Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:31])[N:25]([CH2:29][OH:30])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[C:33]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35][CH2:34]1.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4\[NH:27][C:26](=[O:28])[N:25]([CH2:29][O:30][C:33](=[O:40])[CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:24]\4=[O:31])=[C:11]3[N:10]=2)[CH:7]=1
Reactant: O=C1CCCC(=O)O1
Reactant: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCCC(=O)OCN1C(=O)N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione (100 mg, 0.218 mmol) in pyridine (4.5 mL) was added glutaric anhydride (125 mg, 1.095 mmol), and DMAP (3 mg, 0.022 mmol). The reaction mixture was stirred at 75° C. overnight after which the reaction was not complete. Added glutaric anhydride (125 mg, 1.095 mmol) and DMAP (3 mg, 0.022 mmol) and stirred an additional 16 hours at 75° C. Cooled to 0° C. in ice bath and added 6M HCl until pH was less than 3 by pH paper. Filtered off the solid and washed with 0.1M HCl. Dried under vacuum to provide 40 mg (32%) of (Z)-5-((4-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methoxy)-5-oxopentanoic acid as a yellow solid. LCMS (ES): >95% pure, m/z 572 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCN(Cc1ccco1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(CCC(=O)O)Cc1ccco1
Yield: 101.8 %

Procedure:
Ethyl 3-[(furan-2-ylmethyl) (ethoxycarbonyl)amino]-propionate (13.77 g) prepared in the step 3 was dissolved in 200 mL of methanol, 5.0 g of potassium hydroxide was added thereto and the mixture was heated to reflux for 3 hours. The solvent of the reaction solution was evaporated in vacuo and the residue was dissolved in methylene chloride. The resulting solution was slowly neutralized to pH 3 using 1N aqueous solution of hydrochloric acid (about 80 mL) with stirring. The organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo therefrom to give 12.56 g of the objective compound as yellow liquid.
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([CH2:6][OH:7])[NH:3][CH2:2]1.[Cl:8][CH2:9][CH:10]1[CH2:12]O1>>[Cl:8][CH2:9][CH:10]1[O:7][CH2:6][C@@H:4]2[CH2:5][S:1][CH2:2][N:3]2[CH2:12]1
Reactant: ClCC1CO1
Reactant: OC[C@@H]1CSCN1
Product: ClCC1CN2CSC[C@H]2CO1
Temperature: 25 °C
Yield: 2.4 %

Procedure:
A solution of (4R)-1,3-thiazolidin-4-ylmethanol (0.300 g, 2.52 mmol) in 2-(chloromethyl)oxirane (2.0 mL, 25.5 mmol) was heated under nitrogen to 40° C. for 12 h. The solution was then cooled to room temperature and 2-(chloromethyl)oxirane was removed in vacuo. The crude intermediate was cooled in ice, and was taken up in 2.0 mL of concentrated sulfuric acid. The resulting mixture was heated to 200° C. for 0.5 h then poured carefully onto wet ice, which was allowed to melt. The aqueous solution was carefully made basic using solid sodium bicarbonate and the resulting mixture was filtered using water and 10% methanol in ethyl acetate as eluent. The layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 11.6 mg (2.4% yield) of crude (8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine as a mixture of diastereomers which was directly taken on to the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:33])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(-c5ccncc5)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
10 mg (0.04 mmol) of {3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}amine (from example XLII) and 8.40 mg (0.04 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 1.5 ml of water. 5.6 μl of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline using saturated sodium carbonate solution and extracted three times with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=2)[C@H:18]([NH:29]C(OC(C)(C)C)=O)[CH2:17][C@@H:16]1[CH:37]1[CH2:39][CH2:38]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=2)[C@H:18]([NH2:29])[CH2:17][C@@H:16]1[CH:37]1[CH2:38][CH2:39]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N)C[C@@H]1C1CC1
Yield: 37.9 %

Procedure:
Trifluoroacetic acid (3.4 g) was added in portions to a solution of cis-4-tert-butoxycarbonylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (Example 107B) (3.4 g; 7.4 mmol) in 150 ml dichloromethane, and the reaction was stirred until no starting material was observed by thin-layer chromatography. A small amount of 1N NaOH was added and the reaction mixture was dried (MgSO4), filtered and concentrated. Chromatography on silica gel (50% ethyl acetate:hexane through 5% MeOH:dichloromethane) afforded the title product (1.0 g). 1H NMR (CDCl3) δ 1.5 (s, 9H), 1.7 (m, 1H), 2.5 (m, 1H), 4.1 (q, 1H), 7.6 (m, 3H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[CH:5]
Reactant: C[Si](C)(C)C#CC1(O)CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{(trimethylsilyl)ethynyl}tetrahydropyran-4-ol (1.0 g, 5.04 mmol) in THF (SnL), a 1 M solution of tetrabutyl ammonium fluoride in THF (5.29 mL, 5.29 mmol) was added and the reaction was stirred 2 hours at room temperature. The reaction mixture was then poured into an aqueous 5% NH4OAc solution and diluted with ethyl acetate. The isolated organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 4.61 (s, 1H), 3.87-3.77 (m, 2H), 3.60-3.50 (m, 2H), 2.98 (s, 1H), 1.89-1.81 (m, 2H), 1.77-1.65 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH3:21])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 83.8 %

Procedure:
A mixture of 8.0 g (0.026 mol) of product of Example 2, 3.6 g (0.026 mol) of potassium carbonate, 20 g of methyl iodide, and 50 ml of acetone was held at reflux for 6 hours and concentrated. The residue was treated with water and extracted with ether. The ether extract was washed once with 30 ml of 10% NaOH, dried, and concentrated. The residue was crystallized from hexane to give 6.91 g (82.5%) of product; mp 58.5°-59.5° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][CH:9]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH2:10][SH:11].C(NC(C)C)(C)C>>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:12][CH:9]1[O:8][C:4](=[O:5])[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10]1
Reactant: OC(CS)COc1cccc(Cl)c1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)NC(C)C
Product: O=C(O)CC1SCC(COc2cccc(Cl)c2)OC1=O

Procedure:
Analogously to Example 1, from maleic acid anhydride and 2-hydroxy-3-m-chlorophenoxypropane-1-thiol in the presence of diisopropylamine and the usual working up of the reaction mixture, 6-m-chlorophenoxymethyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained. It is separated into two isomers using chromatographic purification:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:44][CH2:43]1)=[O:16]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 68.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (483 mg, 1.26 mmol, 68%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:5]=1[CH3:19])(=[O:3])[CH3:2].Cl[C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][CH2:22][C:21]([C:8]1[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:19])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[C:7]=1[CH3:9])=[O:28]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(=O)CCC(=O)OC)c2C)cc1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) and methyl 4-chloro-4-oxobutyrate (0.56 mL, 4.5 mmol) reacted to give 4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]4-oxo-butyric acid methyl ester as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.06 (d, 2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.67 (s, 3H), 3.03 (t, 211), 2.74 (t, 2H), 2.41 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.45 (t, 3H); MS (ESI) 372 (M+H)+.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1(C2[O:26]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13]([CH3:14])=[O:26])[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][N:8]=3)[CH2:2][CH:3]([CH2:4]1)[CH2:5]2
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(NC23CC(C2)C3)ncc1C(N)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(NC23CC(C2)C3)ncc1C(N)=O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a stirring solution of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carboxamide (410 mg, 1.638 mmol) in chloroform (39.0 mL) was added portionwise, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (514 mg, 1.965 mmol). The resulting pale yellow solution was stirred at ambient temperature for two nights under nitrogen. The reaction mixture was concentrated under reduced pressure to give the crude product as a white solid. Ethyl acetate (15 mL) was added to these solids and the slurry was stirred at room temp for 1 h, filtered, washed with ethyl acetate, and dried in a vacuum oven for a few hours to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (397 mg, 1.491 mmol, 91% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67-9.14 (m, 2H), 7.93-8.11 (m, 1H), 7.41-7.54 (m, 1H), 2.68-2.79 (m, 3H), 2.43-2.48 (m, 1H), 2.02-2.21 (m, 6H). MS (ESI) m/z 267.0 [M+1]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.CN(C)C=O.[NH2:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:41]>ClCCl>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:41])=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCC[C@@H](C)N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC[C@@H](C)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg), 1-hydroxybenzotriazole (23.7 mg), JANDAJEL-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (289 mg) and N,N-dimethylformamide (1 mL) were mixed together and the mixture was stirred at room temperature for 3 hours. Subsequently, (2R)-2-aminoheptane (46.6 μL) was added and the mixture was stirred at room temperature for 17 hours and 40 minutes. This was followed by addition of dichloromethane (0.5 mL) and (2R)-2-aminoheptane (11.6 μL), stirring at room temperature for 4.5 hours, addition of JANDAJEL-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (96.6 mg) and additional stirring at room temperature for 17 hours. Subsequently, (isocyanatomethyl)polystyrene (232 mg) was added and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column (eluant:ethyl acetate:methanol=10:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[(2R)—N-(2-heptyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (9.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([S:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[S:27][C:26]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[N:25][C:24]=4[CH3:34])=[O:22])[CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:34])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2cnc3cc(Cl)ccc3c2O)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2cnc3cc(Cl)ccc3c2Cl)CC1

Procedure:
A suspension of 1-(7-chloro-4-hydroxyquinoline-3-sulfonyl)-4-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]-piperazine (200 mg) in phosphoryl chloride (6 ml) was refluxed for 2 hours. The reaction mixture was concentrated, and ice water was added to the residue. To the mixture was added an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The extract was dried and concentrated to give brown crystals of the title compound (223 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]3)=[CH:32][CH:31]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 323 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(4-hydroxypiperidino)benzoate. [M+H]+ calcd for C37H39N4O5: 619.29; found: 619.10.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.0509 g, 0.000209 mol) was dissolved in tetrahydrofuran (3.00 mL, 0.0370 mol) in a capped 40 mL EPA vial equipped with a magnetic stir bar. Cis-4-tert-butylcyclohexanol (0.0392 g, 0.000251 mol) was added, followed by triphenylphosphine (0.0878 g, 0.000335 mol) and the reaction was heated to reflux. Diisopropyl azodicarboxylate (0.0659 mL, 0.000335 mol) was added and the reaction was heated at reflux overnight with stirring. TLC analysis showed that the reaction was complete. The mixture was concentrated under vacuum. The resulting product was purified by flash chromatography (0-30% EtOAc in methylene chloride) to give 0.3141 g of the title compound (66% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][NH:24][NH2:25]>CO>[CH3:1][O:2][C:3]([C:5]1[N:25]([NH:24][CH3:23])[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: CNN
Reactant: COC(=O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Solvent: CO
Product: CNn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 6-chloro-4-phenylisocoumarin-3-carboxylic acid methyl ester (1.3 g) in methanol (15 ml) was added methylhydrazine (3.0 g) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was dissolved in methanol (15 ml). Sulfuric acid (1.5 ml) was added and the mixture was refluxed for 2 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) and crystallized from isopropyl ether to give the title compound (980 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](Br)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br
Agent: CN
Product: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2N1CCOCC1

Procedure:
By substituting the product of Example 11 in the procedure of Example 5 and substituting morpholine for the methylamine, 1-benzyl-4-(morpholino)-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[K+].O.Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)Cc1ccccc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccccc1Br)C(=O)O
Yield: 64 %

Procedure:
65.5 g of ethyl 3-(2-bromophenyl)-2-methylpropionate (243 mmole) and 20.5 g of potassium hydroxide (364 mmole) were dissolved in 250 ml of ethanol and heated under reflux for 6 hours, and 500 ml of water was added. After 50 ml of concentrated hydrochloric acid was added, and the product was then extracted with toluene, dried and concentrated to give 37.8 g of 3-(2-bromophenyl)-2-methylpropionic acid as a yellow oil (yield, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:28]([CH:24]1[C:25]([CH3:27])([CH3:26])[C:23]1([CH3:31])[CH3:22])=[O:29])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cccc(OCc4ccccc4)c23)C1(C)C
Yield: 33.3 %

Procedure:
A mixture of 4-benzyloxyindole (1.1 g, 4.8 mmol), ethylmagnesium bromide (1.0 M solution in THF, 5.2 mL, 5.2 mmol), zinc chloride (1.0 M solution in Et2O, 5.2 mL, 5.2 mmol) and the product of Example 1A (4.8 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.56 g, 1.6 mmol, 34% yield). MS (DCI/NH3) m/z 348 (M+H)+.