Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19][CH2:18][CH:17]2[CH2:24]O)=[O:15])[CH:5]=[CH:6][CH:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19][CH2:18][CH:17]2[CH2:24][N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC1CCC(CO)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1
Reactant: O=C1NC(=O)c2ccccc21
Product: COC1CCC(CN2C(=O)c3ccccc3C2=O)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1

Procedure:
2-((1-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidin-2-yl)methyl)isoindoline-1,3-dione was prepared according to general procedure I using (5-(3-fluorophenyl)-2-methylthiazol-4-yl)(2-(hydroxymethyl)-5-methoxypiperidin-1-yl)methanone and phthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:20]=[O:21]
Reactant: Clc1ccnc(Br)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Br
Temperature: -70 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (1.6 g, 8.0 mmol) in anhydrous tetrahydrofuran (40 mL) cooled at −70° C. was added the solution of lithium diisopropyl-amide (5.0 mL, 10.0 mmol, 2.0 M) over a period of 5 minutes and stirred at −70° C. for another 1 h. Anhydrous DMF (1.3 g) was introduced over a period of 3 minutes and the mixture was stirred for another 30 minutes. It was then quenched with saturated NH4Cl (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (20:1) to afford 103a as a yellow solid (900 mg, 48%). 1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 7.79 (d, J=5.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[OH:10])[CH:5]=[CH:4][N:3]=1>C(N)(C)C>[Cl:16][C:13]1[S:12][C:11]([C:9](=[O:10])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:7][CH:6]([CH3:8])[CH3:5])[N:7]=2)=[CH:15][CH:14]=1
Reactant: OC(Cc1ccnc(Cl)n1)c1ccc(Cl)s1
Solvent: CC(C)N
Product: CC(C)Nc1nccc(CC(=O)c2ccc(Cl)s2)n1
Temperature: 110 °C
Reaction time: 1.17 h
Yield: 196.8 %

Procedure:
A mixture of 2-(2-chloropyrimidin-4-yl)-1-(5-chloro-2-thienyl)ethanol (1 eq, 14.6 mmol) in 20 mL of isopropylamine was stirred at 110° C. in the microwave for 70 min. The solvent was evaporated and HCl 1M was added until pH=1. The resulting white precipitate was filtered and dried to afford 4.25 g of 1-(5-chloro-2-thienyl)-2-[2-(isopropylamino)pyrimidin-4-yl]ethanone (98% yield).
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C>[CH3:13][C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:7][N:6]2[C:8]([CH:11]=[O:12])=[CH:9][N:10]=[C:5]2[CH:4]=1
Reactant: Cc1cc2ncc(C=O)n2cc1Br
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2ncc(C=O)n2cc1-c1cccnc1
Yield: 62 %

Procedure:
6-bromo-7-methylimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1, 2000 mg, 7.90 mmol), Pyridine-3-boronic acid (1170 mg, 9.49 mmol), dichlorobis (triphenylphosphine) palladium (II) (200 mg, 10% mmol) and 2M aqueous Na2CO3 (7 mL) were added to DMF (25 mL) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 62%; 1H NMR (DMSO-d6; 300 MHz): δ 9.92 (s, 1H), 9.20 (s, 1H), 8.69-8.70 (m, 2H), 8.54 (s, 1H), 7.95-7.99 (m, 1H), 7.90 (s, 1H), 7.53-7.58 (m, 1H), 2.34 (s, 3H); MS: m/z 238 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cc1cc(=O)[nH]c(C)n1
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(C)n1
Yield: 28 %

Procedure:
The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g, 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) in the presence of a base K2C3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[Cl:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2Cl)C(=O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1

Procedure:
A solution of product from step D (2.75 g, 8.48 mmol), tert-butyldiphenylchlorosilane (2.20 mL, 8.48 mmol), and imidazole (860 mg, 12.7 mmol) in DMF (50 mL) was stirred at 60° C. for 15 hours. The reaction was poured into EtOAc (200 ml) and washed with H2O (3×100 ml). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-30% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19](C)[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24](O)(=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:24](=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:12][CH2:11]2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: O=C(O)CCCC(=O)O
Product: O=C(O)CCCC(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and glutaric acid
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12]C2C=CC=CC=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.Cl.[NH3:21]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]([C:4]2[C:3]([NH2:12])=[C:2]([CH3:1])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[CH:9]3)[C:3]=1[NH2:21]
Reactant: Cc1cc2ccccc2cc1Nc1ccccc1
Reactant: N
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc2ccccc2c(-c2c(N)c(C)cc3ccccc23)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
At 50° C., 3.1 g (20 mmol) of 3-methyl-2-naphthylamline, 6.5 g (40 mmol) of FeCl3 and 80 mL of H2O were stirred for 2 hours. To the reaction mixture was added 2 mL of concentrated hydrochloric acid at room temperature. The mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added 20 mL of methylene chloride and 20 mL of a saturated aqueous ammonia solution. After vigorous stirring at room temperature, the reaction mixture was filtered over Celite and the filtrate was washed with methylene chloride. The organic layer was concentrated by distilling off the solvent under reduced pressure. The residue was purified by Florisil (trade name) and then by chromatography on a silica gel column (hexane/ethyl acetate=4/1 to 3/1). By recrystallization from hexane-chloroform, 0.76 g (yield: 24%) of 3,3′-dimethyl-1,1′-binaphthyl-2,2′-diamine was obtained.
Reaction SMILES: [N:1]1[C:6]2[O:7][CH2:8][C:9](=O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH3:11][O:12][NH2:13].CC([O-])=O.[Na+]>CCO>[CH3:11][O:12][N:13]=[C:9]1[C:5]2[CH:4]=[CH:3][N:2]=[N:1][C:6]=2[O:7][CH2:8]1
Reactant: CON
Reactant: O=C1COc2nnccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C1COc2nnccc21
Temperature: 30 °C

Procedure:
To a solution of furo[2,3-c]pyridazin-5(6H)-one (4.81 mmol) in 30 mL EtOH were added O-methyl-hydroxylamine (9.62 mmol) and NaOAc (9.62 mmol). After heating to 30° C. for 4.5 h the reaction mixture was concentrated in vacuo to half of its volume. Water and DCM were added and the aqueous phase was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as beige solid;
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:3]4[N:4]([CH3:7])[N:5]=[CH:6][C:2]=4[Cl:1])=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cn1ncc(Cl)c1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A dry 25 mL flask was charged with 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid (0.139 g, 0.873 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The tan solids were filtered and washed with ˜3 mL of THF to afford the pure 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.264 g, 0.667 mmol, 84%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[F:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]([CH2:41][CH2:42][NH2:43])=[CH:37][NH:38]2)=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:43][CH2:42][CH2:41][C:36]3[C:35]4[C:39](=[CH:40][C:32]([F:31])=[CH:33][CH:34]=4)[NH:38][CH:37]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3c[nH]c4cc(F)ccc34)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(6-Fluoro-1H-indol-3-yl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.8 (d, 1H) 7.5 (m, 4H) 7.3 (m, 1H) 6.8 (m, 2H) 4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 2H) 3.3 (m, 2H) 3.1 (m, 1H) 2.8 (m, 5H) 1.7 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19][N:20]([C:22]1[CH:27]=[N:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=1)[CH3:21])=[CH:14]2)C1C=CC=CC=1.C(O)C>[C].[Pd].C(OCC)(=O)C>[C:28]1([C:25]2[N:26]=[CH:27][C:22]([N:20]([CH2:19][CH:13]3[CH2:12][CH2:11][C:10]4[C:15](=[CH:16][CH:17]=[CH:18][C:9]=4[OH:8])[CH2:14]3)[CH3:21])=[N:23][C:24]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(CC1=Cc2cccc(OCc3ccccc3)c2CC1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CC1CCc2c(O)cccc2C1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 31 h
Yield: 66.9 %

Procedure:
To 800 mg of 5-(benzyloxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3,4-dihydronaphthalene, 18 ml of ethanol, 15 ml of ethyl acetate and 80 mg of 10% palladium-carbon were added and, after the mixture was hydrogenated under 3 atm at room temperature for 31 hours, the reaction was continued at 30° C. for 23 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 443 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:72])[CH3:2].C1C=CN=CC=1.F>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of the product from Step A (29 mg) in THF (400 μl) was added hydrogen fluoride/pyridine and the reaction mixture stirred at room temperature for 24 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 70% hexane:30% ethyl acetate to give the title compound (11 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH:12]=[CH:11]2.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@@H:33]([NH2:38])[CH2:32][CH2:31]3)[CH2:23][CH2:22]1>CN1C(=O)CCC1>[CH3:19][O:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@@H:33]([N:38]2[CH:12]=[CH:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]5[CH2:3][CH2:4][CH2:5][O:1]5)[CH:9]=4)[C:14]2=[O:18])[CH2:32][CH2:31]3)[CH2:25][CH2:26]1
Reactant: COC1CCN(Cc2ccc3c(c2)CC[C@H](N)C3)CC1
Reactant: O=c1occc2cc(OC[C@@H]3CCCO3)ccc12
Solvent: CN1CCCC1=O
Product: COC1CCN(Cc2ccc3c(c2)CC[C@H](n2ccc4cc(OC[C@@H]5CCCO5)ccc4c2=O)C3)CC1
Temperature: 220 °C

Procedure:
A mixture of 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]isochromen-1-one (50 mg), NMP (0.2 ml) and (S)-6-(4-methoxypiperidin-1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-2-ylamine (55 mg) was heated to 220° C. in a microwave reactor for 3×30 minutes. The cooled reaction mixture was purified by preparative HPLC. The product was thus obtained with the molecular weight of 502.66 (C31H38N2O4); MS (ESI): 503 (M+H+).
Reaction SMILES: C=O.[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:28])[N:17]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:18]4=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:5]=1.[CH3:29]C([O-])=O.[Na+]>CC(O)=O.O>[CH2:29]=[C:22]1[C:18]2=[N:19][C:20]3[C:15]([C:16](=[O:28])[N:17]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:14][CH:13]=[C:12]([C:10]([NH:9][C:7]1[S:8][C:4]([CH3:3])=[CH:5][N:6]=1)=[O:11])[CH:21]=3
Reactant: Cc1cnc(NC(=O)c2ccc3c(=O)n4c(nc3c2)CCCCCC4)s1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=C1CCCCCn2c1nc1cc(C(=O)Nc3ncc(C)s3)ccc1c2=O
Yield: 144 %

Procedure:
Paraformaldehyde (10 mg), N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide (60 mg, 0.16 mmol) and NaOAc (3 mg, 0.0365 mmol) in 5 mL HOAc was stirred at 120° C. overnight in a sealed tube. The completion was monitored by TLC and LC-MS. The sealed tube was then placed in water until cool. The suspension was diluted with water (30 mL) and adjusted pH to 8, then extracted with ethyl acetate (3×50 mL). The organic phase was concentrated to give crude product and 20 mg of the desired product was obtained by column chromatography. MS (ESI): 381 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.45-8.42 (d, J=8.22 Hz, 1H), 8.27 (s, 1H), 8.04-8.00 (dd, J=8.39, 1.61 Hz, 1H), 7.28 (s, 2H), 5.52 (s, 1H), 5.30 (s, 1H), 4.39-4.33 (m, 2H). 2.72-2.59 (m, 2H), 2.42 (s, 3H), 1.96-1.88 (m, 2H), 1.72-1.68 (m, 2H), 1.56-1.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:12]=3[F:28])=[CH:6][N:5]2[CH:29]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.O.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:30]1([C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:13][C:12]=4[F:28])=[CH:6][N:5]3[CH:29]=2)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of benzyl {4-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-3-fluorophenyl}carbamate (10.0 g, 25.5 mmol) in N,N-dimethylacetamide (100 mL) was added cyclopropanecarbonyl chloride (2.77 mL, 30.6 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (9.2 g, 78%) as a thin-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]([CH:12]([CH3:14])[CH3:13])=[CH:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)C(=CO)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 70.9 %

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-(1-methylethyl)-propenol (2.0 g, 6.9 mmol) and pyridinium chlorochromate (3 g) in 100 mL dichloromethane was stirred for 20 hrs. during which time a dark gummy solid separated. The solvent was decanted from the solid and concentrated in vacuo. The residue was extracted with hexane and the hexane solution concentrated in vacuo. The residue was crystallized from petroleum ether to give 1.4 g of the title compound; m.p. =78°-84° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1)[S:9]([NH:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C.O>[C:38]1([NH:44][C:45](=[O:46])[O:37][CH2:36][CH:33]2[CH2:32][CH2:31][CH:30]([CH2:29][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:9]([NH:12][C:13](=[O:28])[C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:15]=3)(=[O:11])=[O:10])[CH2:35][CH2:34]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(CO)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Intermediate (4) (80 mg, 140 μmole, 1.0 eq) was dissolved in acetonitrile (10 mL) and phenyl isocyanate (18 μL, 168 μmole, 1.2 eq) was added. The mixture was refluxed for 24 hours, then diluted with water and extracted repeatedly with dichloromethane. Reconstituted in dichloromethane, filtered off precipitate and purified material isolated from filtrate by RP-HPLC to give title compound. 1H NMR (400 MHz, MeOH-d4): δ 0-75-9.0 (m, 4H), 1.38-1.60 (m, 2H), 1.68-1.84 (m, 4H), 3.21 (d, 2H, J=8 Hz), 3.86 (d, 2H, J=8 Hz), 4.51 (s, 2H), 7.0 (t, 1H, J=8 Hz) 7.17-7.30 (mult, 5H), 7.33-7.7.45 (mult, 4H), 8.11 (s, 1H), 8.42 (s, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][Cl:8])=[O:3].[NH2:9][C:10]1[N:42]=[C:13]2[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[C:15]([CH3:31])[C:16]([C:18]3[N:22]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[CH:17][N:12]2[N:11]=1.N1C=CC=CC=1>C1COCC1>[Cl:8][CH2:7][CH2:6][CH2:5][O:4][C:2](=[O:3])[NH:9][C:10]1[N:42]=[C:13]2[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=3)=[C:15]([CH3:31])[C:16]([C:18]3[N:22]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[CH:17][N:12]2[N:11]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)OCCCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)OCCCCl)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
3-Chloropropyl chloroformate (133 μL, 1.089 mmol) was added to a mixture of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and pyridine (107 μL, 1.308 mmol) in THF (3 mL) and the mixture was stirred rapidly for 20 mins at RT then heated at 60° C. 20 mins using microwave irradiation. The reaction mixture was concentrated in vacuo to give the title compound (125 mg of impure product contains chloroformate).