Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[N:18]=[C:19]([CH3:22])[S:20][CH:21]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[CH:29]1([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:17]4[N:18]=[C:19]([CH3:22])[S:20][CH:21]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1nc(-c2nn3ccccc3c2-c2ccnc(F)c2)cs1
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 3-(2-fluoro-4-pyridinyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine (220 mg, 0.71 mmol) and potassium carbonate (98 mg, 0.71 mmol) in cyclopentylamine (5 mL) was heated at 100° C. for 12 days. After cooling to room temperature, the solution was diluted with ethyl acetate and the organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (1:9 methanol/chloroform) gave N-cyclopentyl-4-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine (265 mg, 100%) as an oil. 1H NMR (CDCl3): δ 8.49 (d, 1H), 8.04 (d, 1H), 7.49 (d, 1H), 7.08 (t, 1H), 6.74 (t, 1H), 6.59 (d, 1H), 6.43 (s, 1H), 5.44 (d, 1H), 3.79 (m, 1H), 2.73 (s, 3H), 1.92–1.42 (m, 8H). MS m/z 376 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][N:28]=[C:27]([CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][N:28]=[C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nc(C3CCNCC3)no2)N1OCc1ccccc1
Reaction time: 2 h
Yield: 143.4 %

Procedure:
CF3COOH (4 mL) was added to the solution of tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (960 mg, 2.0 mmol) in 16 mL of CH2Cl2 at 0° C. The mixture was stiffed at 0° C. for 2 hrs, then concentrated to give (2S,5R)-6-(benzyloxy)-2-(3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.1 g) as a brown oil, which was used directly in the next step. ESI-MS (EI+, m/z): 384.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]1([CH:26]2[CH2:31][CH2:30][CH2:29][N:28](Cl)[CH2:27]2)[CH:25]=[CH:24][N:23]=[N:22]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH2:31][CH:26]([N:21]5[CH:25]=[CH:24][N:23]=[N:22]5)[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: ClN1CCCC(n2ccnn2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCCC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 66.9 %

Procedure:
To a suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.18 mmol) and 3-(1,2,3-triazol-1-yl)piperidine-1-yl hydrochloride (83 mg, 0.44 mmol) in 3 ml of acetonitrile was added 67 mg (0.44 mmol) of DBU. The solution was heated at reflux under nitrogen for 16 hrs. The suspension was cooled and the solid collected, washed with water, dried to yield 50 mg of the title product, m.p. 239°-240° C. 1H NMR (TFA) δ: 9.35 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.16 (d, J=10.6Hz, 1H), 5.45-5.15 (m, 1H), 4.7-3.55 (m, 5H), 2.85-2.05 (m, 4H), 1.8-1.3 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1.[CH:19]12[CH:24]([C:25](O)=[O:26])[CH:23]1[CH2:22][O:21][CH2:20]2>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:25]([CH:24]3[CH:23]4[CH:19]3[CH2:20][O:21][CH2:22]4)=[O:26])[N:14]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)C1C2COCC21
Product: Cc1ccncc1-c1ccc2cc(NC(=O)C3C4COCC43)ncc2c1

Procedure:
The title compound was prepared following a procedure similar to example 98 using 7-(4-methylpyridin-3-yl)isoquinolin-3-amine and 3-oxabicyclo[3.1.0]hexane-6-carboxylic acid.
Reaction SMILES: [CH:1]1CCCCC=1.[O:7]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[C:9]([C:16]2[NH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=2)=[N:8]1>>[CH3:1][N:17]1[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=[C:16]1[C:9]1[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[O:7][N:8]=1
Reactant: O=[N+]([O-])c1cnc(C2=NOC3CCCCC23)[nH]1
Reactant: C1=CCCCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=NOC2CCCCC12

Procedure:
Following the same procedure as in Example 30, the hydroxamoylchloride prepared as in Example 7 is reacted with cyclohexene. The product, 2-(3a,4,5,6,7,7a-hexahydro-1,2-benz-isoxazol-3-yl)-5-nitroimidazole has a melting point of 119°-121° C.
Reaction SMILES: COC1C=CC(C=O)=CC=1.Cl[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C)[C:16](=[O:22])[CH2:15]2.N1CCCC1>CO>[N:17]1[C:16](=[O:22])[CH:15]=[C:14]2[C:18]=1[CH:19]=[CH:20][CH:12]=[CH:13]2
Reactant: CN1C(=O)Cc2cc(Cl)ccc21
Agent: COc1ccc(C=O)cc1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1C=c2ccccc2=N1
Temperature: 25 °C
Yield: 11 %

Procedure:
3-(exo-Bicyclo 2.2.1!hept-2-yloxy)-4-methoxybenzaldehyde (677 mg, 2.75 mmol; disclosed in WO 87/06576 published Nov. 5, 1987), and 5-chloro-1-methyloxindole (500 mg, 2.75 mmol; Chemical Abstracts registry number 41192-33-0, were dissolved in 10 ml of methanol under an inert atmosphere. To this brown, homogeneous mixture was added 0.23 ml of pyrrolidine (2.75 mmol) via syringe. The reaction mixture was stirred at room temperature for ten hours. The solvent was then stripped off and the resulting yellow oil was purified via flash chromatography (1:1 ethyl ether/hexane) to provide the desired Z-adduct 3- 3-(bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-chloro-1,3-dihydro-1-methyl- 1α,2α(Z),4α!-2H-indol-2-one (125 mg, 11% yield) as a yellow solid (Example 1): m.p. 149°-151°. Analysis calculated for C24H24ClNO3 : C, 70.32; H, 5.90; N, 3.42. Found: C, 70.26; H, 5.87; N, 3.38. The corresponding E-adduct 3- 3-(bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-chloro-1,3-dihydro-1-methyl- 1α,2α(E),4α!-2H-indol-2-one (Example 2) was also obtained in 6% yield, m.p. 142°-144° C. Analysis calculated for C24H24ClNO3 : C, 70.32; H, 5.90; N, 3.42. Found: C, 70.34; H, 5.85; N, 3.36.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[CH3:20][C:18]1[CH:19]=[C:14]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:3][N:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: c1cc2c(cn1)CNCC2
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCc3ccncc3C2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 45.7 %

Procedure:
A mixture of commercially available 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (207 mg, 1.0 mmol), 5-fluoro-2-nitrotoluene (0.244 mL, 2.0 mmol), and Na2CO3 (0.53 g, 5.0 mmol) in 3.0 mL NMP was heated at 110° C. for 2.5 hours. The solids were filtered off and then rinsed with EtOAc. The EtOAc portion was washed with a H2O/brine mixture, H2O, brine, dried with anhydrous Na2SO4, and evaporated to an oil. The oil was chromatographed eluting with CHCl3/EtOAc and the resulting solid triturated with EtOAc/hexane to give the title compound as a yellow solid (123 mg, 45%). 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.44 (d, J=5.3 Hz, 1H), 8.14 (d, J=9.1 Hz, 1H), 7.15 (d, J=5.0 Hz, 1H), 6.76 (dd, J=9.2, 2.8 Hz, 1H), 6.68 (d, J=2.9 Hz, 1H), 4.58 (s, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.01 (t, J=5.9 Hz, 2H), 2.68 (s, 3H)
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:16][CH2:15][C:14]4[C:10](=[CH:11][N:12]([CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[N:13]=4)[C:9]=3[S:26][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[NH2:31].Cl.O1CCOCC1>C(O)(C)C>[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[N:3]=[CH:4][N:5]=[C:6]3[S:26][C:9]4[C:10]5[C:14]([CH2:15][CH2:16][C:8]=4[C:7]=23)=[N:13][N:12]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:11]=5)[CH:32]=[CH:33][C:34]=1[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Cl)c23)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(N5CCOCC5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-2-[2-(4-methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazole (50 mg, 0.13 mmol) and 3-chloro-4-morpholinoaniline (82 mg, 0.39 mmol) in isopropanol (3 mL) was added HCl in dioxane (4M, 0.26 mL, 1.03 mmol). The reaction mixture was sealed in a microwave reaction vessel and it was placed in a microwave instrument at 160° C. for 10 min. After it was cooled to room temperature, solvents were evaporated and the residue was dissolved in water/DMF and purified by prep. HPLC. After drying, the TFA salt was neutralized with aq saturated NaHCO3 and extracted with a mixture of CHCl3:isopropanol (3:1). The organic phase was dried over Na2SO4 and concentrated to dryness. The desired product was obtained as a pale solid (40 mg, 55%). 1H-NMR (CD2Cl2) δ 8.43 (s, 1H), 7.84 (d, 1H), 7.53 (m, 2H), 7.08 (m, 2H), 4.20 (t, 2H), 3.86 (m, 4H), 3.37 (t, 2H), 3.11 (t, 2H), 3.04 (m, 4H), 2.80 (t, 2H), 2.53 (m, 4H), 2.43 (m, 4H), 2.26 (s, 3H); LCMS RT=2.29 min; [M+H]+=565.4.
Reaction SMILES: [N:1]1C(Cl)=NC(Cl)=N[C:2]=1Cl.CN.O.C(=O)([O-])O.[K+].[CH3:18][NH:19][C:20]1[N:25]=[C:24]([NH:26][CH3:27])[N:23]=[C:22](Cl)[N:21]=1>C(#N)C>[CH3:18][NH:19][C:20]1[N:25]=[C:24]([NH:26][CH3:27])[N:23]=[C:22]([NH:1][CH3:2])[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNc1nc(Cl)nc(NC)n1
Agent: CN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNc1nc(NC)nc(NC)n1
Temperature: 0 °C
Yield: 78 %

Procedure:
After 18.5 g (0.1 mol) of cyanuric chloride was dissolved into 150 ml of acetonitrile, the resulting mixture was cooled to 0° C. and 15.5 g (0.2 mol) of 40% aqueous solution of methylamine was added dropwise in 1 hour thereto under stirring in such a manner that the reaction temperature did not exceed 5° C. While further stirring, 100 ml of water including 20.0 g (0.2 mol) of potassium hydrogencarbonate was added dropwise at the same temperature. Thereafter, the reaction temperature was gradually raised, and stirred at 45° C. for 8 hours. After confirming that an inversion to 2.4-bis(methylamino)-6-chloro-1,3,5-triazine was completed, the reaction solution was cooled and products were filtered off. The filter cake was fully washed with water, and then the resulting 2,4-bis(methylamino)-6-chloro-1,3,5-triazine was suspended into 100 ml of water, and 31.1 g (0.4 mol) of 40% aqueous solution of methylamine was added, and further heated under reflux for 6 hours. After cooling, the deposited crystal was filtered, washed fully with water and dried to give 13.1 g (yield: 78%) of the titled compound. Melting point 133° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Reactant: CC#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 246 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 119 mg of 3-pentyn-2-ol, to which 57 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 200 mg of 4-(3-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (173)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][OH:20])=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([OH:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:19][OH:20])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(CCCl)ccc1O
Reactant: OCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cc(CCN2CCC(c3nc(CO)c(-c4ccc(F)cc4)o3)CC2)ccc1O
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A solution of [5-(4-fluoro-phenyl)-2-piperidin-4-yl-oxazol-4-yl]methanol (0.20 g; 0.72 mmol) in dry dioxane (6 ml) is treated with 5-(2-chloroethyl)-2-hydroxy-benzenesulfonamide (0.36 g; 1.45 mmol), sodium iodide (0.22 g; 1.45 mmol) and diisopropylethylamine (0.50 ml; 2.88 mmol) and heated to 100 C. for 16 hours. The reaction is cooled and partitioned between ethyl acetate (30 ml) and water (10 ml). The aqueous phase is washed with ethyl acetate (2×15 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography using a methanol/ethyl acetate gradient (5%-40%) is followed by a second chromatography using a methanol/dichloromethane gradient (5%-30%). Crystallization from methanol/ethyl acetate afforded the product as a white solid (0.055 g; 16%). HNMR (CD3OD): 7.75 (m, 2H), 7.64 (d, 1H, J=2.1 Hz), 7.31 (dd, 1H, J=8.4; 2.1 Hz), 7.23 (t, 2H, J=8.8 Hz), 6.92 (d, 1H, J=8.4 Hz), 4.63 (s, 2H), 3.12 (m, 2H), 2.96 (m, 1H), 2.82 (m, 2H), 2.66 (m, 2H), 2.34 (m, 2H), 2.17 (m, 2H), 1.99 (m, 2H). Mass spectrum: m/e calculated (MH+)=476.6; observed (MH+)=476.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:16]=[N:15][N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CN(C)CCCl
Reactant: Clc1cc2c(-c3cn[nH]c3)cccc2cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2cccc3cnc(Cl)cc23)cn1
Temperature: 190 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 28 mg, 0.122 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (35.1 mg, 0.244 mmol) and K2CO3 (50.5 mg, 0.366 mmol) in DMF (4 mL) was stirred at 190° C. under microwave irradiation for 90 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])(C)(C)C.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCC>[C:11]([O:10][C:9]([NH:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:21]([OH:23])=[O:22])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-fluorophenylcarbamate (44.0 g, 208 mmol) in tetrahydrofuran (660 mL) at −78° C. was added tert-butyllithium in pentane (1.7 M, 306 mL, 2.5 equivx) dropwise. After addition was complete, the reaction was stirred at −78° C. for 30 min. The solution was allowed to gradually reach −20° C. before being recooled to −78° C. and transferred via canula to a slurry of carbon dioxide (excess) and tetrahydrofuran (500 mL). The solution was allowed to slowly warm to room temperature. The reaction mixture was concentrated to remove most of the tetrahydrofuran, and poured into a sep funnel containing water and diethyl ether. The layers were separated, and the aqueous extracted with diethyl ether twice more. The ethereals were discarded. The aqueous was acidified with 5% citric acid, extracted with diethyl ether (3×). The ethereal was dried over magnesium sulfate, and concentrated to give a light yellow solid which was recrystallized from hot toluene to give 37.1 g (70%) as a faint yellow solid.
Reaction SMILES: [C:1]([N:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:10]1=[CH:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:29][C@H:17]1[CH2:16][CH2:15][C@H:14]2[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:28])[C:10]([N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26](=[O:27])[CH2:25][CH2:24]1)=[CH:11][CH2:12]3)[CH3:37]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the alcohol product from Step B, above and ethyl diazoacetate (0.5 ml) in methylene chloride (6.5 ml) was added rhodium diacetate dimer (15 mg) intermittently during 2 hours. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was purified via preparative TLC using two silica gel plates (2000μ) developed with 40% EtOAc in hexanes to afford the title compound (Rf =0.33).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19])[C:12]3([CH2:14][CH2:13]3)[CH2:11]2)=[N:3][CH:2]=1.[CH3:29][S:30]([CH2:33][CH2:34][CH2:35]O)(=[O:32])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(/N=N\C(=O)OC(C)C)=O)(C)C>C1COCC1.O>[CH3:29][S:30]([CH2:33][CH2:34][CH2:35][N:21]([S:18]([N:15]1[C:12]2([CH2:14][CH2:13]2)[CH2:11][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:17][CH2:16]1)(=[O:19])=[O:20])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)CCCO
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: CC(C)OC(=O)/N=N\C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Tert-butyl N—[[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octan-8-yl]sulfonyl]carbamate (Intermediate 53)(0.12 mmol) was dissolved in dry THF (1 mL) and added 3-methylsulfonylpropan-1-ol (0.13 mmol) and triphenylphosphine (0.15 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.15 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1ccc2ccccc2c1
Product: CCOC(=O)c1nc(-c2ccc3ccccc3c2)[nH]c1-c1ccc(C)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate(12.8 g) and 2-aminomethylnaphthalene (10.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(2-naphthyl)imidazole-4-carboxylate (4.8 9g). 0.5 g therefrom was dissolved in ethyl alcohol (10 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(2-naphthyl)imidazole-4-carboxylic acid (0.26 g), melting point 227° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH3:31])[C:17](=[O:27])[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C(=O)c2ccc([N+](=O)[O-])cc2)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of N-(2-benzyloxy-4-methylphenyl)-4-nitrobenzamide (4.7 g) in N,N-dimethylformamide (50 ml) was treated with sodium hydride (623 mg, 60% w/w in mineral oil) at 0° C. After 30 minutes, iodomethane (1.21 ml) was added, and the reaction mixture was stirred for 3 hours. The reaction was quenched with water and the mixture diluted with ethyl acetate. The organic phase was washed with water and brine. The organic solution was dried over magnesium sulfate and concentrated to give N-(2-benzyloxy-4-methylphenyl)-N-methyl-4-nitrobenzamide (4.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:11](=[O:13])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 73.7 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.252 g, 1.26 mmol) were, used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.40 (9H, s), 1.75 (2H, m), 2.82 (2H, m), 3.18 (2H, d), 3.92 (3H, m), 7.25 (5H, m), 7.54 (2H, d), 7.88 (4H, d), 38 (1H, brs).