Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].N1C=CN=C1.[Si:60](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.01 g) in dry methylene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tert-butyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethylacetate:hexane (1:3)) to give the title compound (941 mg) (1H NMR consistent with the desired structure).
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>N1C=CC=CC=1>[O:27]=[C:15]1[O:14][N:13]=[C:12]([C:8]2[C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][S:28]([NH2:31])(=[O:30])=[O:29])=[N:11][O:10][N:9]=2)[N:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NS(N)(=O)=O
Agent: I
Solvent: c1ccncc1
Product: NS(=O)(=O)NCCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 3-{4-[(3-aminopropyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (1.5 g, 3.0 mmol) and sulfamide (1.7 g, 18 mmol) in pyridine (60 mL) was heated in a microwave at 130° C. for 10 min. The reaction mixture was concentrated to give the crude intermediate N-{3-[(4-{5-oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]propyl}sulfamide. A solution of the crude intermediate in methanol (90 mL) was treated with 2 N NaOH (12 mL, 24 mmol) and stirred at 25° C. for 30 min. The reaction mixture was treated with 6 M HCl until the solution was acidic and extracted with ethyl acetate (250 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue. This material was purified by preparative LCMS to give the desired product (1.1 g, 82%) as a gummy solid. LCMS for C13H17F3N7O4S (M+H)+: m/z=424.0. 1H NMR (400 MHz, DMSO-d6): δ 11.6 (s, 1H), 9.12 (s, 1H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.21-7.18 (m, 1H), 7.07 (s, 1H), 6.95 (d, J=10.0 Hz, 1H), 6.52 (br s, 3H), 6.17 (t, J=6.0 Hz, 1H), 3.28-3.22 (m, 2H), 2.93-2.89 (m, 2H), 1.77-1.73 (m, 2H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O>[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([S:2]([Cl:1])(=[O:5])=[O:3])[N:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1nc(S(=O)(=O)Cl)c[nH]1
Temperature: 150 °C
Yield: 40 %

Procedure:
Carefully add chlorosulfonic acid (30 mL) to neat 2-methylimidazole (5 g, 60.9 mmol). Heat the mixture at 150° C. for 3 h and cool to room temperature. Add thionyl chloride (10 mL), heat at 100° C. for 3 h and cool to room temperature. Carefully pour the mixture into ice. Slowly add solid sodium carbonate to neutralize the solution. Filter the precipitate formed and wash with water. Dry the solid under high vacuum overnight at 45° C. to give the desired intermediate (4.38 g, 40%). MS (ES+) m/z: 181 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC1C=CC(O)=C(C=1)CN[S@](C(C)(C)C)=O.Cl[SiH](Cl)Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=2)[CH2:9][CH3:10])[CH:18]=[CH:19][CH:20]=1
Reactant: CCC(=O)c1ccc(Cl)c(C)c1
Reactant: Nc1cccc(Br)c1
Agent: CC(C)(C)[S@](=O)NCc1cc(F)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](Nc1cccc(Br)c1)c1ccc(Cl)c(C)c1
Temperature: -26 °C
Reaction time: 1.5 h

Procedure:
To a solution of INT 5 (360 g, 1.941 mol) and 3-bromoaniline (509 g, 2.957 mol) in toluene (3.5 L) was added p-toluenesulfonic acid monohydrate (18.8 g, 0.099 mol). The mixture, equipped with a Dean stark trap, was refluxed overnight. After 1.5 hours, 300 mL of turbid toluene was removed from the Dean stark trap. After 5 hours 150 mL of turbid toluene was removed from the Dean stark trap and dry toluene and molecular sieves 4 Å (20 g) were added. On the next day, more molecular sieves 4 Å (60 g) were added and the reaction mixture was refluxed for an additional 4 hours. The molecular sieves were filtered off and the filtrate was concentrated. The crude imine and (S)—N-(5-fluoro-2-hydroxybenzyl)-2-methylpropane-2-sulfinamide (68.5 g, 0.279 mol, prepared according to: Pei, Dong; Wang, Zhouyu; Wei, Siyu; Zhang, Yu; Sun, Jian. Org. Lett. (2006), 8 (25), 5913-5915.) were dissolved in CH2Cl2 (6.6 L) and the mixture was cooled to −26° C. Trichlorosilane (302 g, 2.233 mol) was added dropwise within 20 minutes and the resulting mixture was stirred overnight keeping the temperature between −25° C. and −22° C. The mixture was poured onto saturated aqueous NaHCO3 (7 L) and extracted with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc). The resulting product was further purified by formation of the HCl salt and washing it with Et2O. The resulting solid was dissolved in hot EtOH and cooled to room temperature while stirring. The resulting solid was filtered off and dried in vacuum. The salt was then liberated to give INT 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (6.51 g, 32.3 mmol) and triethylamine (6.8 ml, 1.5 mol eq) in dichloromethane (70 ml) at 0° C. was added a solution of methanesulphonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) over 30 minutes. The reaction was stirred at 0° C. for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried over magnesium sulphate. Evaporation under reduced pressure yielded (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester, 9.03 g (100%). NMR (CDCl3 7.27d) m 4.73(1H), m 3.63d(2H), m 3.44d(1H), m 3.32d (1H), s 3.05d(3H), m 1.95d(2H), m 1.83d(1 H), m 1.54d(1H), s 1.46d(9H)
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=2[C:25]([F:28])([F:27])[F:26])(=[O:12])=[O:11])[CH2:7][N:6]1[C:29]1[N:30]([CH:35]([CH3:37])[CH3:36])[N:31]=[C:32]([CH3:34])[CH:33]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC(OCC(F)(F)F)=CC=2C(F)(F)F)(=O)=O)CN1C1N(C(C)C)N=C(C)C=1)=O.[OH-].[Li+]>>[CH:35]([N:30]1[C:29]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[CH:15][C:14]=3[C:25]([F:28])([F:27])[F:26])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:33][C:32]([CH3:34])=[N:31]1)([CH3:37])[CH3:36]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1c1cc(C)nn1C(C)C
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1c1cc(C)nn1C(C)C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)O)n(C(C)C)n1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-(2-isopropyl-5-methyl-2H-pyrazol-3-yl)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-(2-isopropyl-5-methyl-2H-pyrazol-3-yl)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as colorless solid. MS (ESI): m/z=544.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[C:15]1([C:13]2[N:14]=[C:10]3[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[N:3]=[CH:2][N:11]3[CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(-c2cn3cnc4c(c3n2)CCCC4)cc1
Reaction time: 4 h

Procedure:
A mixture of 5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg), triethylamine (0.5 mL), and 100 mg of 10% palladium on carbon catalyst in 200 mL ethanol was hydrogenated at 30 psi for 4 hours. The reaction mixture was then filtered through celite, and the solvent was removed in vacuo. The resulting mixture was chromatographed using 30% ethyl acetate/hexane as eluant to yield 2-Phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 42), m.p. 175°-181° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[C:19](O)=[O:20])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:58][O:59][C:60]([C:62]1([NH2:67])[CH2:66][CH:65]=[CH:64][CH2:63]1)=[O:61]>CN(C=O)C>[CH3:58][O:59][C:60]([C:62]1([NH:67][C:19]([C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:1])([F:25])[F:24])=[CH:4][CH:5]=2)=[O:20])[CH2:66][CH:65]=[CH:64][CH2:63]1)=[O:61]
Reactant: O=C(O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1(N)CC=CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)cc2)CC=CC1
Reaction time: 0.5 h
Yield: 118 %

Procedure:
To a solution of 200 mg 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid in 2 ml abs. DMF under inert atmosphere 72 mg 1-hydroxybenzotriazole, 285 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 288 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 229 mg of 1-amino-cyclopent-3-enecarboxylic acid methyl ester hydrochloride, followed by 223 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate and concentrated to yield 320 mg of 1-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-cyclopent-3-enecarboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]1([NH:27][CH2:28][CH2:29][OH:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([N:27]([CH2:28][CH2:29][OH:30])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: OCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.9 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), N-phenylethanolamine (165 mg, 1.2 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (2 mL) was stirred at room temperature for 3 h. The mixture was poured into water (30 mL), extracted with ethyl acetate (10 mL×3). The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 51 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[(2-hydroxy-ethyl)-phenyl-amino]-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=427.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[Na].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:21][CH:20]=1.[OH-].[Na+]>C(O)C.O>[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:21][CH:20]=1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: COc1ccc(OCCCCBr)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1cnc2c1c(=O)n(CCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 64.8 %

Procedure:
3-Methyl-7-propylxanthine (10.4 g) was dissolved in 200 ml of an ethanol/water (3:2 (v/v)) mixed solution containing 2.2 g of sodium hyddroxide and 15.5 g of 4-(4-methoxyphenoxy)butylbromide was added to the solution. The mixture was then refluxed at elevated temperatures for 12 hours. The reaction mixture was concentrated under reduced pressure to give the residual liquid which in turn was alkalized with 1N-sodium hydroxide solution and then extracted with chloroform. The extract was dried and concentrated under reduced pressure to dryness. The residue was then subjected to silica gel column chromatography using a chloroform/ethanol (40:1 (v/v)) eluent to yield 12.5 g (65%) of 1-[4-(4-methoxyphenoxy)butyl]-3-methyl-7-propylxanthine.
Reaction SMILES: [OH:1][C@H:2]([C@@H:14]([NH:19][C:20](=[O:43])[O:21][C@H:22]([CH2:27][N:28]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[N:29]1)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].O[C@@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][C:2]([C@@H:14]([NH:19][C:20](=[O:43])[O:21][C@H:22]([CH2:27][N:28]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=2)=[N:29]1)[C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])(=[O:6])=[O:7]
Reactant: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
To a solution of 90 mg (0.14 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate in 2 mL of dichloromethane was added 76 mg (0.18 mmol) of Dess-Martin periodinane. The reaction mixture was stirred for 15 min, and then filtered through a celite plug with dichloromethane. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (6.5:3.5) to afford 56 mg (62%) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. 1H-NMR (300 MHz, T=100° C., DMSO6): δ 8.66 (d, J=4 Hz, 1H), 8.08–7.60 (m, 9H), 7.17 (m, 1H), 6.72 (d, J=2 Hz, 1H), 4.90 (d, J=9 Hz, 1H), 4.49 (d, J=14 Hz, 1H), 4.26–3.85 (m, 4H), 1.56 (m, 1H), 1.40 (m, 1H), 1.29–1.01 (m, 13H) 0.78 (m, 3H); ES-LCMS m/z 646 (M+Na); HRMS C29H36F3N5O5S1 m/z 646.2287 (M+Na)+Cal; 646.2283 (M+Na)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[S:41][CH:42]=3)[N:31]=[C:30]([N:50]3[CH2:53][CH2:52][CH2:51]3)[C:29]=2[C:54]#[N:55])=[CH:24][CH:23]=1)=[O:17])[CH3:15])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=4)[S:41][CH:42]=3)[N:31]=[C:30]([N:50]3[CH2:51][CH2:52][CH2:53]3)[C:29]=2[C:54]#[N:55])=[CH:26][CH:27]=1)=[O:17])[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)CCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90 mg (0.113 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-beta-alanyl-L-alaninate (Example 4A) were initially charged in 3.5 ml of dichloromethane. 0.347 ml (4.502 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). For further purification, the product was once more purified by preparative HPLC (column material: XBridge; mobile phase: acetonitrile/0.1% aq. ammonia=65/35). This gave 51 mg (65% of theory) of the target compound.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH2:21]CC(C)C)[C:11]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(=CC=CC=2)N(CC)C1=O)(=O)C1C=CC=CC=1>>[C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c(O)c1
Agent: CCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: CCN1C(=O)C(Cc2ccc(OC)cc2O)(OC(=O)c2ccccc2)c2ccccc21

Procedure:
This compound was prepared in a similar manner to 3-(2-hydroxy-4-methoxybenzyl)-5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate by reacting 1-ethyl-2-oxoindolin-3-yl benzoate with tert-butyl (2-(hydroxymethyl)-5-methoxyphenyl)carbonate. 1H-NMR δ 8.04 (d, 2H), 7.6 (t, 1H), 7.43 (t, 2H), 7.30 (t, 1H), 7.25 (d, 1H), 7.08 (t, 1H), 6.78 (d, 1H), 6.47 (m, 2H), 6.24 (dd, 1H), 6.15 (bs, OH), 3.83 (m, 1H), 3.71 (s, 3H), 3.61 (m, 1H), 3.48 (d, 1H), 3.43 (d, 1H), 1.02 (t, 3H). Calculated mass for C25H23NO5, 417.16. Observed 440.0 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][Br:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 5-bromo-2-methylbenzonitrile (5.0 g, 25.5 mmol), N-bromosuccinimide (4.54 g, 25.5 mmol), 2′,2′-azobis(2-methylpropionitrile) (0.05 g) and carbon tetrachloride (25 mL) is heated at reflux for 75 min. After cooling to room temperature, the solids are removed by filtration. The filtrate is concentrated and the residue purified by chromatography eluting with cyclohexane-20% ethyl acetate. Product containing fractions are combined and concentrated to afford 5-bromo-2-bromomethylbenzonitrile (2.69 g, 38%). LC/MS: MS showed no parent molecular ion peak; RT 3.52 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Yield: 90.9 %

Procedure:
Dissolve 2,2,2-trifluoro-1-(7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone (10.0 g, 36.6 mmol) in dichloromethane (750 mL). Add BBr3 (11.0 mL, 116 mmol) and stir for 4 hours. Quench the reaction mixture with water (350 mL). Filter the suspension, then separate the two layers. Extract the aqueous layer with dichloromethane (2×300 mL). Dry the combined organic extracts over MgSO4, filter and concentrate to give the title compound (8.62 g, 91%): MS ES+ 260 (M+H)+, ES− 258 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 micron) acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=8.8 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.Cl>C1COCC1>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[NH:4][CH2:2][CH3:1])([O-:13])=[O:12]
Reactant: CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Product: CCNc1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 8 g (44 mmol) of 3-nitroacetanilide in 200 ml of dry THF, a solution of 5.5 ml (58 mmol) of borane dimethyl sulfide complex in 5 ml of THF was added, followed by stirring at 80° C. for 4 hours. To the reaction mixture, 3 ml (32 mmol) of borane dimethyl sulfide complex were further added, followed by stirring at 80° C. for 3 hours. After 1N hydrochloric acid was added to the reaction mixture until the solution became uniform, the solvent was concentrated under reduced pressure. To the residue, a 10N aqueous solution of sodium hydroxide was added, followed by extraction with chloroform. The extract was washed with saturated saline and then dried over magnesium sulfate. The solvent was distilled out under reduced pressure. The residue was purified by chromatography on a column (ethyl acetate/n-hexane=4/1), whereby 6.6 g of the title compound were obtained as brown powder (yield: 89%).