Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[F:34][C:35]1[CH:36]=[N:37][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[N:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=3)[CH2:42][CH2:43]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.023 g (44%). 1H NMR (400 MHz, CD3OD): δ 8.59 (d, J=0.4 Hz, 2H), 7.98-7.94 (m, 2H), 7.87 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.18 (s, 1H), 4.09 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.79-1.76 (m, 2H), 1.52-1.48 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.62 (TFA), −112.36, −122.73, −145.58 LCMS: (ES+) m/z=587.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:30]([F:33])([F:32])[F:31])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[C:17]4[CH2:27][CH2:28][CH2:29][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.[F:43][CH2:44][CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:43][CH2:44][CH2:45][NH:46][C:24]([CH2:23][NH:22][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)([C:30]([F:31])([F:32])[F:33])[O:14][N:13]=2)=[C:16]2[CH2:29][CH2:28][CH2:27][C:17]=12)=[O:21])=[O:26]
Reactant: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Reactant: NCCF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of compound ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid (100 mg, 0.19 mmol) in acetonitrile (5 mL) is added N,N-diisopropylethylamine (49.3 mg, 0.38 mmol), 2-fluoro-ethylamine (14.4 mg, 0.23 mmol) and HATU (108.8 mg, 0.29 mmol), after finished the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (100 mg, 92%). MS (m/z): 570.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:20](OCC)[CH:21]([CH3:29])[CH:22](OCC)OCC)C>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[CH:22]=[C:21]([CH3:29])[CH:20]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc2c3c(nn2c1)CN(C(=O)OC(C)(C)C)C3
Temperature: 50 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (5 g; 22.3 mmol; 1 eq.) and 1,1,3,3-tetraethoxy-2-methylpropane (4.32 mL; 22.3 mmol; 1 eq.) in AcOH (50 mL) was stirred at 50° C. for 20 hours then diluted with water (250 mL). The precipitate was filtered off and dried to afford the title compound (3.5 g, 57%) as a pale beige solid. 1H NMR (DMSO-d6) δ 8.98-8.95 (m, 1H), 8.43 (d, J=2.1 Hz, 1H), 4.61-4.54 (m, 4H), 2.31 (s, 3H), 1.47 (s, 9H). HPLC (max plot) 99.7%; Rt 3.27 min. UPLC/MS: (MS+) 275.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[C:34]([F:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[C:34]([F:43])=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-2-fluorobenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6](=[O:9])[CH2:7][Cl:8])=O.[CH2:10]([O:17][C@@H:18]1[C@@H](CO)[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:17][C@@H:18]1[C@@H:2]([CH2:3][O:5][C:6](=[O:9])[CH2:7][Cl:8])[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Solvent: c1ccncc1
Product: O=C(CCl)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 45 %

Procedure:
Chloroacetic anhydride was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at room temperature overnight. Then the same subsequent procedures as in Reference Example 54 were conducted, giving 0.11 g of the title compound as an oil in a yield of 45%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][CH2:36][C:37]#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:36]([CH2:37][NH:38][C:31](=[O:33])[C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:25][C:24]1[C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:19][CH:18]=2)=[N:21][O:22][CH:23]=1)#[N:35]
Reactant: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Reactant: N#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a 0° C. solution of N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)leucine (46 mg, 0.10 mmol), aminoacetonitrile hydrochloride (21 mg, 0.23 mmol) and HATU. (140 mg, 0.36 mmol) in DMF (3 mL) was added triethylamine (0.06 mL, 0.43 mmol). The solution was stirred 1 h, then partitioned between ether and pH 3.5 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (40% to 60% ethyl acetate/hexanes) gave 15.5 mg of N1-(cyanomethyl)-N2-[3-(4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl)isoxazol-4-yl]leucinamide.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH2:17][C@@H:18]([CH2:31][O:32][C:33](=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>O>[C:33]([O:32][CH2:31][C@H:18]([CH2:17][CH2:16][O:15][C:13](=[O:14])[C@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8])[CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2)(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 0 °C

Procedure:
The product from step b) (138 mg, 0.192 mmol) was cooled in an ice bath and trifluoroacetic acid (5 ml) was added. The solution was kept in the ice bath for 45 minutes and was then evaporated to give an oil. Water (0.5 to 1 ml) was added and evaporated twice. The residue was once more dissolved in water (5 ml), filtered and freeze-dried to give 148 mg of the desired product as the bistrifluoracetate salt.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([NH2:32])[N:26]=[C:25]2[C:33]([N:35]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])=[O:12])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([NH2:32])[N:26]=[C:25]2[C:33]([N:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43]1)=[O:34])=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC(=O)OCc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 ml of 4N HCl in dioxane are added to 1 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzyl 2-tert-butoxycarbonylaminoacetate in 50 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off and rinsed with 5 ml of dichloromethane.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:14])[C:6]=4[N:7]=[C:8]3[CH3:13])=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 1,3,8-trimethylxanthine (0.97 g) in DMF (20 ml) were added potassium carbonate (0.83 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with acetone to provide the title compound as white powder (1.34 g, 61%). 1H-NMR (CDCl3) δ: 2.46(3H,s), 3.41(3H,s), 3.60(3H,s), 5.63(2H,s), 7.25-7.80(8H,m).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:12](=O)(O)[O-].[Na+]>CO.O>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ncccc1O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncccc1O

Procedure:
To a solution of 3-hydroxypyridine-2-carboxylic acid (100 g, 719 mmol) in anhydrous methanol (300 ml) was added dry HCl gas until the saturation point of the solution was achieved. The reaction was heated to reflux for 15 h and then cooled and degassed with argon. The solution was concentrated in vacuo to give a white solid which was dissolved in water (250 ml). The pH of the solution was adjusted to ˜7.5 with the slow addition of solid sodium bicarbonate. The resulting suspension was extracted with EtOAc (2×300 ml), and the organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to yield methyl 3-hydroxypyridine-2-carboxylate as an oily residue which crystallized on standing (99.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:29]2N=CC=C[C:28]=2N=N1.Cl.N=C=N.C(O)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([O:18][CH2:28][CH3:29])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2cccnc21
Reactant: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(c1ccc(NC(=O)OC(C)(C)C)cc1)N(C)C(C)C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 25 (1.50 g, 4.66 mmol), THF (45 mL), 1-hydroxy-7-azabenzotriazole (1.27 g, 9.32 mmol) and 1-ethyl-3-[3-dimethyl amino)propyl]-carbodiimide hydrochloride (1.79 g, 9.32 mmol), and the reaction mixture was stirred for 15 min. Ethanol (429 mg, 9.32 mmol) and 4-dimethylamino pyridine (57 mg, 0.47 mmol) were added, and the reaction mixture was stirred at room temperature for a further 16 h. After this time, the reaction was partitioned between water (40 mL) and methylene chloride (50 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×30 mL). The organic extracts were combined and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was dried to a constant weight under vacuum to afford 26 in 73% yield (1.20 g) as a white solid: mp 87-88° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.40 (d, 2H, J=7.5 Hz), 7.28 (d, 2H, J=7.5 Hz), 4.16 (s, 1H), 4.05 (m, 2H), 2.80 (septet, 1H, J=6.5 Hz), 2.02 (s, 3H), 1.47 (s, 9H), 1.11 (t, 3H, J=7.0 Hz), 0.94 (d, 3H, J=6.5 Hz), 0.88 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 351 (M+H).
Reaction SMILES: COC([CH:5]1[C:12](=[O:13])[NH:11][C:8]2([CH2:10][CH2:9]2)[C:7]2([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:6]1=[O:24])=O>C(#N)C.O>[C:20]([O:19][C:17]([N:15]1[CH2:16][C:7]2([C:6](=[O:24])[CH2:5][C:12](=[O:13])[NH:11][C:8]32[CH2:10][CH2:9]3)[CH2:14]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C1C(=O)NC2(CC2)C2(CN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(C1)C(=O)CC(=O)NC21CC1

Procedure:
8,10-Dioxo-6,11-diaza-dispiro[2.0.3.4]undecane-6,9-dicarboxylic acid 6-tert-butyl ester 9-methyl ester (160 mg; 0.47 mmol) in acetonitrile/water (3 ml/0.3 ml) is refluxed for 1 hour and evaporated to dryness to deliver the title compound as off-white crystals (125 mg; 94%).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Si:27]([O:34][CH:35]([C:41]1([CH2:45][CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42]1)[CH2:36][CH:37]=[CH:38][CH2:39]O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl.CCCCCC>[Br:1][CH2:39][CH:38]=[CH:37][CH2:36][CH:35]([C:41]1([CH2:45][CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42]1)[O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: BrBr
Reactant: CCCC1(C(CC=CCO)O[Si](C)(C)C(C)(C)C)CCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCC1(C(CC=CCBr)O[Si](C)(C)C(C)(C)C)CCC1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Bromine (0.17 mL, 3.22 mmol) was added to a solution of triphenylphosphine (844 mg, 3.22 mmol) and imidazole (219 mg, 3.22 mmol) in CH2Cl2 (11.0 mL) at 23° C. After 0.5 h a solution of the alcohol 7 (838 mg, 2.68 mmol) in CH2Cl2 (2.7 mL) was added. The reaction was stirred for 1 h, diluted with hexane and then filtered through celite. The filtrate was concentrated in vacuo and purified by FCC (silica gel, 100% hex) to give 870 mg (86%) of the bromide 8 as a clear, light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:15]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture of p-nitrophenylacetic acid (7.14 g, 0.0394 mol), ethylheptylamine (5.64 g, 0.0394 mol) and 1-hydroxybenzotriazole (6.0 g, 0.044 mol) in 35 ml of dimethylformamide (DMF), under nitrogen, is cooled in an ice bath. The mixture is then treated with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (7.68 g, 0.04 mol) in portions over 15 min. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The mixture is diluted with 400 ml of ethyl acetate and washed twice with saturated NaHCO3. (Each wash is back extracted with ethyl acetate.) The pooled organic extract is washed sequentially with water (50 ml), 1N KHSO4 solution (3×50 ml), water (50 ml) and finally brine (50 ml). It is dried (Na2SO4) and concentrated in vacuo to yield the title compound. This residue is treated with Et2O-pentane, a solid filtered off and the filtrate concentrated in vacuo. The residue is chromatographed over 1400 ml of silica gel with 25% EtOAc-SSB with 42 ml fractions being collected. Fractions at approximately 70-104 yield the title compound as an oil.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:10]=1)=[O:8])C.O.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:43]([N:6]1[CH:5]=[CH:4][C:13]2=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:10]=[C:9]2[C:7]1=[O:8])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (2,2-diethoxyethyl)-amide (I-1A-1a; 528 mg, 0.92 mmol) and p-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) in toluene (5 ml) was heated to reflux in round bottom flask fitted with a Dean-Stark condenser. After 1 hour, the reaction was cooled to room temperature, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), a concentrated, in vacuo. The crude material (0.49 g) was purified on a Biotage™ Flash 40S column using 10–20–40% ethyl acetate in hexanes as eluant to afford I-1A-1b as a solid (69 mg, 16%): +ES MS (M+1) 480.1; 1H NMR (500 MHz, CD2Cl2) δ 7.50 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 2.1 Hz, 1H), 7.38–7.27 (m, 7H), 7.18 (d, J=8.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz, 1H), 5.21 (s, 2H).
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC1CCCc2cccnc21
Yield: 102.5 %

Procedure:
To 10 g of 8-acetoxy-5,6,7,8-tetrahydroquinoline in 30 mL of methanol was added 30 mL of 30% sodium hydroxide in water. The mixture was heated to reflux for 2 min and the methanol was removed in vacuo. The residual organic product was extracted with chloroform. The chloroform extracts were dried over sodium sulfate and evaporation of the solvent gave 8 g of product as an oil, characterized by its NMR.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.[CH3:37][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:34])[CH3:37])=[CH:35][CH:36]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a solution of 13 (90 mg, 0.18 mmol) was dissolved in 0.885 mL of dry THF. A solution of 3 M of methylmagnesium bromide in ether (71 μL, 0.213 mmol) was added. The solution was allowed to stir at ambient temperature for 2 hours when TLC indicated complete consumption of starting materials. The reaction mixture was diluted with EtOAc and washed with water and saturated aqueous NH4Cl. The organic layer was reduced in vacuo to 1 mL and cooled to get the product 16 to crystallize from the solvent (92 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 1.16 (d, 18H, J=8 Hz), 1.55 (septet, 3H, J=8 Hz), 1.78 (s, 3H), 2.29 (s, 1H), 4.04 (s, 3H), 4.72 (ABqt, 2H, J=13 Hz), 6.99 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=6,9 Hz), 7.52 (dd, 1H, J=4, 9 Hz), 8.42 (dd, 1H, J=2, 8 Hz), 8.87 (dd, 1H, J=2, 4 Hz); 19F NMR (282.6 MHz, CDCl3) δ 60.8.