Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH:20]=[O:21])[CH:9]1[CH2:22][CH2:23][CH:24](OC1CCCCO1)[CH2:25][CH2:26][CH2:27][CH2:28]C.C(OCCCCCCCC1C(C#N)CC(OC2CCCCO2)C1=O)(=[O:39])C.O1CCCCC1OC1C(OC2CCCCO2)CC(C#N)C1CCC(OC1CCCCO1)CCCCC.O1CCCCC1OC1C(O)CCC1>>[CH:20]([CH:10]1[CH2:11][CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:8]([OH:7])[CH:9]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:39])=[O:21]
Reactant: CC(=O)OCCCCCCCC1C(=O)C(OC2CCCCO2)CC1C#N
Reactant: CCCCCC(CCC1C(C=O)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: CCCCCC(CCC1C(C#N)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: OC1CCCC1OC1CCCCO1
Product: O=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO

Procedure:
By proceeding in a similar manner to that described above in Example 1(m) for the preparation of 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde, but substituting the appropriate quantity of 2-(7-acetoxyheptyl)-3-cyano-5-(2-tetrahydropyranyloxy)cyclopentanone [prepared as described above in Example 2(d)] for the 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbonitrile used as starting material, there was prepared 3-formyl-2-(7-hydroxyheptyl(-5-(2 -tetrahydropyranyloxy)cyclopentanol, νmax 3400 cm-1, 1710 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[S:21]
Reactant: COC(=O)c1cccc(I)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(I)c1
Yield: 84.5 %

Procedure:
52.5 g (0.2 mol) of methyl 3-iodobenzoate were heated to reflux for 18 hours with 81 g (0.2 mol) of Lawesson reagent in 330 ml of xylene. By working-up in an analogous manner to that described in Example 1(B) there were obtained 47 g (84.4%) of O-methyl 3-iodothiobenzoate as a yellow evil-smelling oil which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][NH:17][CH3:18]>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([N:17]([CH3:18])[CH3:16])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reactant: CNC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of (4-methanesulfonyl-phenyl)-methanesulfonyl chloride from Step 2 (1.0 g, 3.7 mmol) in CH2Cl2 (40 mL) was added dimethylamine (0.42 g, 9.3 mmol) dropwise. After 18 h, the resulting reaction mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (HCl 10%, NaHCO3, brine), dried (MgSO4), filtered, and concentrated to provided the C-(4-methanesulfonyl-phenyl)-N,N-dimethyl-methanesulfonamide compound.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])(CC)C.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH:12]1[CH:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Boc-pyrrolidine (5.0 g) was dissolved in diethyl ether (60 mL) and the solution was cooled to −78° C. N,N,N′,N″-Tetramethylethylenediamine (TMEDA) (4.4 mL) was added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, benzaldehyde (3.6 mL) was added and the mixture was stirred at −70° C. for an additional 30 min. The reaction mixture was allowed to warm to room temperature and was then quenched with water and poured into EtOAc (200 mL). The separated organic layer was washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (heptane/EtOAc, 8/1; 6/1) to afford 6.3 g of N-Boc-2-(hydroxy(phenyl)methyl)-pyrrolidine as a mixture of diastereomers. The resulting N-Boc-2-(hydroxy(phenyl)methyl)pyrrolidine (5.6 g) was dissolved in dichloromethane (500 mL) and trifluoroacetic acid (60 mL) was added. The mixture was concentrated, dissolved in dichloromethane (200 mL), and washed with saturated aq. sodium bicarbonate (3×100 mL). The aqueous layers were extracted with dichloromethane (4×50 mL) and the combined organic layers were concentrated. The crude product was distilled in a Kugelrohr apparatus (150-175° C., 0.2 Torr) to afford 2.47 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 178 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH:30]=O)=[CH:24]3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:29][CH:28]=2
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of 5-bromo-2-oxindole (46 mg, 0.22 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.22 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (64%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33]([NH:37][S:38](Cl)(=[O:40])=[O:39])(=[O:36])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:38]([NH:37][C:33](=[O:36])[CH2:34][CH3:35])(=[O:40])=[O:39])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CCC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A mixture of Example 34B (52.2 mg, 0.110 mmol) and the product of Example 100A (94.6 mg, 0.55 mmol) in dichloromethane (5 mL) was treated with triethylamine (66.5 mg, 0.658 mmol). The mixture was stirred at rt for 15 minutes. The reaction mixture was partitioned between dichloromethane and 1N hydrochloric acid, and the aqueous phase extracted with additional dichloromethane. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (36.3 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ 0.41 (s, 2H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3H) 0.88 (t, J=7.54 Hz, 3H) 1.33 (m, 2H) 1.57 (s, 3H) 2.04 (m, 1H) 2.14 (q, J=7.35 Hz, 2H) 2.25 (m, J=13.97, 3.31 Hz, 1H) 7.48 (dd, J=9.01, 2.39 Hz, 1H) 7.54 (m, J=8.27, 3.86 Hz, 1H) 7.59 (d, J=2.21 Hz, 1H) 7.71 (d, J=8.82 Hz, 1H) 7.76 (d, J=3.68 Hz, 2H) 8.16 (d, J=8.09 Hz, 1H) 10.94 (s, 1H) 11.98 (s, 1H) 13.80 (s, 1H).). MS (ESI+) m/z 575.2 (M+H)+, 592.2 (M+NH4)+, (ESI−).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])C(F)(F)F)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[OH-:20].[Na+].Cl>C(OCC)(=O)C>[O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12]([OH:17])=[O:20])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)O)c1cccc2c1OCC2
Temperature: 80 °C
Yield: 99 %

Procedure:
4-(2,3-Dihydrobenzofur-7-yl)-1,1,1-trifluoro-4-methyl-2-pentanone (1.00 g) was treated with NaOH (3.6 mL, 4 M in ethanol-water (2:1)) at room temperature. The mixture was heated to 80° C. for 1 hour. After the mixture had been cooled to room temperature, 20 mL of ethyl acetate, and approximately 15 mL of 2 M HCl were added. The organic phase was separated and the aqueous layer was extracted with three 20 mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed to yield 800 mg (99%) of 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanoic acid as an orange-brown solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH:23]=[CH:24][N:25]=[CH:26]5)[CH:19]=[CH:20][C:14]=3[C:13](=[O:31])[NH:12][C:11]=2[CH:32]=1)([CH3:6])[CH3:5].O[Li].O>C1COCC1.O>[CH:26]1[C:27]2[C:22](=[C:21]([C:18]3[CH:19]=[CH:20][C:14]4[C:13](=[O:31])[NH:12][C:11]5[CH:32]=[C:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:33])=[O:2])[CH:8]=[CH:9][C:10]=5[NH:16][C:15]=4[CH:17]=3)[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)NC(=O)c1ccc(-c3cccc4cnccc34)cc1N2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc2c(c1)NC(=O)c1ccc(-c3cccc4cnccc34)cc1N2
Temperature: 25 °C

Procedure:
A mixture of Example 806 (85 mg, 0.2 mmol) and LiOH.H2O(42 mg, 1 mmol) in THF (3 mL) and water (5 mL) was heated under reflux for 6 hours. After the reaction mixture cooled to room temperature, it was neutralized to pH=6. The solution was extracted with EtOAc three times, and combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to give the title compound. MS (ESI) m/e 424 (M+H)+, 1H NMR (DMSO-d6, 500 MHz): □ 9.85 (s, 1H), 9.56 (s, 1H), 8.55 (br s, 1H), 8.30 (dd, J=6.08, 3.28 Hz, 1H), 7.99 (s, 1H), 7.85-7.88 (m, 4H), 7.14 (d, J=1.87 Hz, 1H), 7.05 (s, 1H), 7.03 (dd, J=7.96, 1.72 Hz, 1H), 6.95 (d, J=1.25 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>CCO>[CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 3-oxo-butyric acid ethyl ester (7 mL, 53.7 mmol), aniline (5 g, 53.7 mmol), acetic acid (0.060 mL) and 4 Å molecular sieves (5 g) in EtOH (20 mL) was refluxed for 5 h. After cooling to r.t., the mixture was filtered. EtOAc was added to rinse the solids, and the filtrate was concentrated to give a reddish oil, which was purified by silica gel chromatography (0-10% EtOAc/hexanes) to give 7 g of the title compound as a pale yellow oil. 1H NMR (CDCl3, 200 MHz): δ=10.38 (br s, 1H), 7.00-7.40 (m, 5H), 4.69 (s, 1H), 4.15 (q, 2H, J=7.0 Hz), 2.00 (s, 3H), 1.29 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)C(C)(C)C)cs2)ccc1-n1cnc(C)c1
Yield: 98.8 %

Procedure:
96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 25 mg (0.2 mmol) pivaloylchloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure to yield 90 mg (99%) N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-2,2-dimethyl-propionamide as a light yellow solid. MS ISP (m/e): 456.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.37 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.22 (d, 1H), 7.05-6.99 (m, 2H), 6.44 (s, 1H), 4.95 (m, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.73 (m, 2H), 1.65 (m, 1H), 1.14 (s, 9H), 0.91 (d, 3H), 0.87 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1([CH2:17][N:18]([CH3:19])[CH3:20])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(CN(C)C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(CN(C)C)CCNC1
Yield: 96.5 %

Procedure:
A mixture of 1-benzyl-3-dimethylaminomethyl-pyrrolidine-3-carboxylic acid methyl ester (400 mg), 10% Pd/C (40 mg) and methanol (30 ml) was shaken in a hydrogen parr shaker at 45 psi for overnight. The mixture was filtered through celite, washed with ethyl acetate. The combined filtrate was concentrated to give the title compound as oil (260 mg, 96%).
Reaction SMILES: CO[CH:3]([O:22]C)[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]([O:20][CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].S(=O)(=O)(O)O>O1CCCC1.CCCCCC>[CH3:21][O:20][CH:9]([C:5]1[S:6][C:7]([CH:31]=[O:32])=[CH:8][C:4]=1[CH:3]=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(C(OC)c2sccc2C(OC)OC)cc1OC
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(OC)c2sc(C=O)cc2C=O)cc1OC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
16.9 g of 3-dimethoxymethyl-2-(α-methoxy-3,4-dimethoxybenzyl)thiophene are dissolved in 200 ml of tetrahydrofuran. 37.5 ml of 1.6M n-butyl lithium in hexane are added dropwise thereto at -78° C., and the reaction mixture is warmed up to -30° C. gradually. After the mixture is chilled at -78° C., 4.3 ml of N,N-dimethylformamide are added thereto. The mixture is stirred for 30 minutes. The reaction mixture is warmed up to ambient temperature. The mixture is acidified with diluted sulfuric acid, stirred for one hour and extracted with chloroform. The extract is washed with aqueous sodium bicarbonate solution and water, dried and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography [solvent: hexane-ethyl acetate (2:1)], and the eluate is condensed. 14.6 g of 2-(α-methoxy-3,4-dimethoxybenzyl)thiophen-3,5-dicarbaldehyde are obtained as an oil.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1

Procedure:
A solution of 0.55 g methyl 4-({5-cyclohexyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}methyl)benzoate from Step C Example 1 in 16 mL ethanol and 6 mL water was treated with 2.4 equivalents of 5 N NaOH solution till the hydrolysis was complete based on HPLC. After evaporating ethanol under reduced pressure, the residue was acidified with 20% molar excess of 2 N HCl to precipitate the acid product. Extract the reaction mixture with 2×35 mL EtOAc. Wash the combined organic layer with saturated brine, dry over anhydrous Na2SO4, and evaporate to give the title compound as a white solid. It can be recrystallized from 5:3 MeCN and water to give fine crystalline needles. 1H NMR (CDCl3, 500 MHz) δ 7.95˜7.97 (m, 2H), 7.84˜7.87 (m, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 6.56 (s, 1H), 5.48 (s, 2H), 2.60 (tt, J=3.0 & 11.8 Hz, 1H), 1.72˜1.78 (m, 4H), 1.68˜1.72 (m, 1H), 1.37˜1.44 (m, 2H), 1.23˜1.35 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1([NH2:36])[CH2:35][CH2:34]1>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:36][CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(NC(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 44.2 %

Procedure:
Following the same procedure in Example 105, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole (0.095 mmol) and cyclopropylamine (13 uL, 11 mg, 0.19 mmol) in THF (6.0 mL). The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 22 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.29-0.40 (m, 2 H), 0.57-0.66 (m, 2 H), 1.49-1.64 (m, 2 H), 1.67 (s, 9 H), 1.70-1.86 (m, 4 H), 1.99-2.15 (m, 2 H), 2.20-2.31 (m, 1 H), 2.31-2.41 (m, 1 H), 3.65-3.78 (m, 2 H), 3.94-4.06 (m, 2 H), 4.15-4.30 (m, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.92 (dd, J=8.69, 1.66 Hz, 1 H), 8.05 (d, J=8.79 Hz, 1 H), 8.18 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=524.3; Anal. Calcd for C25H35F2N5O3S+1.20 TFA+0.60H2O+0.40 EtOAc (711.33): C, 49.64; H, 5.75; N, 9.85. Found: C, 49.62; H, 5.71; N, 9.83.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:2]1[NH:15][N:16]=[N:17][C:1]=1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(OCC#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2nn[nH]n2)cc1

Procedure:
A mixture of methyl 4-cyanomethyloxybenzoate (53.5 g, 0.20 mol), sodium azide (16.9 g, 0.26 mol) and ammonium chloride (13.9 g, 0.26 mol) in DMF 1000 (mL) was refluxed overnight under N2. After cooling, the mixture was concentrated in vacuo. The residue was suspended in cold water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo, to afford methyl 4-(2H-tetrazol-5-ylmethoxy)benzoate. This compound was used as such in the following step.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[C:8]([S:21][CH3:22])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)(=[O:5])=[O:4].[OH:25]O>C(O)(=O)C>[F:24][C:2]([F:1])([F:23])[S:3]([O:6][C:7]1[C:8]([S:21]([CH3:22])=[O:25])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)(=[O:5])=[O:4]
Reactant: OO
Reactant: CCCC(C)n1ccc2c(SC)c(OS(=O)(=O)C(F)(F)F)ccc21
Solvent: CC(=O)O
Product: CCCC(C)n1ccc2c(S(C)=O)c(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 4-(methylthio)-1-(pentan-2-yl)-1H-indol-5-yltrifluoromethanesulfonate (13) (1.3 g, 3.4 mmol) in acetic acid (CH3COOH, 5.0 mL) at around 5° C. was added hydrogen peroxide (H2O2, 30%, 0.42 ml, 3.7 mmol). The mixture was allowed to warm to room temperature, stirred overnight, and then concentrated to dryness in vacuo to give 4-(methylsulfinyl)-1-(pentan-2-yl)-1H-indol-5-yl trifluoromethanesulfonate (17) (1.32 g, 100%). 1H NMR (500 MHz, CD2Cl2): δ 7.58 (d, J=9.0, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.35 (m, 1H), 7.13 (d, J=9.0, 1H), 4.57 (m, 1H), 3.07 (d, 3H), 1.87 (m, 2H), 1.55 (m, 3H), 1.26 (m, 2H), 0.92 (m, 3H). Mass (ESI, M+H): 398.4. See also Bronner, S. M.; Bahnck K. B.; Garg, N. K.; Org. Lett., 11: 1007 (2009).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C(O)C.C(OCC)(=O)C.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>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7](=[O:8])[C:2]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2-c2ccccn2)cc1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of 3-bromo-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one (0.5 g, 1.32 mmol) from Example 22, Step 2 and 2-tributylstannylpyridine(0.58 g, 1.58 mmol) and tetrakis(triphenylphosphine)palladium(0.15 g, 0.13 mmol) in N-methyl-2-pyrrolidine(50 ml) and ethanol(1 ml) was heated at a temperature of 100° C. for 24 hours. Then the mixture was cooled to room temperature and diluted with ethyl acetate and filtered through a pad of celite. The mixture was washed with 5% aqueous KF, dried and concentrated. The residue was subjected to flash chromatography to yield the title compound as a pale yellow solid(0.27 g).