-2-methylpropyl acetate (3.35 g, 25.3 mmol) and 1,1′-carbonyldiimidazole (4.11 g, 25.3 mmol) in DCM was stirred for 8 h at rt. The mixture was then transferred to a closed vessel and heated to 100° C. overnight. The mixture was concentrated in vacuo before ether and water were added. The organic phase was separated, dried and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with THF:heptane (1:1), to give the title compound in 20% yield.
Reaction SMILES: [CH2:1]([C@:3]([OH:31])([C:15]1[CH:23]=[C:22]2[N:18]([CH2:19][CH2:20][C:21]32OCC[O:24]3)[C:17](=[O:28])[C:16]=1[CH2:29][OH:30])[C:4](N[C@H](C1C=CC=CC=1)C)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([C@:3]1([OH:31])[C:15]2[CH:23]=[C:22]3[N:18]([CH2:19][CH2:20][C:21]3=[O:24])[C:17](=[O:28])[C:16]=2[CH2:29][O:30][C:4]1=[O:5])[CH3:2]
Reactant: CC[C@@](O)(C(=O)N[C@@H](C)c1ccccc1)c1cc2n(c(=O)c1CO)CCC21OCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Three hundred milligrams of the compound (VII) obtained in the above procedure (1) were dissolved in 80% trifluoroacetic acid solution and the resulting mixture was stirred at room temperature for 2 hours under a nitrogen gas stream. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel (10 g). A colorless oily substance was obtained from a 98:2 eluate of chloroform and methanol. The oily substance was crystallized from a mixed solvent of ethanol and petroleum ether to obtain 170 mg of the title compound as colorless needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](F)[CH:19]=3)=[CH:16][N:17]=2)[CH:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:19]=3)=[CH:16][N:17]=2)[CH:14]=1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccnc(F)c3)cnc12
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccnc(N4CCOCC4)c3)cnc12
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-3-(2-fluoro-pyridin-4-yl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (46.6 mg, 0.10 mmol) and morpholine (0.045 mL, 0.51 mmol) in DMSO (0.8 mL) was heated at 180° C. and stirred for 30 min. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 ml). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to yield the crude 6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(2-morpholin-4-yl-pyridin-4-yl)-imidazo[1,2-a]pyridine-7-carbonitrile intermediate.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](Cl)=[O:11].Cl.[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH2:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([F:16])=[C:7]([F:6])[CH:8]=1
Reactant: CC1CCCC1N
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1CCCC1NC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a mixture of 10 ml of THF and 0.60 g of 3,4-difluorobenzoyl chloride were added 0.37 g of 2-methylcyclopentylamine hydrochloride and 1.0 g of triethylamine, and the mixture obtained was stirred at room temperature for 3 hours. Then, ethyl acetate was added to the reaction mixture and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.55 g of N-(2-methylcyclopentyl)-3,4-difluorobenzamide.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1
Reactant: BrCC1CC1
Reactant: O=Cc1cc2cc(O)ccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc2cc(OCC3CC3)ccc2nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 2-chloro-6-hydroxyquinoline-3-carbaldehyde SLA 47016 (1.00 g, 4.8 mmol), cesium carbonate (3.14 g, 9.6 mmol) and (bromomethyl)cyclopropane (0.94 mL, 9.6 mmol) in dry DMF (30 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was stirred overnight at RT. DMF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 2-chloro-6-(cyclopropylmethoxy)quinoline-3-carbaldehyde SLA 47086 as a pale brown solid (513 mg, 41% yield).