Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[C:12]([O:16][CH2:17][CH:18]1[CH2:20][O:19]1)([CH3:15])([CH3:14])[CH3:13].C([O-])(=O)C.[Na+]>C(O)C>[C:12]([O:16][CH2:17][CH:18]1[O:19][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:20]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: CC(C)(C)OCC1CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OCC1Cn2cc([N+](=O)[O-])nc2O1
Yield: 21 %

Procedure:
2,4-Dinitro-1H-imidazole (10 g, 63.3 mmol), 2-tert-butoxymethyloxirane (27 ml, 189 mmol) and sodium acetate (5.19 g, 189 mmol) were suspended in ethanol (100 ml) followed by stirring under reflux for 17 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 2-tert-butoxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (3.2 g, yield 21%) as a white powder.
Reaction SMILES: Cl[C:2]1([CH:10]=[N:11][OH:12])[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH2:3]1.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][C:21](=[CH2:24])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:13]([O:15][C:16]([CH:18]1[CH2:19][CH2:20][C:21]2([O:12][N:11]=[C:10]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH2:24]2)[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: COC1=CC=CC(Cl)(C=NO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCC2(CC1)CC(c1cccc(OC)c1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-chloro-1-hydroxyiminomethyl-3-methoxybenzene (31 g, 167 mmol) in DCM (50 ml) was slowly added dropwise to a solution of 4-methylenecyclohexanecarboxylic acid ethyl ester (28 g, 167 mmol) in DCM (950 ml) at 0° C. Subsequently, a solution of triethylamine (50 ml) in DCM (50 ml) was slowly added dropwise at 0° C. and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water (500 ml). The combined organic phases were washed with 10% aq. citric acid solution (800 ml) and sat. aq. NaCl solution (500 ml), dried over sodium sulphate and the solvent was removed under vacuum. The desired product 3-(3-methoxyphenyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (51 g) was reacted without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:9]([OH:11])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:19][O:20][C:21]([C@@H:23]([NH2:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22].Cl.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:19][O:20][C:21](=[O:22])[C@@H:23]([NH:30][C:9](=[O:11])[CH:8]([C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=1)[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CN(C)C(=O)C(Cc1ccc(C#N)cc1)C(=O)O
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)N(C)C)C1CCCCC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2-(R,S)-(4-Cyano-benzyl)-N,N-dimethyl-malonamic acid (10 g, 40.6 mmol) and L-cyclohexylglycine methylester hydrochloride (8.3 g, 40 mmol) were dissolved in dimethylformamide (500 ml). After cooling to −10° C. TOTU (13.1 g, 40 mmol) and diisopropylethylamine (10.34 g, 80 mmol) were added. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation ethyl acetate was added to the residue and the organic layer was extracted with aqueous sodium hydogen carbonate solution, potassium hydrogen sulfate solution and water. The organic layer was evaporated. Yield: 14.53 g (90%); MS m/z: 400.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH2:22][C:20](=[O:21])[O:19]1.CCN=C=NCCCN(C)C.O>CO.CN(C1C=CN=CC=1)C.[Pd]>[F:16][C:2]1([F:1])[CH2:3][CH:4]([C:6]([CH:22]2[C:23](=[O:24])[O:25][C:18]([CH3:26])([CH3:17])[O:19][C:20]2=[O:21])=[O:8])[CH2:5]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)C(C(=O)C2CC(F)(F)C2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A mixture of benzyl 3,3-difluorocyclobutanecarboxylate (28 g, 0.12 mol) and Pd/C (5 g) in methanol (150 mL) was hydrogenated for 2 h at ambient temperature. Pd/C was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane (200 mL) and cooled to 0° C. DMAP (30.8 g, 0.250 mol), Meldrum's acid (19.6 g, 0.140 mol) and EDCI (26.9 g, 0.140 mol) were added successively. The reaction mixture was stirred overnight at ambient temperature. Water (200 mL) was added and the resulting mixture was extracted with dichloromethane (300 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 20:1) to afford 5-(3,3-difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (24 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].C(OCC)C>C(O)C>[Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)CC)c(OCCOC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To 11.3 g (0.03 mole) of the ethyl 2-chloro-3(2-methoxyethoxy)-4-ethylsulfonylbenzoate in 100 ml of 96% ethanol was added dropwise 16 ml (1.2 eq) of 10% sodium hydroxide. After stirring at room temperature for 4 hours, 100 ml of diethyl ether was added and the organic phase was extracted with 50 ml of 5% NaOH. The aqueous phase was acidified with 10% HCl and extracted two times with 50 ml chloroform. The organic phase was dried with MgSO4 and concentrated under vacuum to yield 8.8 grams of 2-chloro-3-(2-methoxyethoxy)4-ethylsulfonylbenzoic acid as a viscous oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][NH:13][C:12](=[S:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+].O.[CH3:22]I>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][N:13]=[C:12]([S:17][CH3:22])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)CC(=S)NCCS1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
The compound (2.00 g, 6.54 mmol) obtained in Example 4-0) was dissolved in tetrahydrofuran (11 mL). Potassium hydroxide (2.16 g, 39.72 mmol), water (7 mL), and methyl iodide (2.44 mL, 39.27 mmol) were added to the solution at room temperature, and the mixture was stirred for 1 h under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.09 g, quant.) in a yellow oily form.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:12]1=2)=[O:10])([CH3:7])([CH3:6])[CH3:5].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:33])[F:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:2]#[N:1])[C:13]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([C:38]([F:41])([F:39])[F:40])=[CH:37][C:12]1=2)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#CBr
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 67.5 °C
Yield: 76.4 %

Procedure:
Add cyanogen bromide (0.352 g, 3.33 mmol) to a solution of (S)-5-(3,5-Bis-trifluoromethyl-benzylamino)-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.647 g, 1.11 mmol) and diisopropylethylamine (0.679 mL, 3.89 mmol) in tetrahydrofuran (3 mL) at room temperature under nitrogen and heat the mixture at 65-70° C. for 16 hours and then for another 90° C. 16 h. Partition the cooled mixture between dichloromethane (40 mL) and brine (40 mL), separated layers. Extract aqueous with more dichloromethane (40 mL). Combine organic layers, dry over anhydrous sodium sulfate, filter and concentrated under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-20%), to provide the title compound (0.517 g, 76%), MS (ES+): 627 (M+NH4), 632 (M+Na).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[N:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1.Cl.Cl.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:44]=1[CH2:43][NH:42][CH2:41][CH2:40]2)=[O:34]>C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:44]=1[CH2:43][N:42]([C:8]1[N:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)[CH2:41][CH2:40]2)=[O:34]
Reactant: CC(C)(C)OC(=O)c1cccc(F)n1
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
Cs2CO3 (831 mg, 2.55 mmol) and 500 mg of 4 Å sieves were dried under high vacuum at 150° C. for 6 hours before the start of the reaction. Once cooled down, compound 120A (100 mg, 0.51 mmol) and compound 1B (327 mg, 0.61 mmol) were transferred to the reaction vessel and the atmosphere was purged with nitrogen. 1.5 mL of anhydrous DMA was then added and the reaction was stirred at 90° C. for 3 hours and then 100° C. for 2 hours. The cooled reaction mixture was then diluted with ethyl acetate and citric acid 10%. The organic phase was washed three times with citric acid, once with water and brine, and dried over Na2SO4. Concentration of the organic phase afforded an orange film/foam. This residue was purified by flash chromatography using SiO2 (AcOEt/Pet. Eth. 0:100 to 40:60). to provide a white solid (72 mg, 29% yield): 1HNMR (ppm, CDCl3) 1.54 (s, 9H), 3.01 (t, J=5.85 Hz, 2H), 4.05 (t, J=6 Hz, 2H), 5.04 (s, 2H), 6.92 (dd, J=8.55 and 0.63 Hz, 1H), 7.09-7.29 (m, 5H), 7.34 (dd, J=7.32 and 0.63 Hz, 1H), 7.60-7.51 (m, 2H), 7.81 (d, J=9 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.S1C=CN=C1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:37][C:38]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>CN(C)C=O.C(OC(=O)C)C>[Cl:37][C:38]1[CH:45]=[C:44]([O:46][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: FC(F)(F)c1ccc(-c2nc(COC3CCCCO3)c(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cscn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
3.0 g 5-(Chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluormethyl)phenyl]-1,3-thiazole (synthesis is described in WO2002/067912) thiazole were dissolved in 100 ml dimethylformamide. 5.0 g of cesium carbonate and 1.53 g 2-Chloro-4-hydroxybenzonitrile were added and the mixture was stirred at room temperature overnight. Then 300 ml of ethylacetate were added, the mixture washed three times with saturated NaHCO3 solution and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 4.1 g of crude 2-Chloro-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as yellow oil. This material was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=2[CH:18]=1)#[CH:13].BrC1C=CC(S(NC2CCC3CC2C3(C)C)(=O)=O)=CC=1.C(O)CC#C>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:13]#[C:12][C:14]2[O:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=3[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#Cc1cc2ccc(OC)cc2o1
Agent: C#CCCO
Agent: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Product: COc1ccc2cc(C#Cc3ccc(OC(C)=O)cc3)oc2c1
Yield: 56 %

Procedure:
When 4-iodophenyl acetate and 2-ethynyl-6-methoxybenzofuran were substituted for 4-bromo-N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)benzene sulphonamide and but-3-yn-1-ol respectively in Example 18, Step B, the similar process afforded the title compound in 56% yield, as creamy paste. 1H-NMR (CDCl3) 7.56 (d, 2H, J=8.67 Hz); 7.41 (d, 1H, J=8.58 Hz); 7.10 (d, 2H, J=8.7 Hz); 6.97 (d, 1H, J=1.92 Hz); 6.9 (s, 1H); 6.88 (bd, 1H, J=8.61 Hz); 3.85 (s, 3H); 2.3 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.O1CCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C([Sn](CCCC)(CCCC)[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)CCC>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]>[F:27][C:4]1[CH:3]=[C:2]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:13]2[CH2:17][CH2:16][C@@:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[O:18]3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4F)CC3)C2)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccncc5)cc4F)CC3)C2)c2ccccc21
Temperature: 120 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30 mg, 0.00007 mol, this compound was prepared by using a method that was analogous to that used for the synthesis of 238) in tetrahydrofuran (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.000003 mol), tri-tert-butylphosphine (1.7 mg, 0.0000083 mol), 4-(tributylstannyl)pyridine (30.7 mg, 0.0000835 mol), and the mixture was heated to 120° C. under microwave for 30 minutes. The reaction mixture was then filtered and the filtrate was diluted with methanol, and the product was isolated and purified by prep-HPLC. LC/MS (M+H+) 429.2.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:36][CH3:35])=[O:26])[CH2:22][CH2:23]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Yield: 54.5 %

Procedure:
A solution of 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxylic acid (Compound 244, 80 mg, 0.189 mmol), methylamine (33 μL, 0.378 mmol), EDCI (72 mg, 0.378 mmol), and HOBT (13 mg, 0.094 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 30-50% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a yellow oil (45 mg, 55%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.80-7.87 (m, 1H), 7.60 (d, 2H), 7.41 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.46 (d, J=12.1 Hz, 2H), 3.10 (td, J=12.3, 2.8 Hz, 2H), 2.59 (d, J=4.5 Hz, 3H), 1.71-1.90 (m, 4H), 1.44 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([CH3:26])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].N1C=CC=CC=1.[CH:42]([O:45][C:46](Cl)=[O:47])([CH3:44])[CH3:43]>ClCCl>[CH:42]([O:45][C:46]([N:14]1[CH2:15][CH2:16][CH2:17][CH:11]([N:7]([C:8](=[O:10])[CH3:9])[CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=2)[C:12]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([CH3:26])[C:13]1=2)=[O:47])([CH3:44])[CH3:43]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0210 g, 0.0410 mmol) and pyridine (0.0100 ml, 0.123 mmol) in dichloromethane (1.00 ml) was added 1M isopropylchloroformate (solution in toluene) (0.120 ml), 0.123 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvents were evaporated on a rotavapor (rotary evaporator). Purification by silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hexane) provided the titled compound (0.0180 g, 72%) as white crystalline. MS (ES+): 599 (M+H).
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:39]([O:42][CH2:43][CH2:44]Br)(=[O:41])[CH3:40]>C(Cl)(Cl)Cl.O.CN(C=O)C>[CH2:43]([O:42][C:39](=[O:41])[CH2:40][N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:21]([C:17]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[C:12]3=[N:19][C:18]=2[CH3:20])=[O:22])[CH2:25]1)[CH3:44]
Reactant: CC(=O)OCCBr
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)CN1CCC[C@H](NC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)C1
Reaction time: 3 h

Procedure:
To a suspension of 307 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride, 335 mg of potassium carbonate, 5 ml of acetonitrile, and 5 ml of DMF was added 92 μl of bromoethyl acetate under ice-cooling, followed by stirring for 3 hours under ice-cooling. To the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 299 mg of ethyl[(3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidin-1-yl]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[C:18]=3[O:24][CH3:25])[C:11]([CH3:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([OH:29])=[O:28].[OH-].[K+].C.Cl>C(O)C.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([O:24][CH3:25])=[C:19]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([C:27]([OH:29])=[O:28])[CH:35]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(NN=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)cccc1-c1cccc(C(=O)O)c1
Reaction time: 8 h

Procedure:
A mixture of 1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyrazolone (10 g) prepared as in Example 16, 3-carboxyphenylboronic acid (5.2 g), bis(triphenylphosphine)palladium(II)chloride [PdCl2(PPh3)2] (0.84 g), potassium hydroxide (6.72 g) in ethanol (200 mL) and water (15 mL) was heated to about reflux temperature under nitrogen atmosphere and stirred for about 8 hours. The reaction mixture was cooled to about 30° C. to about 35° C. and stirred for about 4 hours at about the same temperature. The reaction mixture was treated with Norit™ charcoal and filtered over celite bed. The filtrate was treated with EDTA and Scavenger Type 2S. The mixture was stirred at about 30° C. to about 40° C. for about 20 hours and filtered over celite bed. To the filtrate, hydrochloric acid was added to adjust the pH to about 3 to about 5. The mixture was stirred for about 2 hours at about 80° C. to about 85° C. The mixture was cooled to about 40° C. to about 45° C. and filtered. The wet cake was treated with potassium hydroxide in methanol and stirred to give a clear solution. The solution was treated with 50% tributylphosphene in ethyl acetate and stirred for about 20 hours at about room temperature. The pH of the solution was adjusted to about 2 to about 4 using hydrochloric acid and the solid obtained was filtered and purified using tetrahydrofuran. Yield: 9.3 g
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])/[CH:13]=[CH:14]\[C:15](OC)=[O:16])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:13]2[CH2:14][C:15](=[O:16])[NH:3][NH:2]2)=[O:19])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1
Reactant: NN
Reactant: COC(=O)/C=C\C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1
Solvent: CCO
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Reaction time: 5.5 h
Yield: 52 %

Procedure:
3.58 g of hydrazine monohydrate was dropwise added to a mixed liquid comprising 25 g of methyl 4-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylamino)-4-oxoisocrotonate and 250 ml of ethanol, followed by reflux with heating. After stirring for 5.5 hours, the reaction liquid was stood to cool. The precipitated crystals were subjected to suction filtration. The crystals collected after the filtration were washed with ethyl acetate and then with hexane and air dried to obtain 13 g of the desired product.