Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[NH2:25][NH2:26]>O1CCOCC1.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH:25][NH:26][C:14]([C:13]3[C:9]([C:7]4[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[N:10][N:11]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)=[O:15])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(NNC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 72 %

Procedure:
Add a solution of 476 mg of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 25 ml of dioxane dropwise to 210 mg of hydrazine dihydrochloride in 2 ml of water, whereupon N,N'-bis-[3-(5-nitro-2-furyl)-1-phenyl-4-pyrazolylcarbonyl]hydrazine [m.p. 313° to 314° C (with decomposition) from dimethylformamide] precipitates with a yield of 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[CH2:14]([NH2:16])[CH3:15]>C(Cl)Cl>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([NH:16][CH2:14][CH3:15])=[O:7]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C)c(N)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-methyl-3-nitro-benzoyl chloride (1.0 g, 5.0 mmol) was dissolved in DCM, and the solution was cooled to 0° C. Ethyl amine (2.0 M in THF, 5.0 mL, 10 mmol) was added dropwise to the acid chloride, and the reaction stirred at 0° C. for 5 min. The ice bath was removed and reaction continued to stir for 3. The solution was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting aniline (0.75 g) was used without further purification.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20](I)=[CH:19][C:15]4[CH2:16][CH2:17][O:18][C:14]=4[CH:13]=3)[NH:8]2)=[C:4]([NH2:22])[N:3]=1.C(O)(C(F)(F)F)=O.C1C(=O)[N:34](I)C(=O)C1>C(#N)C>[O:18]1[C:14]2[CH:13]=[C:12]([CH2:11][C:7]3[NH:8][C:9]4[C:5]([N:6]=3)=[C:4]([NH2:22])[N:3]=[C:2]([NH2:34])[N:10]=4)[CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17]1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nc(F)nc2[nH]c(Cc3cc4c(cc3I)CCO4)nc12
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2nc(Cc3ccc4c(c3)OCC4)[nH]c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H-purin-6-amine (S16-9). To a suspension of S16-8 (0.45 g, 1.6 mmol) in 50 mL acetonitrile was added 1 mL of TFA. To the resulting solution was added NIS (1.06 g, 4.7 mmol) and the reaction mixture was stirred at rt for 3 h. It was then evaporated to dryness and purified by flash chromatography to give S16-9 (0.408 g, 63%) as a yellow solid. 1H NMR (500 MHz, MeOH-d4) δ 7.67 (s, 1H), 6.76 (s, 1H), 4.59 (m, 2H), 4.28 (s, 2H), 3.21 (m, 2H); MS: m/z 412 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[CH:10]1>CC#N>[Br:1][C:13]1[N:9]=[CH:10][NH:11][C:12]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c[nH]cn1
Solvent: CC#N
Product: COC(=O)c1[nH]cnc1Br
Reaction time: 12 h
Yield: 69.1 %

Procedure:
N-bromosuccinimide (0.900 g, 5.0 mmol) was added to a stirred solution of methyl 1H-imidazole-4-carboxylate (0.630 g, 5.0 mmol) in CH3CN (50 mL). The reaction mixture was stirred for 12 h in the dark and then concentrated in the presence of silica gel. The absorbed crude material was purified by column chromatography (20-100% EtOAc/hexanes) to afford the title compound (0.708 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (br. s., 1H), 7.81 (s, 1H), 3.81 (s, 3H). ES-LCMS: m/z 204.9, 206.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:19](=[O:21])[CH3:20])=[CH:5][C:4]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1OCOCC[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(NC(C)=O)cc1OCOCC[Si](C)(C)C

Procedure:
A mixture of Example 476B, acetic anhydride (20 mL), and 4-(dimethylamino)pyridine (722 mg, 5.9 mmol) in dichloroethane (150 mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was diluted with hexanes and stirred vigorously until a solid formed. The solid was filtered, rinsed with hexane, and dried under vacuum to produce 15 g (81% over 3 steps from Examples 476A-C) of the desired product. MS (ESI) m/e 334 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) □ 9.74 (s, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.18 (dd, J=2.5, 8.7 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.13 (s, 2H), 3.67-3.73 (m, 2H), 3.71 (s, 3H), 1.98 (s, 3H), 0.86-0.92 (m, 2H), -0.02 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:43])([F:42])[S:29]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:17]=[C:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=2[NH:32][S:29]([C:28]([F:43])([F:27])[F:42])(=[O:31])=[O:30])=[CH:19][CH:18]=1
Reactant: Nc1ccc(CN2C(=O)CCc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(CN2C(=O)CCc3ccccc32)cc1)c1ccccc1NS(=O)(=O)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2.52 g of 1-p-aminobenzyl-1,2,3,4-tetrahydro-2-oxoquinoline, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of methylene chloride is cooled to 5° and a solutoin of 2.88 g of o-trifluoromethanesulfonamidobenzoyl chloride in 20 ml of methylene chloride is added dropwise. The mixture is stirred for a further 16 hours at 20°, evaporated and worked up in conventional manner to give 1,2,3,4-tetrahydro-2-oxo-1-[4-(2-trifluoromethanesulfonamidobenzamido)benzyl]quinoline.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])=[CH:13][CH:12]=1
Reactant: Oc1ccccn1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccccn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.61 g, 25 mmol) was added to a solution of 2-hydroxypyridine (2 g, 21 mmol) in DMF (20 mL) at 0 C. After stirring for 15 min, p-fluorobenzyl bromide (4.4 g, 2.9 mmol, 23 mmol) was added and the reaction mixture allowed to warm gradually to RT. The reaction mixture was quenched by addition of ice then poured into ether and extracted several times with ice water. The organic phase was then dried over Na2SO4, concentrated and the resulting yellow oil purified by normal phase Gilson chromatography eluting with 10% DCM, 70% Hexane, 20% EtOAc. 1-(4-Fluorobenzyl)pyridin-2(1H)-one was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([CH:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[OH:16])=[C:13]([Cl:22])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H-].[Na+].I[CH3:26]>O1CCCC1.[Cl-].[Na+]>[Cl:1][C:2]1[C:14]([CH:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[O:16][CH3:26])=[C:13]([Cl:22])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccco2)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccco1)c1c(Cl)ccc(C(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At room temperature, 3.0 g (8.8 mmol) of tert-butyl 2,4-dichloro-3-((2-furyl)(hydroxymethyl))benzoate in 40 ml of tetrahydrofuran are stirred for 1 h with 0.4 g (16.6 mmol) of sodium hydride. 6.3 g (43.8 mmol) of iodomethane are added dropwise and the mixture is stirred at room temperature for a further 3 h. The reaction mixture is taken up in 100 ml of saturated aqueous sodium chloride solution, extracted with methyl tert-butyl ether, dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by silica gel chromatography using cyclohexane/ethyl acetate. Yield: 2.7 g; 1H NMR, δ [ppm], (CDCl3): 1.6 (s), 3.5 (s), 6.2 (m), 6.3 (m), 7.4 (m), 7.5 (d)
Reaction SMILES: C([Li])CCC.[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[NH:8]1.[F:19][C:20]([F:27])([F:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>CCCCCC.O1CCCC1>[CH3:6][C@@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[N:8]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]([F:27])([F:26])[F:19]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)CCC(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A solution of n-butyllithium (2.0 mole) in hexane was added to a stirred solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (353 g) in dry tetrahydrofuran (2500 ml) at -78° C. under an inert atmosphere. The solution was stirred at -70° c. for 15 min, then 4,4,4-trifluorobutyryl chloride (320 g) was added over 30 min at -60° C. and the mixture warmed to room temperature and stirred overnight. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The ethereal layer was washed (1N hydrochloric acid, brine (twice)), dried (MgSO4), and evaporated to yield crude product (604 g, about 100%). Filtration through 3000 ml of silica gel using 1:1 methylene chloride:hexanes as the eluent afforded a white solid. Recrystallization from methylene chloride:hexanes afforded (4R,5S)-4-methyl-3-(4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (519 g, 86%); m.p. 93°-95° C.; partial NMR (300 MHz, CDCl3): 0.91 (d, 3H, CH3), 2.45-2.65 (m, 2H, CF3CH2), 3.18-3.40 (m, 2H, CH2CO), 4.78 (m, 1H, 4-H oxazolidinone), 5.70 (d, 1H, 5-H oxazolidone), 7.30-7.44 (m, 5H, Ar).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[CH2:4].[Cl:12][C:13]1[CH:14]=[C:15]([OH:21])[C:16](=[CH:19][CH:20]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([O:21][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[CH2:4])[CH:14]=1
Reactant: C=C(CBr)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(COc1cc(Cl)ccc1C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 106.8 %

Procedure:
A mixture of 19.2 g (0.083 mol) of the product from Step A, 10.0 g (0.064 mol) of 4-chlorosalicylaldehyde, 17.6 g (0.13 mol) of potassium carbonate and 64 mL of DMF was stirred at RT for 72 h. Resulting mixture treated with 125 mL of H2O and filtered. Solids were washed with several portions of H2O and dried in a vacuum oven at 40° C. to give 21.0 g of a brown solid. 1H NMR (CDCl3, 200 MHz) δ4.99 (s, 2H), 5.51 (s, 1H), 5.65 (s, 1H), 7.04-7.07 (m, 2H), 7.25-7.45 (m, 4H), 7.77 (d, 1H), 10.28 (s, 1H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N+:16]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22](Cl)=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=2)CC[C@H:32]1[N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:29])([O-:18])=[O:17].[N+](C1C=CC=CC=1CC(O)=O)([O-])=O.N1C=CC=CC=1.Cl.O(CC)CC.Cl>>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:27][C:28]([N:30]([CH3:49])[C@@H:31]([C:40]1[CH:35]=[CH:36][CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=1)[CH2:32][N:44]1[CH2:45][CH2:46][CH2:47][CH2:48]1)=[O:29])([O-:18])=[O:17].[ClH:25]
Reactant: CN(C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-])[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CN(C(=O)Cc1ccccc1[N+](=O)[O-])[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared via the general DCC/pyr coupling procedure from 8 (1.4886 g, 5.97 mmol), 2-nitrophenylacetic acid (2.1619 g, 11.93 mmol), DCC(2.5402 g, 12.31 mmol), and pyridine (1.00 mL, 12.36 mmol). The crude product was converted to the HCl salt with Et2O—HCl without chromatography and crystallized from MeOH—Et2O. The first crop was recrystallized again from MeOH—Et2O to yield 10 HCl.(1.3663 g, 51%): m.p. (HCl salt) 258-259° C.; 1H NMR (HCl salt, DMSO-d6) δ1.97 (br s, 4H, —CH2CH2—), 2.91 (s, 3H, —NCH3), 3.11-4.45 (complex, 8H, 4 —CH2—), 6.17 (m, 1H, —CH—), 7.51-8.25 (complex, 8H, aromatic). MS(FAB) m/z 413. Anal. (C, H, N) C21H24N4O5.HCl.0.25H2O.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]([O:50]C(/N=N/C(OC(C)C)=O)=O)C.C(O)(=O)C>C1COCC1>[C:48]([O:13][C@@H:11]1[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1)(=[O:50])[CH3:47]
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](OC(C)=O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 41, Step E, 260 mg, 0.702 mmol) and PPh3 (460 mg, 1.75 mmol) in THF (10.0 mL) was added DIAD (276 μL, 1.40 mmol) followed by acetic acid (80.4 μL, 1.40 mmol). The reaction was stirred at ambient temperature for 48 hours and then concentrated. The residue was purified by reverse phase column chromatography (0-70% acetonitrile/water) to afford ethyl 5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (228 mg, 79% yield). MS (apci) m/z=413.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CC(=O)CC.[I-:21].[Na+]>C(OC(=O)C)C>[I:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: [I-]
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: N#Cc1ccc(OCCCCCI)cc1
Reaction time: 6 h
Yield: 98.9 %

Procedure:
While 50 g of 4-(5-chloro-pentoxy)-benzonitrile (8) prepared in Example 5 were added to 500 ml of 2-butanone and stirred, 167 g of sodium iodide were added. Subsequently, the reaction temperature was gradually increased and stirring was continued at 70-80° C. for 6 hr. After the reaction was completed, the reaction temperature was decreased to room temperature, and the resultant reaction mixture was added with 1 L of ethylacetate, and then washed with water and brine. The ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residual solution was crystallized with methylalcohol, thus obtaining 69.7 g (yield: 99%) of a title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4,4-diphenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield. mp 198°-199°. FDMS m/e=426 (M+ of free base). α[D]589 =-17.80 (c=0.66, methanol).
Reaction SMILES: [Cl-].[C:2]([CH2:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH3+:13])([OH:4])=[O:3].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[OH-].[Na+]>[C:14]([NH:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[O:6][CH2:5][C:2]([OH:4])=[O:3])(=[O:16])[CH3:15]
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N[C@@H]1CCCC[C@H]1OCC(=O)O
Reaction time: 0.5 h
Yield: 278.8 %

Procedure:
To a cooled solution of trans-2-carboxymethoxy-cyclohexyl ammonium chloride (1.048 g, 5 mmoles) in 2N NaOH (5 ml), there were added under stirring first 1N NaOH (1 ml) and then acetic anhydride (0.102 g, 1 mmol). When the reaction of anhydride was completed and a homogeneous solution was obtained, the same amount of 1N NaOH and acetic anhydride as above was added four times. After the addition of the last portion the reaction mixture was stirred for 30 minutes, the solution was acidified to pH 2 and extracted with ethyl acetate (5×20 ml). The organic extracts were dried with MgSO4, the drying agent was filtered off and the filtrate was evaporated under reduced pressure. The residue was recrystallized from a mixture of chloroform/n-hexane. Thus, there were obtained 0.60 g (56%) of the title compound, melting point 141°-143° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[CH3:11]>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CC[Mg]Cl
Reactant: O=Cc1ccc(Br)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)nc1
Reaction time: 4 h

Procedure:
To a chilled (0° C.) solution of 6-bromopyridine-3-carboxaldehyde (15.0 g, 80.6 mmol) in a 1:1 mixture of ether-toluene (400 mL) is added a 2 M solution of ethylmagnesium chloride (40.0 mL, 80.0 mmol) in THF over a 15 minute period. After 4 hours, the mixture is diluted with saturated aqueous ammonium chloride (300 mL) and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material is passed through a pad of silica gel eluting with dichloromethane-hexanes (0-100%). The material from the pad is purified by silica gel chromatography eluting with EtOAc-hexanes (2:98, then 4:96, then 6:94, then 8:92, then 1:9, then 12:88, then 15:85) to afford 1-(6-bromopyridin-3-yl)-propan-1-ol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.2 g, 0.71 mmol) and 2.0 M aqueous sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-chloro-4-[4-(2-hydroxy-ethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.100 g, 42%) as a solid. MS calcd. for C22H21ClNO5S [(M−H)−] 446, obsd. 446.4.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:21]1([NH:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:27]2[C:13]([C:10]3[C:9]([CH3:19])=[N:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[OH:12])=[CH:14][C:15]([CH3:16])=[N:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NNC1CCCCC1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(C2CCCCC2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and cyclohexylhydrazine hydrochloride according to the procedure of Example 28.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.O=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[N:18]=[C:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:20][C:21]([OH:23])=[O:22].Cl>O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[C:20]([C:21]([OH:23])=[O:22])=[C:13]2[CH2:17][CH2:16][CH2:15][N:14]2[N:18]=1
Reactant: O=C(O)CC(=NN1CCCC1=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Add sodium ethoxide (145 g, 2.03 mol), followed by toluene (7 L) and 3-(2-oxo-pyrrolidin-1-ylimino)-3-pyridin-2-yl-propionic acid (280 g, 1.02 mol) to a 22 L flask equipped with mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture to 100° C. for 21 h. Cool to room temperature. Add water (6 L) and adjust to pH 5 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous layer with 10% isopropyl alcohol in chloroform (2×9 L). Combine the organic layers, dry (sodium sulfate), filter and concentrate in vacuo to yield the title compound as a yellow solid (218 g, 93%). MS ES+ m/e 230 (M+1).