Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:37][N:38]1CCOC[CH2:39]1.C(OC(Cl)=O)C(C)C.CNC>ClCCl.C1COCC1>[CH3:37][N:38]([CH3:39])[C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:26]2([CH3:34])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:30]([C:29]=3[CH2:28][CH2:27]2)([CH3:33])[CH2:31][CH2:32][C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:10]4([CH3:36])[CH3:35])=[CH:16][CH2:17]1)[CH3:25]
Reactant: CN1CCOCC1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](CCC(=O)N(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.30 g) is dissolved in 10 ml of dry dichloromethane. After cooling to −15° C., 0.07 ml of N-methylmorpholine and 0.084 ml of isobutylchloroformate is added and the mixture is stirred at −15° C. for 20 minutes, whereupon 1.74 ml of a 2.0 M solution of N,N-dimethylamine in THF) is added. The mixture is stirred overnight and the temperature is slowly elevated to room temperature. After aqueous work-up and crystallization from methanol, 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid-N,N-dimethyl amide (0,231 g) is obtained. M.p. 143-145° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.35 (1H, s); 3.20 (1H, m); 3.03 (3H, s); 2.95 (3H, s); 0.90 (9H, s); 0.05 (6H, m).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1.[F:25][C:26]([F:47])([F:46])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:34][CH2:33][C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:46])[F:47])=[CH:32][CH:31]=4)[CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCNC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(CCc3ccc(C(F)(F)F)cc3)C2)c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A mixture of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (50 mg, 142 μmol), toluene-4-sulfonic acid 2-(4-trifluoromethyl-phenyl)-ethyl ester (90% pure, 55 mg, 142 μmol), triethylamine (60 μL, 426 μmol) and acetonitrile (1.5 mL) was heated at reflux for 16.5 hours and cooled to room temperature. The mixture was concentrated, and the residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, to provide a white amorphous solid (30 mg, 45%). 1H NMR (300 MHz, CDCl3) δ8.26 (s, !H), 7.87 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.51 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 1H), 6.06 (bm, 1H), 4.15 (s, 3H), 3.23 (t, J=6 Hz, 2H), 3.03 (m, 1H), 2.86 (m, 2H), 2.61 (m, 2H), 2.1-1.5 (m, 7H), 1.05 (m, 1H). Mass spec (ES+) m/z 488.5 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:44])C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCCC1.O.C(OCC)(=O)C>[OH:44][C@H:12]([CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]([N:15]1[C@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])=[O:14]
Reactant: COc1ccc(CCCCC(=O)N2C(=O)OC[C@H]2c2ccccc2)cc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCC[C@@H](O)C(=O)N2C(=O)OC[C@H]2c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
(4R)-3-[5-(4-Methoxyphenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (Reference Example 20) (1.0 g) was dissolved in tetrahydrofuran (10 ml) and the resulting solution was cooled to −78° C., followed by adding thereto sodium hexamethyldisilazide (1M, 3.4 ml). After 30 minutes, a solution of Davis reagent (0.9 g) in tetrahydrofuran (5 ml) was added dropwise thereto. After stirring for 1 hour, a solution of camphorsulfonic acid (1.5 g) in tetrahydrofuran (5 ml) was added thereto and stirred for 30 minutes. Ethyl acetate and water were added to the reaction mixture to effect separation and extraction. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution, dried, concentrated, and then the residue was purified by a silica gel chromatography (100 g, ethyl acetate:hexane=1:3) to obtain (4R)-3-[(2R)-2-hydroxy-5-(4-methoxyphenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (0.75 g).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:15])(=O)=O>CCCCCCC>[Cl:15][C:2]([CH3:4])([CH3:3])[C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C(=O)c1ccccc1
Solvent: CCCCCCC
Product: CC(C)(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyrophenone (30.0 g, 0.20 mole) was dissolved in heptane (10 ml) and sulfuryl chloride (35 g, 0.26 mole) was added at once. After a few minutes gas evolution occurred. After 3 h of stirring at room temperature the reaction mixture was concentrated. The concentrate was dissolved in heptane (250 ml) and washed with 150 ml of an aqueous 2 wt % sodium bicarbonate solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The yield of 2-chloro-2-methylpropiophenone was 36.4 g or 98%.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=C1.[CH3:8][N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(C1C=CC(B(O)O)=CC=1)(C)(C)C>>[CH3:8][N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([C@H:5]2[CH2:4][CH2:3][C:1](=[O:7])[CH2:6]2)=[CH:12][CH:11]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: O=C1C=CCCC1
Agent: CC(C)(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc([C@H]2CCC(=O)C2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 28A, substituting 2-cyclopenten-1-one for cyclohexen-1-one, S-BINAP and 4-(dimethylamino)-phenylboronic acid for 4-(tertbutyl)-phenylboronic acid. The mixture was purified on SiO2 (hexane/ethyl acetate 4/1) to provide the title compound. [α]D=−22.31 c=1.0 (CH3OH). 1H NMR (CD3OD, 300 MHz); δ 1.85-2.01 (m, 1H), 2.21-2.40 (m, 4H), 2.42-2.50 (m, 1H), 2.88 (s, 6H), 3.29-3.39 (m, 1H), 6.78-6.81 (m, 2H), 7.11-7.21 (m, 2H). MS (DCI) m/z 204 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH2:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Br:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:21][C:26]1[C:27]([Br:31])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](N)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-3-amino-3-(4-(tert-butyldimethylsiloxy)pheny)propanoic acid ethyl ester (1.0 eq), 2,4-dichloro-5-bromopyrimidine (1.2 eq) and DIEA (1.2 eq) in DMF was stirred at 50° C. for 2 hr, and then the DMF was evaporated. The residue was dissolved in EtOAc, and the resulting solution was washed successively with 0.1 M H3PO4, sat. NaHCO3 and sat. NaCl. The EtOAc extracts were treated with MgSO4, filtered, and evaporated to give (R)-3-(5-bromo-2-chloropyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12.C[N+]([O-:28])(C)C.CS(C)=O.C(Cl)Cl>C(OCC)(=O)C.O>[OH:13][C:11]1[CH:12]=[C:3]([CH:2]=[O:28])[C:4]2[CH2:5][CH:6]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9]=2[CH:10]=1
Reactant: C[N+](C)(C)[O-]
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol), trimethylamine N-oxide (0.03 g, 0.4 mmol), DMSO (1.5 ml), and methylene chloride (0.5 ml) and stir at 0-5° C. for 30 minutes. Add water and ethyl acetate. Wash organic layer 5× with water, dry over anhydrous sodium sulfate and concentrate to a residue which yields after separation on silica gel with 33% EtOAC/hexanes, the titled compound (0.12 g, 39%). 1H NMR (CD3OD) 10.26 (s, 1H), 7.18 (d, J=8.4, Hz, 2H), 7.12 (s, 1H), 6.97 (s, 1H), 6.77 (d, J=7.9 Hz, 2H), 3.4 (m, 1H), 3.15 (m, 1H), 3.0 (m, 2H), 2.55(m, 1H) 2.2 (m, 1H), 1.6-1.2. MS m/z 307 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][N:21]([CH2:32][CH2:33]O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:33][CH2:32][N:21]([CH2:20][CH2:19][OH:18])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCN(CCO)S(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid(naproxen, 5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89 g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol) in CH2Cl2 (250 mL) and DMF (3 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at room temperature, and then partitioned between CH2Cl2 and HCl (1N). The aqueous layer was washed with CH2Cl2 and the combined organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAC/hexane (1:1) to give the title compound as a thick oil (7.15 g, 15.16 mmol, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q, J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H), 2.18 (t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 472 (MH+), 489 (M+18+).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCCC1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (134 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (116 mg, 91%) as a pale-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:7]=2)[CH:8]=[CH:9][N:10]=1
Reactant: COc1cc(C#N)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 8 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in tetrahydrofuran (1 ml), and 12% lithium methylate in methanol (1.0 g, 3.2 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (0.30 g) containing 2-methoxyisonicotinonitrile. This mixture and methyl thiosalicylate (1.0 g, 5.9 mmol) were dissolved in toluene (3.0 ml), and triethylamine (1.0 ml, 7.2 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs, subjected to a silica gel (60 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) to give the titled compound (0.05 g, 8%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11]C)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Cl.[NH+]1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1cc(Cl)cc([N+](=O)[O-])c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=[N+]([O-])c1cc(O)cc(Cl)c1
Temperature: 200 °C
Reaction time: 8 h

Procedure:
1.65 g 3-chloro-5-nitroanisole are combined with 20.3 g pyridinium hydrochloride and heated to 200° C. for 1 hour. Then the mixture is left overnight to come up to ambient temperature, 200 ml of water are added, the precipitated solid is suction filtered and dried in vacuo.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:42].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:42].[F:41][C:37]1[CH:36]=[C:35]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24]2)[CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)O)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(C(=O)CCC(=O)O)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 174 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoic acid in 1.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. Diisopropylether was added thereto, and the resulting precipitate was collected by filtration, and then dried under reduced pressure to obtain 100 mg of 4-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-4-oxobutanoic acid hydrochloride as a white solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl[Sn]Cl>C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:18]=[CH:19][C:2]([C:2]3[CH:19]=[CH:18][CH:5]=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(Cl)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc(NC(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 60 °C

Procedure:
500 mg (1.81 mmol) of 4-chloro-N-(3-nitrophenyl)benzamide was dissolved in 50 mL of anhydrous ethanol. When dissolution was complete, 0.3 mL (3.62 mmol) of concentrated HCl and 1 g (5.43 mmol) of SnCl2 were added. The reaction mixture was then heated to 60° C. for 5 hours, monitoring the formation of the anticipated product by TLC using a petroleum ether/AcOEt (1/2, v/v) mixture as the eluent. When the reaction had finished, a saturated solution of NaHCO3 was added to the reaction medium. After elimination of the ethanol under vacuum, the reaction medium was extracted with ethyl acetate. After filtration, the organic phases were dried over Na2SO4. 440 mg of the compound with formula (VI-2) (yield 94%) was obtained in the form of a brown solid. This compound was then engaged in the subsequent synthesis steps with no supplemental purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]2[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C@H:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]2[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2nncs2)cc1Cl
Yield: 74.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (0.377 g, 0.620 mmol) prepared in Example 87a, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (0.212 g, 75%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][N:38]=[C:30]([F:29])[CH:31]=2)[S:19][CH:20]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccnc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 200 mg, 0.60 mmol) in CH2Cl2 (2.0 mL) was added triethylamine (0.20 mL, 1.9 mmol) followed by 2-fluoroisonicotinic acid (107.7 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243.9 mg, 1.27 mmol) and hydroxybenzotriazole (172.0 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}-2-fluoroisonicotinamide (19, 68.4 mg) as yellow solids in 25% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1 H), 8.47-8.50 (m, 2 H), 8.36-8.41 (m, 2 H), 7.96 (s, 1 H), 7.80 (s, 1 H), 7.41 (s, 2 H), 7.33 (s, 1 H), 2.13 (s, 6 H); ESI-MS: m/z 438.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].Cl[C:13]1[CH:14]=[C:15]2[N:22](C(OC(C)(C)C)=O)[C@@H:21]([CH3:30])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][O:11][C:13]2[CH:14]=[C:15]3[NH:22][C@@H:21]([CH3:30])[CH2:20][N:16]3[C:17](=[O:19])[N:18]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(CO)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)cc(C#N)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[CH:23]1([CH2:22][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][CH2:13][CH3:14])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCCCC1
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OCC1CCCCC1
Temperature: 50 °C

Procedure:
To a solution of 22-4 (915 mg, 5.0 mmol) in 10 mL of DMF was added 1.78 g (5.50 mmol) of Cs2CO3 followed by 0.68 mL (4.9 mmol) of bromomethyl cyclohexane. The resulting solution was then heated at 50° C. for 24 h. The solvent was distilled under reduced pressure and the residue was taken up in 20 mL of EtOAc. The organic phase was extracted with 1N NaOH (2×50 mL), water (5×5 mL) and brine (5 mL), dried (MgSO4) and concentrated to afford 22-5 as an oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[O:20])=[CH:17][CH:16]=1
Reactant: CCCCc1cc2ccccc2o1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
A solution of 2-n-butylbenzofurane (19.8 g, 114 mmol) and 4-bromobenzoyl chloride (25.0 g, 114 mmol) in dry dichloromethane (300 mL, 0.4 M) was cooled to 0° C. and treated with AlCl3 (16.6 g, 1.1 equiv., 125.4 mmol) in 3 portions. After the additions were complete, the solution was stirred for 3 h and carefully added to ice water. After separation, the aqueous layer was extracted with dichloromethane (2×200 mL) and the combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (1-2% ethyl acetate in heptane) afforded (4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone (14.6 g, 36%).