Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:49][CH2:48][C:12]4[N:13]=[C:14]([C:27]5[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]6[C:28]=5[C:29]([CH3:47])=[N:30][N:31]6[S:37]([C:40]5[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=5)(=[O:39])=[O:38])[N:15]=[C:16]([N:17]5[CH2:22][CH2:21][C@@H:20]([O:23][CH3:24])[C:19]([CH3:26])([CH3:25])[CH2:18]5)[C:11]=4[CH2:10]3)[N:6]([CH3:50])[N:5]=2)[CH2:3][CH2:2]1.[Cl:51]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:51][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]([CH3:50])[C:7]=1[N:9]1[CH2:49][CH2:48][C:12]2[N:13]=[C:14]([C:27]3[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]4[C:28]=3[C:29]([CH3:47])=[N:30][N:31]4[S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:44])=[CH:45][CH:46]=3)(=[O:39])=[O:38])[N:15]=[C:16]([N:17]3[CH2:22][CH2:21][C@@H:20]([O:23][CH3:24])[C:19]([CH3:25])([CH3:26])[CH2:18]3)[C:11]=2[CH2:10]1
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C4CC4)nn2C)CC3)CC1(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.062 g, 0.089 mmol) in DCM (2 mL) under an atmosphere of nitrogen was added N-chlorosuccinimide (0.012 g, 0.089 mmol). The mixture was left to stir for 1 h at rt. The reaction mixture was then directly purified by FCC (40-75% EtOAc/heptanes) to give the title compound. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 8.08 (d, J=8.3 Hz, 1 H), 7.79 (d, J=8.3 Hz, 2 H), 7.45 (d, J=8.8 Hz, 1 H), 7.25 (d, J=8.3 Hz, 2 H), 4.32 (d, J=14.7 Hz, 1 H), 4.22 (d, J=14.4 Hz, 1 H), 3.67 (d, J=11.6 Hz, 1 H), 3.58 (s, 3 H), 3.52 (dq, J=12.8, 6.3 Hz, 2 H), 3.28-3.36 (m, 4 H), 3.09 (br. s., 1 H), 2.99 (br. s., 2 H), 2.92 (dd, J=8.6, 3.8 Hz, 1 H), 2.86 (d, J=11.6 Hz, 1 H), 2.72 (s, 2 H), 2.36 (s, 3 H), 2.25 (s, 3 H), 1.88-1.96 (m, 4 H), 1.78-1.88 (m, 1 H), 1.52-1.69 (m, 3 H), 0.94 (s, 3 H), 0.81-0.90 (m, 8 H); MS (ESI+) m/z 729.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1ccsc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A dry flask was charged with 3-Methyl-thiophene-2-carboxylic acid (0.500 g, 3.520 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (35 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.888 g, 3.517 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 3-Methyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.940 g, 2.50 mmol, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.CN([CH:25]=[O:26])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:25]=[O:26])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a suspension of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 (50 g, 195 mmol, 1.0 equiv.) in THF (anhydrous, 800 ml) at −78° C. was added slowly 2.5 M solution of n-BuLi in hexanes (93.9 ml, 234.6 mmol, 1.2 equiv.). The resulting slurry was allowed to warm up to −60° C. and a clear brown solution was observed. The solution was then cooled to −78° C. and DMF (anhydrous, 22.7 ml, 293 mmol, 1.5 equiv.) was added slowly. The resulting solution was stirred at −78° C. for 0.5 hour, then warmed up slowly to 0° C. over a period of 1-1.5 hours. The solution was then poured slowly to a mixture of 0.25 M aq. hydrochloric acid (1.65 L) and ice water (800 ml). The resulting slurry was stirred at 0-10° C. for 0.5 hour, filtered and rinsed with cold water (200 ml). The cake was dried in vacuum oven at 40° C. for 24 hours to afford 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 5 as a light yellow solid (54.9 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.76 (t, J=4.9 Hz, 1H), 3.95 (t, J=4.9 Hz, 4H), 8.28 (s, 1H), 10.20 (s, 1H). LCMS (ESI pos) m/e 285 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a stirred solution of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (350 mg, 1.06 mmol) from Step 3 of this Example in DCM (15 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (287 mg, 1.17 mmol), and the mixture was allowed to warm to rt and stirred for a further 2 h. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid. The solid was triturated with Et2O, filtered, then dried to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (336 mg, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.41 (br s, 1H), 8.22 (s, 1H), 8.04-8.15 (m, 2H), 7.63 (d, J=8.3 Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19]SC)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][Cl:25])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCCl)cc2C1
Reaction time: 1 h

Procedure:
To a solution of 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (9.6 g) in methylene chloride (100 ml) was added a solution of sulfuryl chloride (2.75 ml) in methylene chloride (30 ml) under an argon atmosphere and with ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated and toluene was added to the obtained residue to filter off insoluble material. The solvent was evaporated and dried under reduced pressure to give the title compound (7.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:66][CH2:67][CH2:68][CH2:69][CH2:70]O>O1CCCC1.O>[Cl:66][CH2:67][CH2:68][CH2:69][CH2:70][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: OCCCCCl
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCl)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
10 g (23 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are dissolved in 400 ml of tetrahydrofuran. 9.2 g (35 mmol) of triphenylphosphine and 6.9 ml (35 mmol) of diisopropyl azodicarboxylate are added and the reaction medium is stirred at room temperature for 30 minutes. 2.8 ml (28 mmol) of 4-chlorobutanol are then added, and the medium is kept stirring for 12 hours, and then poured into 500 ml of water and extracted with ethyl acetate. The residue obtained is purified by chromatography on silica gel (eluent: 80/20 heptane/ethyl acetate). 8.9 g of ethyl 4′-(4-chlorobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a colorless oil (yield=73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:5](=[O:8])[NH:6][CH:7]=1.I[CH3:16]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([O:8][CH3:16])=[N:6][CH:7]=1
Reactant: CI
Reactant: COCCCOc1cc(Br)c[nH]c1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COCCCOc1cc(Br)cnc1OC
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 113.26 mmol of 5-bromo-3-(3-methoxypropoxy)-1H-pyridin-2-one, 79.28 mmol of silver carbonate and 158.56 mmol of iodomethane in 230 ml of benzene is stirred at 45° C. with exclusion of light for 24 hours. The reaction mixture is cooled to room temperature, and the silver salts are filtered off. The filtrate is washed with 2% sodium bicarbonate solution and water (2×). The organic phase is dried over sodium sulphate and evaporated. The crude title compound is obtained as a beige oil from the residue and is employed without further purification in the next stage. Rf=0.45 (EtOAc-heptane 1:2); Rt=4.34 (Gradient I).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:23]([O:22][C:20]([C:18]1[O:19][C:15]([CH2:14][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[Cl:1])=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 24 h

Procedure:
Alternately, combine 2-chlorobenzimidazole (20 mmol) and sodium hydride (20 mmol) in dimethylformamide (30 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (20 mmol) and stir. After 1 day, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:24])([F:23])[F:22])([O:16][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:23])([F:22])[F:24])([OH:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
6,8-Dichloro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.4 g, 1.0 mmol) was dissolved in THF (5 mL) and KOH (280 mg, 5.0 mmol) in H2O (5 mL), was added. The resulting mixture stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were then dried over Na2SO4 and concentrated under reduced pressure to give the crude residue which was purified by column chromatography [EtOAc-hexane (1:19) as eluant] to provide the title compound as a white solid (100 mg, 26%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.03 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 6.6 (s, 1H), 2.72-2.64 (m, 2H), 2.23-2.19 (m, 1H), 2.0-1.9 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC.O.[Br:24][CH2:25][CH2:26]Br>>[Br:24][CH2:25][CH2:26][O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)c1cc(F)ccc1OCCBr
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Dissolved 1-(5-fluoro-2-hydroxyphenyl)ethanone (10.0 g, 64.9 mmol) in 18 mL 1,2-Dibromoethane and added Potassium carbonate (18.8 g, 136 mmol) and 100 mL 2-Butanone. Heated the reaction mixture to reflux and allowed to stir overnight under nitrogen. Reaction was complete by LCMS. Diluted reaction mixture with water and extracted the product with ethyl acetate. Concentrated in vacuo and purified by flash chromatography (0 to 30% ethyl acetate/heptanes) to give 3.71 g (21.9% yield) of 1-(2-(2-bromoethoxy)-5-fluorophenyl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[OH:24]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: O=S([O-])OO
Reactant: C[C@H](Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (Preparation 232, 130 mg, 0.37 mmol) in acetone (1 mL) was added an aqueous solution of Oxone® (1 mL, 287 mg, 0.44 mmol) dropwise with stirring at 0° C. for 15 minutes. The reaction mixture was diluted with water and extracted with DCM (3×5 mL). The mixture was filtered through a phase separation cartridge, the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (62 mg, 69%) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:11]>C(O)CCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH2:11])[C:7]=1[F:8]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1ncnc(Cl)c1F
Temperature: 90 °C
Yield: 89 %

Procedure:
A mixture of 4,6-dichloro-5-fluoro-pyrimidine (1.67 g, 10.0 mmol), n-butanol (6 mL) and 28% ammonium hydroxide (12 mL) in a sealed tube was heated at 90° C. for 2 hours. The precipitated white crystals were collected by filtration to give the desired compound (1.31 g, 89% yield). LCMS (ESI) m/z: 147.9 [M+H+].
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@H:54]1[C:59](O)=[O:60])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]1[C:59]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:60])([CH3:48])([CH3:46])[CH3:47]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.348 g, 1.00 mmol), HOBt (0.135 g, 1.0 mmol), EDCI (0.230 g, 1.2 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid (0.276 g, 1.1 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclohexyl)-carbamic acid tert-butyl ester (573 mg, 100%). The product (0.120 g, 0.21 mmol) was taken up in 1 ml of EtOAc, and cooled in ice bath. 4N HCl-EtOAc (1.0 ml) was added slowly, and the mixture was stirred at room temperature for 5 hours. The solvent was removed and remaining material was triturated with ethyl ether to give the desired product 4 (colorless amorphous, 90 mg, 84%) as hydrochloride salt. LC: 100%. MS: m/z=473.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][C:20](O)=[O:21])=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][N:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[CH2:19][CH2:18][C:17]2[C:13]([CH3:12])=[N:14][O:15][C:16]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)CCc2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.47 g), 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.50 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.75 g, yield 79%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 140–141° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:17]([C:27](=[O:45])[N:28]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=3)[CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:43][C:41]([F:42])([F:44])[C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=1)[CH2:30][N:28]([CH3:29])[C:27](=[O:45])[C:17]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1
Reactant: Cc1ccccc1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8.7 %

Procedure:
To a solution of 6.60 g (104 mmol) 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (Example 43) and 8.40 ml (207 mmol) methanol in 50 ml ethyl acetate 14.7 ml (207 mmol) acetyl chloride were added dropwise at 0° C. After 4 h the reaction mixture was diluted with ethyl acetate and treated with 1 N sodium hydroxide solution. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated to give 5.36 g of crude product. Flash column chromatography afforded 4.86 g (87.4%) of the title compound as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:44]=[CH:43][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:45]3[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=3)[S:7][C:6]=2[CH:52]=1.[OH-].[K+]>C(O)C.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:44]=[CH:43][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40])([C:28]([OH:30])=[O:29])[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:45]3[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=3)[S:7][C:6]=2[CH:52]=1
Reactant: CCOC(=O)C(CCCCCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
Diethyl 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate (1.197 g, 1.59 mmol) was dissolved in ethanol (20 ml), and potassium hydroxide (3.58 g, 63.8 mmol) dissolved in water (10 ml) was then added. After stirring for 24 hours at 80° C., the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove ethanol, adjusted to pH 3 with 3N aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.1 g) as a brown product, which was then used for the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[N:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nc(-c2ccccn2)cs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(-c4ccccn4)cs3)(CC1)CC2
Yield: 15.5 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-(2-pyridyl)thiazole (60.3 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(2-pyridyl)thiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl)pyrrolidine-2-carbonitrile (11.6 mg).