Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1.O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:27]12[O:32][CH:30]([CH2:29][CH2:28]1)[CH2:31][N:25]([C:18]1[N:17]=[C:16]([Cl:15])[N:21]=[C:20]3[N:22]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)[N:23]=[CH:24][C:19]=13)[CH2:26]2
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropyl azodicarboxylate (0.71 mL, 3.6 mmol) was added in drops to a suspension of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.53 g, 2.0 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (0.48 g, 2.4 mmol), and triphenylphosphine (0.79 g, 3.0 mmol) in tetrahydrofuran (20 mL). After stirring at room temperature for 16 hours, the mixture was adsorbed onto flash silica gel and purified by automated flash chromatography (hexanes/ethyl acetate) to provide tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a white solid contaminated with a light yellow material (0.81 g, 90%). MS (ES+): 448.9, 450.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:43][NH:44][OH:45].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:43][N:44]([OH:45])[C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: CNO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(O)C(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 36.1 %

Procedure:
A mixture of 4-(3-(2-benzyloxyphenyl)propyl]benzoic acid (1.0 g), 1-HOBT (0.39 g) and DCCI (0.595 g) in DMF (10 ml) was stirred for 3 hours, then added to a solution of N-methylhydroxylamine HCl (0.24 g) and Et3N (0.29 g) in CH2Cl2 (10 ml) and stirred for 70 hours. The product was extracted in 2N aqueous KOH and washed with ethyl acetate. The aqueous solution was acidified with concentrated HCl and extracted with diethyl ether. The solvent was evaporated and the residue subjected to flash chromatography on silica gel (using diethyl ether:methanol (95:5) as eluant) to give N-methyl-N-hydroxy-4-(3-(2-benzyloxyphenyl)propyl)benzamide as a gum (0.39 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:14][CH:15]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([F:19])([F:18])[F:17])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:19][C:16]([F:17])([F:18])[CH:15]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[O:14][C:5]1[C:4]([NH2:1])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=[N+]([O-])c1cc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
3-Nitro-2-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoline (253 mg, 0.720 mmol) obtained in Step 3 was dissolved in ethanol (12.7 mL). To this, tin chloride dihydrate (817 mg, 3.62 mmol) was added and the mixture was stirred at 90° C. for 1 hour. By addition of an aqueous sodium bicarbonate solution to neutralize the reaction mixture, the reaction was stopped. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1) to give Compound HF (182 mg, yield: 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)=[CH:4][C:3]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(O)cc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1OC(F)(F)F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 4-methyl-3-(trifluoromethoxy)phenol (Intermediate 29, 364 mg, 1.89 mmol) and 2 chloro-5-nitropyridine (300 mg, 1.89 mmol) in acetonitrile (4 mL) was added K2CO3 (653 mg, 4.72 mmol) at room temperature. The mixture was heated at reflux for 18 hrs until completion. The resulting mixture was cooled down to room temperature, diluted with water (10 mL) and ethyl acetate (10 mL). Phases were separated, the organic layer was washed with an aqueous 10% solution of ammonium chloride (10 mL) and aqueous 13% solution of NaCl (10 mL). The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (594 mg) as pale brown oil.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]C)=[O:11])[CH2:6][C@H:5]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N+:2]=[N-:3].[OH-].[Li+].O>O1CCCC1>[N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][C@H:5]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CC[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 36.5 h

Procedure:
(1S,2R,4S)-1-Azido-2-(N-tert-butoxycarbonylamino)-4-methoxycarbonylcyclohexane (509 mg) was dissolved in tetrahydrofuran (40.0 ml), lithium hydroxide (111 mg) and water (5.0 ml) were successively added under ice cooling, and the mixture was stirred at room temperature for 36.5 hours. The solvent was distilled off under reduced pressure, water and 1N hydrochloric acid (4.64 ml) were added to the residue, and the solvent was distilled off again under reduced pressure to obtain crude (1S,2R,4S)-1-azido-2-(N-tert-butoxycarbonylamino)-4-carboxycyclohexane. Dichloromethane (25 ml) and N,N-dimethylformamide (260 μl) were added to this crude product, and the mixture was stirred under ice cooling. Further, oxalyl chloride (216 μl) was added to continuously stir the mixture at room temperature for 1 hour. tert-Butylamine (1130 μl) was added to the reaction mixture under ice cooling to stir the mixture at room temperature for 14 hours. After water and dichloromethane were added to the reaction mixture to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the title compound (197 mg) as a pale yellow amorphous substance.
Reaction SMILES: C1(S(C2C=CC(Cl)=C([N+:16]([O-])=O)C=2)=O)C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:22][C:21]=1[N+:40]([O-:42])=[O:41]>>[NH2:16][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:22][C:21]=1[N+:40]([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccccc2)ccc1Cl
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Product: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
The procedure described in Example 20 is followed, except that as a starting material instead of phenyl-(4-chloro-3-nitrophenyl) sulfoxide a corresponding amount of 4-(4-chloro-3-nitrophenyl-sulfinyl)-biphenyl is employed.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH:7]1([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[CH:14]1([N:13]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: COC(=O)CBr
Solvent: c1ccccc1
Product: COC(=O)CN(C1CCCCC1)C1CCCCC1
Yield: 100 %

Procedure:
3.06 g (20 mmole) of methyl bromoacetate were added, whilst ice-cooling, to a solution of 7.25 g (40 mmole) of N,N-dicyclohexylamine in 50 ml of dry benzene, and the mixture was heated under reflux for 9 hours. At the end of this time, the reaction mixture was cooled, the precipitated materials were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to afford 5.07 g of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[S:27])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCNc1c(N)cccc1N
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Yield: 55.8 %

Procedure:
To a solution of ethyl N-(2,6-diaminophenyl)-beta-alaninate (Reference Example 25; 500 mg, 2.24 mmol) in tetrahydrofuran (22 mL) was added 2,4-dichlorophenyl isothiocyanate (503 mg, 2.46 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and NH-silica gel eluting with a 10-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (533 mg, 1.25 mmol, 56%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:41]1[S:45][N:44]=[CH:43][N:42]=1)[S:7]([C:10]1[C:39]([F:40])=[CH:38][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3([F:37])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[F:40][C:39]1[C:10]([S:7]([NH:6][C:41]2[S:45][N:44]=[CH:43][N:42]=2)(=[O:9])=[O:8])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3([F:37])[CH2:27][NH:28][CH2:29]3)[CH3:19])[C:13]=2[CH:38]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(F)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[C@H](c1ccccc1C1(F)CNC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Reaction time: 0.25 h

Procedure:
In a 1 dram vial, added crude (R)-tert-butyl 3-(2-(1-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-3-fluoroazetidine-1-carboxylate (32-5, 25.8 mg, 0.035 mmol) to DCM (277 μl) and TFA (69.4 μl). After 15 min, diluted with 1 mL MeOH, filtered through Celite and concentrated in vacuo. Dissolved in 2 mL DMSO and purified by reverse-phase HPLC (C18 column, 5-60% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 32-6 as a white solid. 1H NMR δ (ppm) (CH3OH-d4): 8.22 (1H, s), 7.80 (1H, d, J=7.86 Hz), 7.75 (1H, d, J=5.61 Hz), 7.62 (1H, t, J=7.61 Hz), 7.56-7.44 (2H, m), 7.06 (1H, d, J=9.97 Hz), 5.49 (1H, d, J=6.64 Hz), 5.12-4.90 (2H, m), 4.81-4.61 (2H, m), 1.95 (3H, d, J=7.03 Hz). HRMS C20H18F2N5O4S2 [M+H] calc: 494.0763, obs: 494.0754.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24].O1CCOCC1>C(O)(C)(C)C>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:23]([NH2:24])[C:22]([CH2:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[CH:4]2
Reactant: Nc1ccc(Cl)cc1C=O
Reactant: COc1cccc(OC)c1CCC#N
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COc1cccc(OC)c1Cc1cc2cc(Cl)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-chlorobenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile. Instead of dioxane, tert-butanol was used from [sic; as]1 the solvent. 1TN: “aus” (from) appears to be a typo for “als” (as).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1C.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:19](Cl)Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:19])[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(O)ccc1Br
Reactant: ClCCl
Product: Cc1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 100 mL round bottom flask was added 4-bromo-3-methylphenol (1.00 g, 5.35 mmol), benzeneboronic acid (1.30 g, 10.7 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][O:35][C:43](=[O:45])[CH3:44])=[CH:31][CH:32]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCO)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCOC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 24 h

Procedure:
To a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethyl)phenoxy]ethoxycarbonyl)-1,4-dihydropyridine (1.25 g, 2.52 mmoles) in CH2Cl2 (15 mL) cooled to 0° C., were added pyridine (0.25 mL, 3.10 mmoles) and acetic anhydride (0.85 mL, 9.0 mmoles). The reaction mixture was left at room temperature for 24 hours. Water (20 mL) was then added to extract the pyridine. The organic layer was dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product (1.5 g) was purified by flash chromatography (solvent=93:7 CH2Cl2 :acetone) to yield 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-acetoxyethyl)phenoxy]ethoxycarbonyl)-1,4-dihydropyridine, mp=110° C. NMR (CDCl3) δppm: 8.2(m, 9H); 5.15(s, 1H); 4.5-3.9(m, 6H); 3.63(s, 3H); 2.87(t, 2H); 2.37(s, 6H); 2.07(s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[C:33]=1[Cl:41]>C1COCC1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:31][C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[C:33]=3[Cl:41])[C:14]2=[O:19])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCCC2=O)CC1
Reactant: Clc1c(CBr)sc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC(Cc3sc4ccccc4c3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Place cis-1-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one, (300 mg, 0.96 mmol) in 7.0 mL of THF, cool to −78° C. and treat with 2.0 M LDA (0.72 mL, 1.5 mmol). Stir for 5.0 minutes, treat with 2-bromomethyl-3-chloro-benzo[b]thiophene (250 mg, 0.96 mmol) and stir at −78° C. for five hours, and warm to room temperature. Quench reaction with ammonium chloride, extract with dichloromethane, dry over sodium sulfate and purify via silica chromatography (ethyl acetate/hexanes 0-25%) affords 166 mg (35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=2[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([CH3:21])[O:18][C:17]([CH3:23])([CH3:22])[C:16]=3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1Nc2ccc(-c3cccc(Cl)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 17 from 3-chlorophenyl boronic acid and 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine. A orange solid: mp 144-146° C.; 1H-NMR (CDCl3) δ 7.50 (t, 1H, J=1.78 Hz), 7.40 (dt, 1H, J=7.61, 1.45 Hz), 7.33 (t, 1H, J=7.76 Hz), 7.29-7.22 (m, 4H) 6.72 (d, 1H, J=8.24 Hz), 4.90 (q, 1H, J=5.45 Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.46 (d, 3H, J=5.5 Hz); MS (ES) m/z 288/290 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:24]([C:30]([OH:32])=O)=[N:23]2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[NH2:71][C@H:72]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C@@H:73]([OH:77])[C:74]([OH:76])=[O:75]>>[OH:77][C@H:73]([C@H:72]([NH:71][C:30]([C:24]1[CH:25]=[C:26]([CH2:27][CH2:28][CH3:29])[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:17]=2)[N:23]=1)=[O:32])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:74]([OH:76])=[O:75]
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Reaction time: 0.02 h
Yield: 17.9 %

Procedure:
A solution of 1-((2′-(N-(methoxycarbonyl)sulfamoyl)biphenyl-4-yl)methyl)-5-propyl-1H-pyrazole-3-carboxylic acid (40.2 mg, 87.8 μmol), DIPEA (91.8 μL, 527 μmol) and HATU (33.4 mg, 87.8 μmol) in DMF (0.4 mL, 4 mmol) was stirred to pre-activate the acid. After 1 minute, (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (17.1 mg, 87.8 μmol) was added, and the mixture was stirred for 10 minutes. The reaction was quenched by adding 1 N HCl and extracted with DCM. The organic layer was added to AcOH (1 mL) and evaporated in vacuo. The material was then purified by preparative HPLC to yield the title compound (10 mg, 95% purity). MS m/z: [M+H]+ calcd for C32H34N4O8S, 635.21. found 635.20.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2ncccc2o1
Product: C(#Cc1ccccn1)CCc1nc2ncccc2o1
Yield: 28.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (100 mg, 0.49 mmol) and 2-(but-3-ynyl)oxazolo[4,5-b]pyridine (100 mg, 0.58 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 35 mg (0.14 mmol, 29%) of 2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine as a brown semi-solid with a purity of 86%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Oc1ccccc1
Product: COc1ccc2c(Oc3ccccc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenol to give (6-methoxy-1-phenoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:33])=[C:5]([CH2:7][O:8][C:9]2[CH:32]=[CH:31][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:15]3)=[CH:11][CH:10]=2)[N:6]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:3][C:4]([CH3:33])=[C:5]([CH2:7][O:8][C:9]2[CH:32]=[CH:31][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:15]3)=[CH:11][CH:10]=2)[N:6]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(C)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(COc2ccc(Cn3cc(CCC(=O)O)c(-c4ccccc4)n3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A mixture of methyl 3-[1-[4-(2,5-dimethyl-4-oxazolylmethoxy)benzyl]3-phenyl-1H-pyrazol-4-yl]propionate (254 mg), lithium hydroxide monohydrate (69.9 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (1.7 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated to yield 3-[1-[4-(2,5-dimethyl-4-oxazolylmethoxy)benzyl]3-phenyl-1H-pyrazol-4-yl]propionic acid (243 mg, yield: 99%) as an amorphous substance.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:41])[CH3:40]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.9 %

Procedure:
To a solution of Intermediate A (116 mg, 0.714 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 44 mg, 1.1 mmol) and the mixture stirred at RT for 20 min. A solution of Intermediate 63b (280 mg, 0.714 mmol) in DMF (3 mL) was added and the mixture was stirred at 60° C. for 25 min, and up to 150° C. over 20 min. The cooled mixture was diluted with water and extracted with DCM (4×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified twice by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (141 mg, 37%). LCMS (Method 3): Rt 3.12 min, m/z 536 [MH+].