Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:24])=[C:14]([C:16]2([CH3:23])[CH2:21][O:20][CH2:19][C:18]([NH2:22])=[N:17]2)[CH:15]=1>>[NH2:22][C:18]1[CH2:19][O:20][CH2:21][C:16]([C:14]2[CH:15]=[C:10]([NH:9][C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH:11]=[CH:12][C:13]=2[F:24])([CH3:23])[N:17]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: CC1(c2cc(N)ccc2F)COCC(N)=N1
Product: CC1(c2cc(NC(=O)CC(F)(F)F)ccc2F)COCC(N)=N1

Procedure:
In a manner analogous to that described in example E1 (method E), the condensation of 3,3,3-trifluoro-propionic acid with Building block P, (RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine, yielded the title compound as a yellow oil. Mass (calculated) C14H15F4N3O2 [33.283]; (found) [M+H]+=334.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCC1CCOCC1
Reactant: CCCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (218 mg) in dry DMF (3.71 mL) was added potassium carbonate (330 mg). The mixture was stirred at 60° C. for 90 mins. The reaction was cooled and 4-(bromomethyl)tetrahydro-2H-pyran (118 mg) was added. The reaction was stirred at 50° C. for 6 h and was cooled to room temperature. The mixture was taken up in EtOAc (40 mL) and washed with water (2×20 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give a viscous yellow oil. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as a clear oil (92 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:22])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19]Cl)[CH2:14][CH2:13]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:22])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])[CH2:14][CH2:13]1
Reactant: Oc1ccccc1Cl
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)COc2ccccc2Cl)CC1
Reaction time: 48 h

Procedure:
To a solution of 9 (0.194g, 0.6mmol) in 4ml acetone was added 2-chlorophenol (0.092g, 0.72mmol) and potassium carbonate (0.3g, 2.2mmol). The solution was heated to reflux and stirred for 48h. The solution was filtered to remove potassium carbonate, concentrated en vacuo, and purified by Prep TLC (10:1 DCM:MeOH) to yield compound 11. Mass spectrum (M+1)=416.32
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:24][C:25]1[CH:26]=[CH:27][C:28](O)=[C:29]([CH:43]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[Cl:42])=[O:31]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([O:10][C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:43][C:29]=2[C:30](=[O:31])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=2[Cl:42])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1O
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1(C)OC(=O)[C@@H](CC(=O)Oc2ccc(Cl)cc2C(=O)Nc2ccc([N+](=O)[O-])cc2Cl)O1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of (R)-(−)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (Sigma-Aldrich, St. Louis, Mo.) (2.17 g, 12.46 mmol) in chloroform (24 mL) was treated with oxalyl chloride (2.11 mL, 25 mmol) and a drop of N,N-dimethylformamide was added. The progression of reaction was monitored by the observation of gas evolution by means of a bubbler. After 2 hours at room temperature, the reaction mixture was warmed to 50° C. for 2 hours, cooled to room temperature, and concentrated to remove volatiles. This residue was diluted with chloroform (10 mL) and added to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (2.04 g, 6.23 mmol) in pyridine (30 mL) in which 4-dimethylaminopyride (20 mg) had been previously dissolved. The reaction mixture was stirred at room temperature for 16 h and then was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and concentrated to a dark oil. The residue was dissolved in chloroform and placed upon a short column of silica gel (60 mm i.d.×15 mm). The product was eluted with chloroform and concentrated to an oil. The product was crystallized with a mixture of hexanes and ethyl acetate. 1HNMR (300 MHz, DMSO-d6): δ1.456 (s, 3H), 1.495 (s, 3H), 4.939 (m, 1H), 7.352 (d, J=9 Hz, 1H, H3), 7.730 (dd, J=3.9 Hz, 1H, H4), 7.851 (d, J=3 Hz, 1H, H6), 8.110 (d, J=9 Hz, 1H, H6′), 8.255 (dd, J=3, 9 Hz, 1H, H5′), 8.411 (d, J=3 Hz, 1H, H3′), 10.481 (s, 1H, NH).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47].O>CC(C)=O>[CH2:47]([O:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:38])=[N:4]4)[CH2:15][CH2:16]3)[S:21][CH:22]=2)[CH2:29]1)[CH:46]=[CH2:45]
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Yield: 62.3 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (39 mg) and potassium carbonate (47 mg) in acetone (5 ml) is added, at room temperature, allyl bromide (33 mg). The reaction mixture is stirred at reflux for 5 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 1-[4-(4-{5-[2-(allyloxy)-6-chlorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (26 mg).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[OH-].[Na+].Cl>CO.O>[Cl:41][C:32]1[C:33]([C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:15]([CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:42])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(CCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(CCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 65.5 %

Procedure:
A solution of (3-{4-[(2-chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-acetic acid methyl ester (29 mg, 0.05 mmol) and NaOH (126 mg, 3.15 mmol) in MeOH (3 ml) and water (1 ml) was heated to 50° for 30 minutes. The reaction was cooled, neutralized with aqueous HCl (3.15 mmol), diluted with water and extracted with ethyl acetate. The extracts were dried and the solvent evaporated. Trituration of the residue with cyclohexane gave the title compound as a white powder (19 mg, 65%). MS (ESI) 580.2 (M+H)+.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34]([OH:39])[CH:35]=[CH:36][C:37]=1[F:38]>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][C:37]=1[F:38])[O:39][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:22]1[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3ccc(F)c(F)c3)cc12

Procedure:
6-[3-(3,4-Difluoro-phenoxy)-propoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 53% overall yield using the method described in example 161, starting from 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 101A) and 3,4-difluorophenol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:20]([C:22]#[N:23])=[CH:19][CH:18]=[CH:17][C:16]=3[NH:15][C:14]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reaction time: 8 h

Procedure:
To a stirred solution of 1′-benzyl-2-oxospiro[indoline-3,4′-piperidine]-4-carbonitrile (0.88 g, 2.8 mmol) in THF (20 mL) was added dropwise a solution of IN LiAlH4 in THF (11 mL, 11 mmol) at about 0° C. under N2. The reaction mixture was allowed to warm to about room temperature and stirred overnight. The reaction was then heated at reflux for 1 h. After cooling, the reaction was quenched by the dropwise addition of water (0.44 mL), followed by 3N NaOH (0.44 mL) and water (1.3 mL) at about 0° C. The mixture was diluted with Ether and stirred for about 10 min. The reaction mixture was filtered through Celite. The filtrate was concentrated to give crude (1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)methanamine, which was carried forward in the next step without further purification. LCMS (APCI+) m/z 308 [M+H]+; Rt=1.96 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:47][C:48]1([F:54])[CH2:53][CH2:52][N:51]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:50][CH2:49]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: O.[SH2:2].[Na].[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1)#[N:5].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].Cl>O.CN(C)C=O>[NH2:5][C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([F:16])[CH:7]=1)=[S:2]
Reactant: S
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A sodium hydrogensulfide hydrate (9.22 g, 0.165 mol) was added to an N,N-dimethylformamide (74 mL) suspension of methyl 4-cyano-2-fluorobenzoate (WO 2010/115751) (7.37 g, 41.1 mmol) and magnesium chloride hexahydrate (10.0 g, 49.4 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. Subsequently, water (148 mL) was added to the reaction mixture, and the precipitated solid was filtered. The solid thus obtained was added to 1 N aqueous hydrochloric acid solution (148 mL), and the mixture was stirred for 20 minutes. The solid in the reaction mixture was filtered to give the title compound (7.63 g, yield: 87%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.P(Br)(Br)[Br:13]>>[Br:13][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=1
Reactant: Oc1ccnc(C(F)(F)F)n1
Reactant: BrP(Br)Br
Product: FC(F)(F)c1nccc(Br)n1
Temperature: 150 °C

Procedure:
The 2-(trifluoromethyl)pyrimidin-4-ol (328 mg, 2.0 mmol) and PBr3 (0.188 mL, 2.0 mmol) were mixed and heated at 150° C. for 3 h. The reaction was cooled down and quenched with ice water, extracted with DCM (20 mL×2) to yield the titled compound. The organic phase was concentrated and crude material was purified by preparative TLC with 20% Acetone:Hexane to yield titled compound.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].N([C:18](C)([CH2:22][C:23]1C=CC(O)=C(OC)C=1)[C:19](O)=O)N>>[NH2:1][C:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([O:5][CH2:19][CH2:18][CH2:22][CH3:23])=[O:4]
Reactant: CC(N)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: COc1cc(CC(C)(NN)C(=O)O)ccc1O
Product: CCCCOC(=O)C(C)(N)Cc1ccc(O)c(O)c1
Yield: 82 %

Procedure:
The procedure of Example 1 is repeated employing 2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid rather than 2-hydrazino-2-methyl-3-(4-hydroxy-3-methoxyphenyl)propionic acid. The (±)-butyl 2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionate is obtained in a yield of 82%. The product is recrystallized from acetonitrile (77% yield) to give pure ester: mp 121.5° C. to 122° C.; HPLC analysis (C-18 column, 280 nm, tR =14.5 min) showed >99% purity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: Cc1ccccc1B(O)O
Reactant: N#CCc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1ccccc1CC#N
Temperature: 90 °C
Yield: 74.3 %

Procedure:
In a vial, 2-bromophenylacetonitrile (2 g, 10.2 mmol), 2-methylphenylboronic acid (1.53 g, 11.2 mmol) and potassium carbonate (2.82 g, 20.4 mmol, Eq: 2) were combined with toluene (15.0 ml), ethanol (15 ml) and water (5 ml) to give a light brown suspension. The mixture was degassed with argon and then tetrakis(triphenylphosphine)palladium(0) (354 mg, 306 μmol) was added. The reaction mixture was heated at 90° C. for 12 h, cooled and poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Chromatography (silica gel, 0% to 5% EtOAc in hexanes) provided the title product as a colourless oil (1.57 g; 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]=[N:16]1)[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH:23]1([NH:26][C:20]([C:18]2[N:17]=[N:16][N:15]([C:5]3[CH:6]=[CH:7][C:8]([C:10]([NH:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])[CH:19]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCC)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-{2-ethoxy-4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (0.36 g) obtained in Example 131f) in DMF (3 ml) were successively added cyclopropylamine (0.10 ml), triethylamine (0.20 ml), HOBt (0.22 g) and WSC (0.27 g), and the reaction mixture was stirred at room temperature overnight. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol-water to give the title compound as a white powder (0.31 g, 76%).
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>ClCCl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][OH:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:28]([CH3:31])([CH3:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(CO)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Solvent: ClCCl
Solvent: O
Product: CC1(CO)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of 0.59 g of 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 48 and 1.17 ml of 2,6-luthidine in 5 ml of dichloromethane was cooled to 0° C. under nitrogen, combined with 1.25 ml of trimethylsilyl trifluoromethanesulfonate and stirred. After 30 minutes, the reaction solution was poured into water and extracted with ether, and the combined organic layers were concentrated. The residue was dissolved in 10 ml of THF, 5% hydrochloric acid was added and the solution was stirred for 1 hour, after which the reaction solution was concentrated and extracted with water and ether. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9% ethyl acetate to give 0.62 g of 4,6-di-t-butyl-2-hydroxymethyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran as a colorless oil (yield 84%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[NH2:14][OH:15]>>[C:1]([O:4][CH2:5][C:6](=[N:14][OH:15])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: NO
Agent: Cl
Product: CC(=O)OCC(COC(C)=O)=NO

Procedure:
3-(Acetyloxy)-2-(hydroxyimino)propyl acetate was prepared from 3-(acetyloxy)-2-oxopropyl acetate (Tetrahedron Lett., 2001; 3331-3334) and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (250 MHz, CHLOROFORM-d) δ 8.32 (1H, br. s.), 5.02 (2H, s), 4.75 (2H, s), 2.11 (3H, s), 2.10 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([CH3:23])[CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC(C)CO
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
(R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (23.00 g, 82 mmol), 2-methylpentan-1-ol (16.70 g, 163 mmol), and triphenylphosphine (36.46 g, 139 mmol) were combined in tetrahydrofuran (600 mL). After stirring 10 min, diethylazodicarboxylate (21.9 mL, 138 mmol) was added via syringe at room temperature. The reaction was mildly exothermic resulting in the temperature rising to the mid thirties ° C. during the addition. Intermittent cooling with a tap water bath was used to prevent the reaction mixture temperature from rising higher than this, but it was not cooled down to room temperature during the addition. After the addition was complete, the mixture was stirred at room temperature for 18 h. The reaction mixture was transferred to a separatory funnel containing water (400 mL). The aqueous layer was extracted with ether (3×400 mL). The combined organic layers were washed with brine (250 mL), dried over MgSO4, filtered and concentrated. The crude product was taken up in ether (ca. 800 mL) and was stirred for 30 min. The mixture was filtered through a pad of diatomaceous earth (Celite®) to remove most of the triphenylphosphine oxide and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to afford (2R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)acetate (29.43 g, 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.20-7.29 (m, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.45 (d, J=6.5 Hz, 1H), 5.22 (d, J=7.3 Hz, 1H), 3.77 (dd, J=9.1, 5.8 Hz, 1H), 3.69 (s, 3H), 3.65-3.70 (m, 1H), 1.85-1.96 (m, 1H), 1.41 (s, 9H), 1.14-1.50 (m, 4H), 0.98 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 366.4 [(M+H)+, calcd for C20H32NO5 366.2].