Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:34]=[CH:35][CH:36]=1)[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([C:23]1[C:32](Cl)=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2[N:56](C)C)CCCCC1.Cl.[OH-].[Na+]>O1CCOCC1.[Cl-].[Na+].O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH2:56][C:32]1[C:23]([C:21]([N:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[CH2:15][C:14]2[CH:34]=[CH:35][CH:36]=[C:12]([Cl:11])[CH:13]=2)=[O:22])=[N:24][C:25]2[C:30]([N:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C(c1nc2ccccc2nc1Cl)N1CCCC1Cc1cccc(Cl)c1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc2ccccc2nc1C(=O)N1CCCC1Cc1cccc(Cl)c1
Reaction time: 16 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.3 mL, 1.34 mmol, 1.0 M in THF) was added dropwise to a degassed mixture of (2-(3-chlorobenzyl)pyrrolidin-1-yl)(3-chloroquinoxalin-2-yl)methanone (235 mg, 0.61 mmol), tris(dibenzylideneacetone) dipalladium(0) (28 mg, 5 mol %) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (12 mg, 5 mol %) in anhydrous 1,4-dioxane (5.0 mL) at room temperature under nitrogen, after which the mixture was heated to reflux to stir for 16 h. The cooled mixture was treated with 1 N HCl (2 mL), stirred for 30 min and the adjusted to pH 10 with 2 N sodium hydroxide solution and diluted with brine (100 mL). The mixture was extracted with ethyl acetate (2×150 mL) and the combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate and filtered. The filtrate solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to provide (3-aminoquinoxalin-2-yl)(2-(3-chlorobenzyl)pyrrolidin-1-yl)methanone as a brown oil: 1H NMR (400 MHz, CDCl3, ˜2:1 mixture of rotamers) δ 7.88 (d, J=9.5 Hz, 1H, rotamers A and B), 7.67-7.63 (m, 1H, rotamers A and B), 7.49-7.11 (m, 1H, rotamers A and B), 7.34 (s, 1H, rotamer A), 7.28-7.19 (m, 1H, rotamers A and B and 3H, rotamer A), 7.09 (d, J=8.9 Hz, rotamer B), 7.00 (t, J=7.8 Hz, rotamer B), 6.88 (s, 1H, rotamer B), 6.73 (d, J=7.8 Hz, 1H, rotamer B), 6.19 (s, 2H, NH2, rotamer A), 6.08 (s, 2H, NH2, rotamer B), 5.22-5.15 (m, 1H, rotamer B), 4.61-4.54 (m, 1H, rotamer A), 3.96-3.89 (m, 2H, rotamer B), 3.84-3.73 (m, 2H, rotamer A), 3.37 (dd, J=3.3. 12.8 Hz, 1H, rotamer A), 2.95 (dd, J=5.0, 13.4 Hz, 1H, rotamer B), 2.83-2.73 (m, 1H, rotamer A), 2.59-2.53 (m, 1H, rotamer B), 2.07-1.75 (m, 4H, rotamers A and B) ppm; ESI MS m/z 367 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@H](C[C@@H](C)CCCCC)C(O)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Product: CCCCC[C@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
A procedure similar to that used to prepare compound 158 was used except that (S)-2-((S)-2-methyl-heptyl)-succinic acid 4-tert-butyl ester 166 (5.78 g, 20.18 mmol) was used as a reactant to give 167 as an oil (4.18 g, 76%). 1H NMR (400 MHz, CDCl3) δ 3.64-3.58 (m, 1H), 3.84-3.42 (m, 1H), 2.28-2.20 (m, 1H), 2.09-2.02 (m, 1H), 1.43 (s, 9H), 1.26-1.18 (m, 8H), 1.11-1.04 (m, 2H), 0.87-0.83 (m, 6H); MS (APCI) m/z 217 (M+−55, 50%, -tBu).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:22]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].Cl>C1COCC1.CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:22]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
To a cooled (−78° C.) solution of 4-[5-(3,4-dichlorophenyl)pentyl]-phenylamine (0.231 g, 0.75 mmol) in THF (2 mL), LHDMS (2.25 mL, 1 M in hexane, 2.25 mmol) was added dropwise. The reaction mixture was allowed to stir at −78° C. for 10 minutes. A solution of 2-fluoro-5-nitrobenzoic acid (0.139 g, 0.75 mmol) in THF (2 mL) was added dropwise, and this solution was stirred for 30 minutes at −78° C. The reaction mixture was allowed to gradually warm to room temperature and stir for 2 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc, and acidified with 1N HCl (pH 3). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield a brown residue. Purification by flash chromatography (silica gel, 2% MeOH/CH2Cl2) then recrystallization with MeOH yielded 265 mg (0.56 mmol, 75%) of the desired product. mp 147-148° C.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:19][CH:18]=1)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Li+].[OH-].[NH4+].[Cl-].CCOCC>CO>[CH3:32][C:2]([CH3:1])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC#CC(C)(C)OCc1ccc(CCC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCC#CC(C)(C)OCc1ccc(CCC(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of (55) (442 mg, 1 mmol) in MeOH (20 mL), was added LiOH (10 equiv). The resulting mixture was refluxed for 12 hours and then allowed to cool to 25° C. The reaction mixture was poured into a saturated solution of NH4Cl (50 mL) and Et2O (70 mL). The organic layer was separated, dried (MgSO4) and concentrated by rotary evaporation to yield 17) (349 mg, 90%) as a yellow oil; 1H NMR (CDCl3) δ 9.00 (s, 1 H), 7.30 (d, J=7.8 Hz, 2H), 7.18 (d, J=7.8 Hz, 2 H), 4.60 (s, 2 H), 2.94 (t, J=7.8 Hz, 2 H), 2.66 (t, J=7.5 Hz, 2 H), 2.23 (t, J=6.9 Hz, 2 H), 1.52 (s, 6 H), 1.28 (m, 16 H), 0.89 (t, J=6.9 Hz, 3 H); 13 ; C NMR (CDCl3) δ 179.25, 139.24, 137.31, 128.17, 128.08, 84.85, 82.37, 70.79, 6.06, 35.89, 31.89, 30.36, 29.55, 29.32, 29.24, 29.11, 28.82, 28.78, 22.68, 18.60, 14.13. ##STR31##
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][OH:31])[O:27][C:26]5=[O:32])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCCCCC.CCO>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[C@H:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][OH:31])[O:27][C:26]5=[O:32])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCN2c3ccc(N4C[C@H](CO)OC4=O)cc3OCC2C1
Solvent: CCO
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)N1CCN2c3ccc(N4C[C@H](CO)OC4=O)cc3OC[C@@H]2C1

Procedure:
A solution of 50 mg/mL of a mixture of diastereomers 1,2,4a,5-Tetrahydro-8-[5-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-pyrazino[2,1-c][1,4]benzoxazine-3(4H) -carboxylic acid phenylmethyl ester (EXAMPLE 1, Step 8) is made in the mobile phase that consisted of 35% EtOH in hexane (V/V). The solution (200 mg) is injected into a 5.1×50 cm Chiralcel OD column at 30° C. The column is eluted at 45 ml/min and monitored at 305 nm. The two diastereomers are collected using a peak recognition program and fractions are pooled appropriately. Each diastereomer is obtained at >98% diastereomer excess. Diastereomeric excess is determined on a 0.46×25 cm Chiralcel OD-H column at ambient column temperature, using the mobile phase consisted of 0.1% TEA in EtOH and the monitor set at 218 nm detection. The retention times are 58.9 and 65.6 minutes. (α=1.14; 0.2 mL/min).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16])[CH3:6]>>[Cl:16][C:10]1[C:9]([CH2:8][O:7][CH2:5][CH3:6])=[CH:14][C:13]([N+:1]([O-:4])=[O:2])=[C:12]([F:15])[CH:11]=1
Reactant: CCOCc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Product: CCOCc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-40° C.) solution of fuming nitric acid (90%, 25 ml) was added dropwise 2-chloro-4-fluorobenzyl ethyl ether (2.5 g, 0.013 mole) at a rate which maintained the temperature at or below -40° C. Upon completion of addition, the reaction mixture was stirred for 15 minutes at -40° C. The reaction mixture was poured into ice (200 ml) and extracted with methylene chloride (7×40 ml). The extracts were combined, washed with water (2×40 ml), dried (magnesium sulfate) and concentrated under reduced pressure. The residue was passed through a column of silica gel eluting with ethyl acetate:heptane (1:9). Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.07 g of 4-chloro-5-ethoxymethyl-2fluoronitrobenzene. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[CH3:8].[OH-:11].[K+].[BH4-].[Na+]>>[CH3:1][CH:2]1[C:7]([CH3:8])=[N:6][NH:5][C:4](=[O:11])[NH:3]1
Reactant: [OH-]
Reactant: CSc1nnc(C)c(C)n1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CC1=NNC(=O)NC1C
Yield: 35.4 %

Procedure:
5,6-Dimethyl-3-methylthio-1,2,4-triazine (2.48 g) was reacted with potassium hydroxide (1.792 g), and the reaction mixture was reduced by sodium borohydride (0.907 g) in a similar manner to that of Example 32-(3). The above reaction mixture was concentrated, and the residue was treated with 10% hydrochloric acid and then evaporated under reduced pressure. The resultant solid was extracted with a mixture of chloroform and methanol. The extract was evaporated, and the resultant residue was dissolved in a small amount of water. The solution was passed through a column of DIAION NP-20 (Trademark, manufactured by Mitisubishi Chemical Industries Ltd.) (100 ml) using water and then a mixture of methanol and water (1:1) as eluents. The eluate with aqueous methanol was evaporated under reduced pressure and the residue was dissolved in acetone under reflux. The solution was treated with activated charcoal and filtered. The filtrate was evaporated and resultant residue was recrystallized from ethanol to give 5,6-dimethyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.719 g), m.p. 200°~102.5° C.
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[CH2:7][C@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[C@@H:11]([CH2:16][CH3:17])[C:12](OC)=[O:13]>O>[O:2]=[C:3]1[CH2:7][C@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[C@@H:11]([CH2:16][CH3:17])[C:12]([NH2:1])=[O:13]
Reactant: N
Reactant: CCC[C@H]1CC(=O)N([C@@H](CC)C(=O)OC)C1
Solvent: O
Product: CCC[C@H]1CC(=O)N([C@@H](CC)C(N)=O)C1
Temperature: 2.5 °C
Reaction time: 6 h

Procedure:
Ammonia gas was condensed in 2 ml water at 0-5° C. and the temperature of the system was maintained at 0-5° C. 0.68 g of methyl (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate obtained such as described above was then added dropwise, maintaining the reaction mixture at 0-5° C. The system was then stirred for 6 hrs, with TLC indicating completion of reaction. After standing overnight at ambient temperature the reaction mixture was concentrated at 40° C. under vacuum and further dried by azyeotropic distillation with toluene to give 150 mg of crude (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanamide.
Reaction SMILES: CO[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1.B(Br)(Br)[Br:19]>C(Cl)Cl.O>[Br:19][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: COCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
To a solution of 5-(2-methoxyethyl)-2sulfamoylbenzo[b]thiophene (8.3 g, 0.031 mol) in 550 ml of methylene chloride at -78° C. was added dropwise under nitrogen, 100 ml of a solution of boron tribromide (BBr3) (lM in hexane, 0.1 mol). The reaction was stirred at room temperature overnight (15 hours) following the addition. The mixture was cooled and diluted with 100 ml of cold water. The aqueous phase was separated and extracted 2X with methylene chloride. The original organic phase and the extracts were combined, dried, filtered and concentrated to dryness to yield 8.3 g (86%) of product with m.p. 118°-120° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([S:25][CH2:26][CH2:27][CH2:28][OH:29])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[C:6]([S:25][CH2:26][CH2:27][CH2:28][O:29][S:1]([CH3:4])(=[O:3])=[O:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
Mesyl chloride (6 μl, 0.075 mmol) was added to a solution of 3-tritylsulfanyl-propan-1-ol (5 mg, 0.015 mmol) and triethyl amine (32 μl, 0.23 mmol) in THF (1 ml). After 30 minutes THF was evaporated under reduced pressure and the crude product dissolved in DCM, washed with a saturated solution of sodium hydrogencarbonate in water, a saturated solution of sodium chloride and dried with MgSO4. A yield of 10 mg was obtained after evaporation under reduced pressure (analytical HPLC: column Luna C18,00B-4251-E0: solvents: A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 10 min; flow 1.0 ml/minute; retention time 7.12 minutes detected at 214 and 254 nm). Structure verified by NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[CH:26][C:31]=1[O:32][CH3:33]
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (3.23 g, 23.7 mmol) and diisopropyl azodicarboxylate (DIAD, 5.23 g, 25.9 mmol) in THF (20 ml) was added drop wise to a solution of Ethyl 2-(3-Hydroxy-4-methoxyphenyl)acetate (Step A, 5.48 g, 26.12 mmol) and triphenylphosphine (6.79 g, 25.9 mmol) in THF (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4]B1C2CCCC1CCC2.[CH3:16][C@@:17]([O:24][CH3:25])([CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[O:19].C(OCC)C.C(CN)O>CCCCC.CO>[CH3:25][O:24][C@:17]([CH3:16])([CH2:20][CH2:21][CH2:22][CH3:23])[C@@H:18]([OH:19])[C:4]#[C:3][Si:2]([CH3:15])([CH3:14])[CH3:1]
Reactant: CCCC[C@](C)(C=O)OC
Reactant: C[Si](C)(C)C#CB1C2CCCC1CCC2
Solvent: CCCCC
Solvent: CCOCC
Solvent: NCCO
Product: CCCC[C@@](C)(OC)[C@@H](O)C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
Dissolve B-(2-(trimethylsilyl)ethynyl)-9-borabicyclo[3.3.1]nonane.tetrahydrofuran complex (2.13 g, 7.3 mmol) in pentane (25 mL) and add (2R)-2-methyl-2-methoxyhexanal (1.06 g, 7.3 mmol). Stir at room temperature for 72 hours. Remove the solvent under a positive nitrogen pressure to give a yellow solid. Add ethyl ether (30 mL) and methanol (500 μL). Cool to 0° C. and add, by dropwise addition, ethanolamine (440 μL, 7.3 mmol). Stir overnight, centrifuge the reaction mixture and separate the clear supernatant liquid. Wash the precipitate with pentane (2×10 mL) and combine the organic phases. Wash with water (2×25 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography (19:1 hexane/ethyl acetate) to give (3S,4R)-4-methoxy-4-methyl-l-trimethylsilyl-1-octyn-3-ol as a clear liquid (900mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:26](=[O:42])([O:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:30][NH2:31])[NH2:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[C:26](=[O:42])([O:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:30][NH:31][C:23](=[O:24])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:27]
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 40 mg (111 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 156A in WO 2007/134862], 33 mg (133 μmol) of the compound of Example 37A, 25 mg (133 μmol) of EDC and 21 mg (133 μmol) of HOBt in 2.4 ml of DMF was stirred at RT overnight, 1 ml of 1 M hydrochloric acid was then added and the mixture was separated directly by preparative HPLC [Method 20] into its components. This gave 53 mg (81% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:11]1[C:20]([O:22][CH3:23])=[O:21].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:23][O:22][C:20]([N:11]1[CH2:12][CH2:13][CH:14]([C:16]([OH:18])=[O:17])[CH2:15][CH:10]1[C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(F)cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1cc(F)c(F)cc1F
Yield: 83.9 %

Procedure:
Dimethyl 2-(2,4,5-trifluorophenyl)piperidine-1,4-dicarboxylate (2.971 g, 8.97 mmol) was dissolved in acetonitrile (30 mL) and water (0.600 mL), then lithium bromide (6.23 g, 71.74 mmol) was added. Triethylamine (4.97 mL, 35.87 mmol) was added and the resulting brown suspension was heated under reflux. Water and MTBE were added. The organic phase was extracted with water (×2). The pooled aqueous layer was acidified to pH 1 with 3.8 M HCl and then extracted with MTBE (×2). The combined organic layer was washed with water and evaporated. Traces of water were azeotropically removed by MeCN. 1-(Methoxycarbonyl)-2-(2,4,5-trifluorophenyl)piperidine-4-carboxylic acid (2.388 g, 84%) was isolated as a yellow oil. MS m/z 318 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH:46]1[CH2:53][CH:52]2[N:54]([CH3:55])[CH:48]([CH2:49][CH2:50][CH2:51]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:55][N:54]1[CH:48]2[CH2:49][CH2:50][CH2:51][CH:52]1[CH2:53][CH:46]([NH:45][C:18]([C:16]1[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=13)=[O:20])[CH2:47]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: COc1cc(C(=O)O)c2nc(-c3ccccc3)oc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CC3CCCC(C2)N3C)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
A mixture of 6-methoxy-2-phenylbenzoxazole-4-carboxylic acid (100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (99 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.40 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide (24 mg, 16%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.08 (br s, 1H), 8.21-8.19 (m, 2H), 7.81 (d, J=2.5 Hz, 1H), 7.59-7.54 (m, 3H), 7.23 (d, J=2.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.93 (s, 3H), 3.25-3.10 (m, 2H), 2.70-2.55 (m, 5H), 2.27-2.00 (m, 3H), 1.65-1.55 (m, 3H), 1.35-1.20 (m, 2H); MS (ESI+) m/z 406 (M+H); HPLC>99% (AUC), tR=13.14 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Cl:17])[C:15]=1[NH2:16])[C:11]#[N:12].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Cl:17])[C:15]=1[NH2:16])[CH2:11][NH2:12]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To lithium aluminum hydride (0.57 g, 15 mmol) in dry THF (20 mL) was added dropwise 3,5-dichloro-4-aminobenzonitrile (1.87 g, 10 mmol) in THF (30 mL). The mixture was stirred at RT for 2 hours. Then, sodium sulfate decahydrate (4.83 g, 15 mmol) was added and stirred for 30 min. The solid was filtered off and washed with THF for three times. The solvent was removed by rotovap and residue was purified by column with Methanol/DCM (3:7) as the eluant. 3,5-dichloro-4-aminobenzylamine was obtained as an off-white solid (1.5 g, 80%). 1H NMR (300 MHz, CD3OD): δ 7.2 (s, 2H), 3.65 (s, 2H).