Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:25]=1[CH3:26].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Cc1c(I)cnn1-c1ccccn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccn4)c3C)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.12 mmol), 2-(4-iodo-5-methyl-1H-pyrazol-1-yl)pyridine (51.0 mg, 0.18 mmol), copper (I) iodide (6.8 mg, 0.036 mmol), and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.012 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.033 ml, 0.24 mmol). The mixture was sparged with argon for 3 minutes and heated to 60° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)ethynyl]pyrazolo[1,5-a]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+:19]>CO>[CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[N-:17][N:16]=[N:15][N:14]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[K+:19]
Reactant: Cc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccn2c(=O)c(-c3nnn[n-]3)cnc12
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
9-Methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one (63 g, 0.28 mols) is suspended in methanol (1000 ml). The resulting suspension is kept at 45° C. and slowly added with a 45% potassium hydroxide aqueous solution to pH 9-9.5. The suspension is stirred at 45° C. for about 15 minutes and then cooled to 20° C. The precipitate is filtered, washed with methanol and dried under vacuum at 80° C., to obtain Pemirolast Potassium (71.9 g; 0.27 mols, 96% yield) with HPLC purity >99.8%. 1H NMR(D2O, TMS) d (ppm): 2.02 (s, 3H); 6.83 (t, 1H); 7.22 (d, 1H); 8.18 (s, 1H); 8.47 (d, 1H).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:18][C:19]([OH:21])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[CH3:39][C@H:40]1[NH:46][CH2:45][CH2:44][C@@H:43]([CH3:47])[NH:42][C:41]1=[O:48]>ClCCl.CO.ClCCl>[C:9]([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:18][C:19]([N:46]1[CH2:45][CH2:44][C@@H:43]([CH3:47])[NH:42][C:41](=[O:48])[C@H:40]1[CH3:39])=[O:21])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: C[C@@H]1CCN[C@H](C)C(=O)N1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCOCC1
Product: C[C@@H]1CCN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutyl chloroformate (0.085 mL, 0.63 mmol) was added to a solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 210 mg, 0.63 mmol) and N-methylmorpholine (0.080 mL, 0.7 mmol) in 10 mL of dichloromethane at −20 to −30° C. and the resultant mixture was stirred for 1 h. A solution of (3R,7R)-3,7-dimethyl-1,4-diazepan-2-one in dichloromethane (5 mL) was added to the above solution. The reaction mixture was allowed to warm up to room temperature and stirring was continued overnight. The solution was subjected directly to flash chromatography on a Biotage® system (silica gel, 5% methanol/dichloromethane) to yield the title compound as a white solid. MS 358 (M−Boc+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N)(=[S:16])C>C(O)C>[SH:16][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(N)=S
Reactant: CCOC(=O)c1sc(C)nc1CBr
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1CS
Temperature: 95 °C

Procedure:
5 mmol of ethyl 4-(bromomethyl)-2-methyl-1,3-thiazole-5-carboxylate was dissolved in 50 ml of ethanol, then 5.5 mmol of thioacetoamide was added, and the temperature was heated up to 95° C. to carry out the reaction for 4 hours. The reacted liquid was cooled down to a room temperature. Ethanol was evaporated out and then purification was carried out using column separation method with solvents of ethylacetate and hexane, obtaining ethyl 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]([CH3:18])[C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:14])[CH3:13])[O:8][N:7]=1)=[O:4]
Reactant: CN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)N(C)c1cc(C(C)(C)C)on1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a solution of 1,1-dimethyl-3-(5-t-butyl-3-isoxazolyl)-urea (10.99 g) in dry dimethylformamide (10 ml), 50% sodium hydride (2.75 g) is added at room temperature with stirring, and the resultant mixture is heated at 60° C for 15 minutes. A solution of methyl iodide (8.86 g) in dry dimethylformamide (30 ml) is added at 10° C in 1 hour thereto, and the mixture is heated at 80° C for 5 minutes and evaporated to remove the solvent. The residue is combined with water and shaken with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and the solvent is evaporated. The residue is chromatographed on a column of silica gel to give 1,1,3-trimethyl-3-(5-t-butyl-3-isoxazolyl)-urea (10.94 g) as crystals melting at 90 to 91.0° C. The yield is 93.38%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1.[C:17]1(C)[CH:22]=CC(S([O-])(=O)=O)=C[CH:18]=1.[NH+]1C=CC=CC=1.COC(OC)(C)C>CN(C=O)C>[CH3:18][C:17]1([CH3:22])[O:14][C@H:11]([CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[CH2:12][O:13]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: OCCCc1ccc(OC[C@@H](O)CO)cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To (S)-3-[4-(3-hydroxy-propyl)-phenoxy]-propane-1,2-diol (11.5 g, 50.9 mmol) in dry DMF (150 ml) is added pyridinium p-toluenesulfonate (1.28 g, 5 mmol) and 2,2-dimethoxypropane (31 ml, 250 mmol). The mixture is stirred at room temperature for 18 hours and then the solvent is removed in vacuo. The residue is dissolved in EtOAc (150 ml) and washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 1:4 EtOAc/iso-hexane to 1:1 EtOAc/iso-hexane to afford (3-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol as a colourless oil; 1H NMR (CDCl3): 1.25 (1H, br), 1.39 (3H, s), 1.43 (3H,$), 1.85 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.63 (2H, tr, J=6.9 Hz), 3.90 (2H, m), 4.02 (1H, m), 4.12 (1H, m), 4.50 (1H, pent, J=6.8 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[CH:5][CH:4]=1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cccc(-c2csc(-c3ccc(OC)c4oc5ccccc5c34)n2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(-c3cccc(C(=O)O)n3)cs2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a slurry of ethyl 6-(2-(4-methoxydibenzo[b,d]furan-1-yl)thiazol-4-yl)picolinate (50 mg, 0.116 mmol) in ethanol (5 mL), potassium hydroxide (30 mg, 0.535 mmol) in water (0.5 mL) was added. The reaction slurry was stirred at room temperature for 2 h. Subsequently the reaction mixture was poured into water acidified with 1N HCl to a pH of 3-4; the precipitated solid was filtered and washed with ether and hexane. Yield—42%; Rf 0.23 (Chloroform:Methanol (8.5:1.5); HPLC (purity): 96%; 1H-NMR (CDCl3) δ: 4.15 (s, 3H), 7.09 (d, 1H), 7.29-7.32 (m, 1H), 7.51-7.55 (m, 2H), 8.08-8.12 (m, 1H), 8.24 (d, 1H), 8.56 (d, 1H), 8.75 (d, 1H); MS m/z: 403.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].I[C:35]1([S:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:39]1([S:38][C:35]2([O:22][C:19]3[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]4([C:3]([OH:2])=[O:4])[CH2:13][C:12]5[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=5)[CH2:6]4)=[O:33])=[CH:17][C:18]=3[O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH2:37][CH2:36]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: IC1(Sc2ccccc2)CC1
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OC2(Sc3ccccc3)CC2)c1
Yield: 65.4 %

Procedure:
The compound of step 1 of example 254 (50 mg, 0.116 mmol), (1-iodo-cyclopropylsulfanyl)-benzene (G. J. Hollingworth et al., Tetrahedron Lett. 40 (1999), 2633-2636) (64 mg, 0.232 mmol) and silver carbonate (64 mg, 0.232 mmol) in toluene (1 ml) were stirred overnight at 50° C. The mixture was filtered, the filtrate evaporated to dryness and the residue purified by silica gel chromatography (HEP/EA gradient) to yield 44 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19](OC)=[O:20])=[CH:8][C:7]=1[CH2:29][CH3:30].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>C1COCC1.O>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:31])[C:2]([CH3:32])([CH3:33])[CH3:1])=[C:7]([CH2:29][CH3:30])[CH:8]=2)[CH:24]=[CH:23][C:18]=1[CH2:19][OH:20]
Reactant: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1OCC(=O)C(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(CCCc2ccc(CO)c(CO)c2)ccc1OCC(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
900 mg (2 mmol) of dimethyl 4-{3-[4-(3,3-dimethyl-2-oxobutoxy)-3-ethylphenyl]propyl}phthalate are dissolved in 20 ml of THF, and slowly added to a suspension of 375 mg (10 mmol) of lithium aluminum hydride. The reaction medium is stirred for 30 minutes at room temperature, and is then sequentially treated by slow addition of 400 μl of water, 400 μl of 15% sodium hydroxide and 1 ml of water. The reaction medium is poured into a 1% hydrochloric acid solution, and then extracted with ethyl ether. The residue obtained after drying and concentrating is purified by chromatography on a silica column. A thick colorless oil is obtained (m=760 mg, y=95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](OS(C)(=O)=O)=[CH:7][N:6]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][N:6]=1)=[O:4]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cnc(OS(C)(=O)=O)cn1
Product: COC(=O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g (4.3 mmol) 5-methanesulfonyloxy-pyrazine-2-carboxylic acid methyl ester and 0.733 (8.6 mmol) piperidine was shaken at room temperature for 4 h. Subsequent purification on silica eluting with a gradient formed from DCM and methanol yielded after evaporation of the product fractions 0.625 g (66%) of the title compound as light yellow crystals. m/z (ES+): 222.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Chloropyridin-4-yl)ethan-1-one (110 g, 707 mmol, 1.00 equiv) and methanol (1500 mL) were added to a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. NaBH4 (26.4 g, 698 mmol, 1.00 equiv) was added in portions at 0° C. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched by the addition of water (1000 mL). The resulting mixture was concentrated under vacuum and extracted with dichloromethane (3×2000 mL). The combined organic layer was washed with brine (2×2000 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (1:5 ethyl acetate/petroleum ether) to afford 1-(2-chloropyridin-4-yl)ethan-1-ol as colorless oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])=[CH:2][CH3:3].[CH2:10](Br)[CH:11]=[CH2:12].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]=[CH:11][CH3:12])[CH:2]=[CH2:3]
Reactant: CC=COCCCCO
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCCCCOC=CC
Yield: 75 %

Procedure:
A mixture of 20 g 4(1-propenoxy)-1-butanol (0.15 moles), 24.2 g allyl bromide (0.2 moles), 1.26 g tetra-n-butylammonium bromide (3.9 mmoles); 8 g sodium hydroxide (0.2 moles); and 60 mL toluene were stirred at 60° C. for ten hours. After cooling, the reaction mixture was filtered to remove inorganic salts and the filtrate was poured into distilled water. The organic layer was separated and the aqueous layer was washed again with fresh toluene. The toluene layers were combined and the solvent removed on a rotary evaporator leaving 1-allyloxy-4(1-propenoxy)butane (an α-allyloxy-ω-(1-propenoxy)alkane) as a clear oil. Further purification was accomplished by distillation at 110° C. under a vacuum of 0.7 mm Hg, obtaining a 75% yield.
Reaction SMILES: C1([SiH3])C=CC=CC=1.N1CCCC1.CO.[O:15]([C:22]1[CH:23]=[C:24]([C:28]2[CH2:29][CH2:30][CH2:31][N:32]=2)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:15]([C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:29][CH2:30][CH2:31][NH:32]2)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(Oc2cccc(C3=NCCC3)c2)cc1
Agent: [SiH3]c1ccccc1
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(Oc2cccc([C@@H]3CCCN3)c2)cc1
Reaction time: 0.75 h
Yield: 48 %

Procedure:
To oven dried round bottom flask is added S,S-EBTHITiF2 (100 mgs, 0.3 mmol) and diluted with THF (5 mL). The flask is sealed and purged with argon. To the yellow solution is added phenylsilane (4.6 mL, 37.5 mmol), pyrrolidine (100 uL, 1.1 mmol), and anhydrous methanol (100 uL, 1.1 mmol). The resulting yellow mixture is stirred for 45 minutes until green color persisted. A solution of 5-(3-phenoxy-phenyl)-3,4-dihydro-2H-pyrrole (1.2 g, 5.05 mmol) in THF (2 mL) is added to the catalyst and the mixture is stirred for 8 hrs. The reaction is carefully quenched with 10% HCl (100 mL) until gas evolution subsided and the pH˜2. The mixture is diluted with EtOAc (100 mL) and the aqueous layer is removed, neutralized with 3M NaOH (50 mL) until basic and extracted with EtOAc (3×100 mL). The organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressures. The solid residue is purifed by silica gel column chromatography (100% EtOAc) to give (S)-2-(3-phenoxy-phenyl)-pyrrolidine as a yellow solid (580 mgs, 48%). LCMS m/z 240.1 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH2:7][C:6]2[C:8]([CH3:20])=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]4[O:4][C:3]([CH3:21])([CH3:2])[CH2:7][C:6]=4[C:8]=3[CH3:20])[CH2:19][CH2:18]2)=[CH:24][C:25]=1[O:30][CH3:31]
Reactant: COc1cc(Br)ccc1F
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1F
Yield: 53.2 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloric acid salt (311 mg, 1.00 mmol) synthesized in Reference example 147 and 4-bromo-1-fluoro-2-methoxybenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 212 mg (yield 53%). Melting point was 152 to 155° C. (hexane).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])[CH2:5][CH3:6]>C1COCC1.[OH-].[Na+].CO>[CH3:30][C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])([CH2:5][CH3:6])[C:3]([OH:31])=[O:2]
Reactant: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)O

Procedure:
419 mg 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid methyl ester in 25 ml THF, 1.5 ml of 2 M sodium hydroxide and 8 ml methanol were heated under reflux for 3 h. The organic solvents were then removed in vacuo, and the residue was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated. After recrystallization from toluene 240 mg of 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid were obtained.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH:29]=4)[CH2:21]3)[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>CO>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[CH:26]([OH:31])[CH2:27][C:28](=[O:30])[CH:29]=4)[CH2:21]3)[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3=O)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3O)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a mixture of diastereomers from the intermediate of step A according to the procedure of Example 6, step C (NaBH4 in methanol). 1H-NMR (CDCl3): rotamers; δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz), 4.88-4.65 (2H, m), 4.46 (1H, m), 4.07 (0.5H, m), 3.83 (0.5H, m), 3.55 (1H, m), 3.35 (1H, m), 3.28 (1H, m), 2.97 (2H, m), 2.92 (1H, m), 2.58 (1H, m), 2.43 (1H, m), 2.25 (1H, m), 2.13 (1H, m), 2.05-1.85 (2H, m), 1.70-1.55 (2H, m), 1.30 (3H, 2d, J=6.0 Hz). MS: (MH)+572.5 The diastereomers were separated by HPLC on CHIRACEL OD column eluting with hexanes/EtOH (85/15) to afford the individual diastereomers.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[S:31][CH3:32])[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][C:22]=2[S:31]([CH3:32])=[O:6])[CH2:14][CH2:13]1
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)c1cnoc1C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc(C(F)(F)F)ccc1C(=O)c1cnoc1C1CC1
Temperature: -20 °C

Procedure:
3-Chloroperoxybenzoic acid (0.95 g) was added to a cooled solution of 5-cyclopropyl-4-(2-methylsulphenyl-4-trifluoromethylbenzoyl)isoxazole (1.2 g) in dichloromethane with stirring at -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm slowly to 0° C. It was stirred for 1 hour and recooled to -20° C. 3-Chloroperoxybenzoic acid (0.4 g) was added at -20° C. and the mixture was allowed to warm slowly to 0° C. and stirred for 1 hour. The mixture was then filtered and the filtrate was washed with water, aqueous sodium metabisulphite solution, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ethyl acetate and filtered to give 5-cyclopropyl-4-(2-methylsulphinyl-4-trifluoromethylbenzoyl)isoxazole, compound 264 (0.59 g) as a white solid, m.p. 149°-151° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([CH2:23][CH2:24][CH2:25][NH2:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.[H-].[Na+]>CN(C)C=O.O.ClCCl>[CH2:16]([O:15][C:11]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:23][CH2:24][CH2:25][NH:26][C:4](=[O:5])[C:6]3=[CH:14][C:13]=2[CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CCCN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C1NCCCn2c1cc1cc(OCc3ccccc3)ccc12
Yield: 67 %

Procedure:
To the solution of 0.6 g (1.70 mmol) 1-(3-amino-propyl)-5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester in 6 mL N,N-dimethylformamide, 85 μg (1.95 mmol; 55% dispersion in mineral oil) sodium hydride was added. After 2 hours the reaction mixture was diluted with water and dichloromethane, the phases were separated and the aqueous phase was washed three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give the desired compound as a light yellow solid (67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(/C=C/[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1

Procedure:
To a solution of the compound obtained from step e above (0.6 g) in methanol (10 mL), 10% palladium on charcoal (0.05 g) was added at room temperature and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.56 g).