Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][Cl:19])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][CH2:18][CH2:17][CH2:16][C:15]#[C:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCCCCl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: ClCCCC#CC1CCNCC1
Yield: 46.6 %

Procedure:
A solution of 14.6 g (16.3 mmol) of the crude 4-(5-Chloro-pent-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester in 44 ml CH2Cl2 was treated with 44 ml of TFA at 0° C. (for 20 min). The reaction was evaporated and partitioned between aqueous 10% KHSO4/Et2O (3×). The aqueous phase was adjusted to pH>10 by adding 1N NaOH and extracted with EtOAc (3×) The organic phase was dried over Na2SO4 and evaporated to give 1.41 g (50% over two steps) of 4-(5-Chloro-pent-1-ynyl)-piperidine, MS: 186 (MH+, 1Cl).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:26]I>C1COCC1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Yield: 101 %

Procedure:
23.3 mL of lithium bis(trimethylsilyl)amide (1.0 M, 23 mmols) was added dropwise to 4.75 g (23 mmols) of methyl 4-tert-butylphenylacetate in 100 mL of dry THF at −78° C. while stirring under nitrogen. The mixture was stirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyl iodide was added dropwise and the solution was stirred for an additional 1 hour at −78° C. The mixture was poured into 200 mL of H20 and the desired product was extracted with 500 mL diethyl ether. The organic layer was backwashed once with 500 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 5.12 g of a dark oil. The oil was purified via silica gel chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1. The fractions containing the desired product were combined and concentrated under reduced pressure to yield the title compound 2.65 g (53%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][CH2:8][CH:9](O)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]1)[CH3:6].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH:9]([CH2:8][O:7][CH2:5][CH3:6])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCN1CCN(CC(O)COCC)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCN1CCN(CC(Cl)COCC)CC1

Procedure:
To 100 mL of chloroform is added 24 g (0.2 mol) of thionyl chloride and 27.2 g (0.1 mol) of 1-ethoxy-3-(4-hexylpiperazin-1-yl)-2-propanol. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add saturated aqueous sodium bicarbonate until gas evolution ceases. Dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][C:14]2[C:15](Cl)=[N:16][C:17]([Cl:21])=[CH:18][C:19]=2[CH3:20])=[O:12])[C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:9][CH3:10])[C:15]3[N:16]=[C:17]([Cl:21])[CH:18]=[C:19]([CH3:20])[C:14]=3[NH:13][C:11](=[O:12])[C:4]=2[CH:3]=1
Reactant: CCNc1ncc(Br)cc1C(=O)Nc1c(C)cc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
A solution of crude 5-bromo-N-(2,6-dichloro4-methyl-3-pyridinyl)-2-(ethylamino)-3-pyridinecarboxamide (77.7 g, mmol) in anhydrous pyridine (1.0 L) was heated to 50° C. A 1 M solution of NaHMDS in THF (418 mL, 418 mmol) was then added dropwise and stirring was continued for an additional 15 min. After cooling to room temperature, water (50 mL) was added and the mixture concentrated to two-thirds volume on a rotary evaporator. The residue was then poured into water (3 L). Filtration gave the title compound (23.44 g) as a tan solid. The filtrate was extracted with EtOAc (3×) and the combined extracts were washed with water and brine then dried (NgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 9:1 or CHCl3) to give an additional amount of the title compound (14.06 g, for a total of 37.50 g, 50% yield for 3 steps).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.[O:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26][CH2:25]1>>[O:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=4)=[N:9][N:8]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:5]3=[CH:6][N:7]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(Br)cc23)n1
Reactant: CC1(C)OB(C2=COCCC2)OC1(C)C
Product: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(C4=COCCC4)cc23)n1
Yield: 45 %

Procedure:
Following the Suzuki coupling procedure of Example 10, 5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were reacted and purified via silica gel chromatography using a gradient of EtOAc in heptane to afford 68 mg (45%) of 5-(3,4-Dihydro-2H-pyran-5-yl)-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 381.1 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[CH3:24][CH:25](Cl)[O:26][C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28].C(OCC)(=O)C>CN(C=O)C.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH:25]([O:26][C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])[CH3:24])=[O:13])[CH3:3]
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=C(C(=O)OC(C)OC(=O)OC3CCCCC3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 50 °C
Yield: 19.2 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.43 g) was dissolved in dry DMF (4.3 ml) and thereto was added triethylbenzylammonium chloride (0.25 g). Thereto was dropped 1-chloroethylcyclohexylcarbonate (0.62 g) and the mixture was stirred under heating to 50° C. One hour later, the mixture was cooled to room temperature and thereto was added ethyl acetate. The mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2→1:3→ethyl acetate only) to give 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.12 g, yield 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][CH2:35]2)[CH:31]=[N:30][CH:29]=1.C[O-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:38][CH2:39]2)[CH:31]=[N:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)CC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a slurry of tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.186 g, 0.275 mmol) in 2 mL MeOH was added sodium methanolate 25 wt % in MeOH (0.126 mL, 0.550 mmol). 2 mL THF was added. The cloudy mixture was sealed and stirred rapidly. After 1 h, additional sodium methanolate 25 wt % in MeOH (0.126 mL, 0.550 mmol) was added. The reaction became a clear, orange solution. After 2 h, the reaction was concentrated under a stream of N2, and the solid was partitioned between saturated aqueous NH4Cl and DCM. 1 mL 1N HCl was added to acidify the aqueous layer. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM/MeOH and adsorbed onto 1.5 g silica gel, dried, and purified by silica gel chromatography (40 g column) using 20-80% EtOAc/hexane. The product-containing fractions were concentrated to afford tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.104 g, 0.199 mmol, 72.4% yield) as a orange solid. MS (ESI, pos. ion) m/z: 522 (M+1).
Reaction SMILES: C([O:8][C:9]([CH:11]([N:18]1[CH2:21][CH:20]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C:19]1=[O:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:9]([CH:11]([N:18]1[CH2:21][CH:20]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[C:19]1=[O:33])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Yield: 81 %

Procedure:
1-(α-Benzyloxycarbonylbenzyl)-3-phthalimido-2-azetidinone (1.32 g) was dissolved in ethyl acetate (30 ml), and to the solution, there was added 10% palladium on carbon (500 mg), and the mixture was subjected to catalytic reduction in a stream of hydrogen gas at ordinary temperature and ordinary atmospheric pressure. After a calculated volume of the hydrogen gas was absorbed into the reaction mixture in the course of 3 hours. The reaction mixture was adjusted to about pH 8 with 2% aqueous sodium bicarbonate. The catalyst was removed by filtration from the reaction mixture and the aqueous layer was separated from the resultant filtrate. The aqueous solution was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by distillation from solution under reduced pressure to give an crystalline residue, which was washed with diethyl ether to give 1-(α-carboxybenzyl)-3-phthalimido-2-azetidinone (0.85 g), mp 182° to 183° C.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].CN(C)[CH:21]=[O:22].Cl.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.O1CCCC1>[CH:21]([C:8]1[C:7]([NH:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[N:6][CH:11]=[CH:10][CH:9]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Whilst maintaining a reaction temperature of −78° C., 781 ml (1.25 mol) of a 1.6-molar solution of n-butyllithium in n-hexane were added dropwise to a solution of 89.1 g (0.5 mol) of N-(2-pyridinyl)-2,2-dimethylpropanamide in 300 ml of anhydrous tetrahydrofuran. The mixture was allowed to heat slowly up to 0° C. and stirred for 3 hours at this temperature. Then the mixture was again cooled to −78° C. and whilst maintaining this temperature the solution of 109.6 g (1.5 mol) of dimethyformamide in 150 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was allowed to come up to 0° C. and then stirred into 1 l of ice water. It was initially acidified with 12% aqueous hydrochloric acid, then made alkaline by the addition of solid potassium carbonate and extracted thoroughly with diethylether. The combined ether extracts were dried over sodium sulphate and evaporated down. The crystalline residue, after recrystallisation from diisopropylether, had an m.p. of 83° C. Yield: 94.0 g (91.2% of theory).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[N:12]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:12]2[C@@H:11]([C:9]([OH:10])=[O:8])[CH2:15][N:14]([CH3:16])[C:13]2=[O:17])=[CH:19][C:20]=1[C:26]([F:28])([F:29])[F:27])#[N:25]
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1C[C@H](C(=O)O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of (R)-benzyl 3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylate (25d) (0.4 g, 0.99 mmol) in MeOH (10 mL), 10% Pd/C (50 mg) was added and stirred for 2 h under H2 atmosphere. After completion (by TLC), the reaction mixture was filtered through a celite bed, the celite bed was washed with MeOH (10 mL), the combined filtrates were concentrated under reduced pressure to provide the acid 25e (0.280 g, 90%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:7])C.[OH-].[Na+].C(OCC)C>C(O)C.O>[F:14][C:10]1[CH:9]=[C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:15])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(C)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(CC(=O)O)c1cccc(F)c1
Yield: 92.6 %

Procedure:
A crude solution of 3-(3-fluorophenyl)butyric acid ethyl ester, 10.1 g, 48 mmol] in ethanol (50 mL) was treated with 10 M NaOH solution (50 mL, 857 mmol). The reaction mixture was refluxed overnight. The reaction mixture was dried under reduced pressure in order to get rid of the ethyl alcohol. The resulting residue was re-dissolved in 150 mL of water. The mixture was transferred to a separatory funnel using water (50 mL) and diethyl ether (200 mL). The mixture was equilibrated and the ether layer was removed. The aqueous layer was acidified by HCl solution (pH˜2) and extracted with diethyl ether (300 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This afforded 8.1 g of an orange viscous oil, 3-(3-fluorophenyl)butyric acid (92.6% yield). This material was determined to be 100% pure by GC/MS analysis.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20](O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][OH:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:14]([Si:1]([O:18][CH2:19][C@@H:20]1[O:28][CH2:27][C:23]2=[N:24][CH:25]=[CH:26][N:22]2[CH2:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1CO)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1Cn2ccnc2CO1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Separately, prepare a −78° C. solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol (5.3 g; 1.0 equiv; 12.91 mmoles) in dichloromethane (25 mL). Add the in situ prepared iodinating reagent dropwise to the solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol, with the orange color quickly fading to nearly colorless. Maintain the solution at −78° C. for 30 minutes, then allow it to warm to 0° C. and maintain for 10 minutes. Re-cool the solution to −78° C., and add tetrahydrofuran (100 mL) followed by 60% sodium hydride (1.14 g; 2.2 equiv; 28.40 mmoles). Slowly warm the solution to 0° C. over 30 minutes, and then to ambient temperature for 1 hour. Pour the mixture slowly into 50% saturated sodium bicarbonate solution and extract with dichloromethane (4×100 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (10 to 100% ethyl acetate in hexanes) to afford the desired product contaminated with triphenylphosphine oxide. Further purify by SCX ion-exchange chromatography (10% methanol in dichloromethane to 10% (4N ammonia in methanol) in dichloromethane) to afford the desired tert-butyl-[[(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methoxy]-diphenyl-silane (1.86 g; 37%). MS (m/z): 393(M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[F:19][C:20]([F:30])([F:29])[CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([CH2:21][C:20]([F:19])([F:29])[F:30])=[CH:23][CH:24]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: FC(F)(F)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 42.8 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.25 mmol) was reacted with 4-(2,2,2-trifluoroethyl)aniline (0.066 g, 0.37 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.047 g, 62%) as an off-white solid. MW=439.30. 1H NMR (DMSO-d6, 500 MHz) δ 14.07 (s, 1H), 9.77 (s, 1H), 7.91 (t, J=1.8 Hz, 1H), 7.75-7.70 (m, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.46 (q, J=7.9 Hz, 4H), 7.08 (s, 1H), 3.70 (q, J=11.6 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.29-2.19 (m, 2H); APCI MS m/z 403 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.Cl.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)=[O:21])[CH2:18][CH2:19]2)=[O:11])[N:3]=[N:2]1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
4-(1H-1,2,3-Triazol-4-yl)butanoic acid (step 4) (882 mg, 4.95 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (step 2) (1.5 g, 4.95 mmol) were suspended in DMF (20 ml). DIPEA (4.32 ml, 24.74 mmol) was added and the reaction mixture stirred until all components were in solution. 50% T3P® solution in DMF (5.78 ml, 9.89 mmol) was added and the reaction mixture was stirred at RT for 48 hrs. The reaction mixture was diluted with EtOAc and washed twice with 10% citric acid. The aqueous citric acid wash was extracted with DCM (3×) and the combined extracted were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, using a gradient solvent system of 0-10% MeOH in EtOAc. The resulting product was further purified by stirring in diethyl ether over 72 hours. The mixture was filtered and the solid was dried in a vacuum oven to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[H-].[Na+].Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:5](=[N:9][S:28](=[O:30])(=[O:29])[CH2:27][CH2:26]2)[C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1
Reactant: COc1ccnc(N)c1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC1=C(c2ccc(Oc3ccccc3)cc2)C2=NS(=O)(=O)CCN2C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxy-3-(4-phenoxyphenyl)pyridin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 85.0 mg) and 2-chloroethanesulfonyl chloride (0.133 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc then crystallized from THF—IPE to give the title compound (60.0 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[OH:28][C@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 71 using 5-bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 71.1) and 5-fluoropyridin-3-ylboronic acid to afford a brown solid. UPLC-MS (Condition 3) tR=0.92 min, m/z=479.1 [M+H]+, m/z=477.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=10.88, 4.28 Hz, 2H) 3.25 (dd, J=10.64, 5.01 Hz, 2H) 3.92-4.02 (m, 2H) 4.90 (d, J=3.79 Hz, 2H) 7.35 (d, J=8.44 Hz, 2H) 7.80-7.84 (m, 1H) 7.84-7.90 (m, 2H) 8.08 (d, J=2.32 Hz, 1H) 8.47-8.53 (m, 1H) 8.61 (d, J=2.69 Hz, 1H) 8.77 (d, J=2.32 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][CH:11]([OH:15])[CH2:12][CH2:13]Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1
Reactant: Nc1ccccc1Br
Reactant: OC(CBr)CCBr
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: OC1CCN(c2ccccc2Br)C1

Procedure:
2-Bromoaniline (2 g) was heated with 1,4-dibromo-2-butanol (1.58 ml) and diisopropylethylamine (4.9 ml) in toluene (10 ml) at reflux for 20 h. The reaction mixture was allowed to cool, diluted with water (60 ml) and the aqueous phase extracted with ethyl acetate (3×30 ml). The combined extracts were washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0–20% ethyl acetate in isohexane, to afford the product as a yellow oil (2.30 g).