Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:15]([Br:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)CC>[Br-:23].[CH2:1]([N:9]1[CH:13]=[CH:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]1[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCn1ccnc1C
Solvent: CCCO
Product: CCCCCCCCN1C=CN(CCCCCCCC)C1C
Product: [Br-]
Temperature: 105 °C

Procedure:
1 mole of 1-n-octyl-2-methylimidazole is dissolved with 1.1 moles of n-octyl bromide in 500 ml of n-propanol and heated at 105° C for 5 hours. Then, the n-propanol together with the unreacted n-octyl bromide is distilled off and the remaining residue is washed with ether.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]2O.O=P(Cl)(Cl)[Cl:26]>>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]2[Cl:26]
Reactant: CSc1nc(O)c2cc(Br)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (0.65 ml, 3.69 mmol) was added to a suspension of 6-bromo-2-(methylthio)-quinazolin-4-ol (500 mg, 1.85 mmol) in POCl3 (6.5 ml). The reaction was heated at reflux for 6 hours and then cooled to room temperature. The POCl3 was removed under reduced pressure. The residue was diluted with EtOAc (30 ml) and poured onto ice. The organic layer was washed twice with brine (2×30 ml), then dried over sodium sulfate and concentrated. The product thus obtained was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:5]=[N:6][NH:7][CH:8]=1.S(Br)([Br:11])=O>C(Cl)(Cl)Cl>[BrH:11].[Br:11][CH2:2][CH2:3][C:4]1[N:5]=[N:6][NH:7][CH:8]=1
Reactant: OCCc1c[nH]nn1
Reactant: O=S(Br)Br
Solvent: ClC(Cl)Cl
Product: Br
Product: BrCCc1c[nH]nn1

Procedure:
Stir 600 mg of the product of Step A and 1.1 g thionyl bromide in 6 ml of chloroform under a nitrogen atmosphere for 11/2 hours. Evaporate the solvent in vacuo. Dry the resultant residue under high vacuum for 15 minutes to obtain the title compound.
Reaction SMILES: Br.Br[CH2:3][CH2:4][CH2:5][NH2:6].[C:7](=[O:10])([O-])[O-:8].[K+].[K+].O.[C:14](OCC)(=O)[CH3:15].C1CCCCC1>C(Cl)Cl>[N:6]1[CH:15]=[CH:14][CH:3]=[C:4]([C:7]([OH:8])=[O:10])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: NCCCBr
Reactant: CCOC(C)=O
Agent: Br
Agent: [K+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 8.4 g (22.5 mmol) of acid chloride starting material used in Example 1 in 50 ml of methylene chloride were added 5.4 g of 3-bromopropylamine hydrobromide and 5.5 g of potassium carbonate. The mixture was stirred at room temperature for one hour and then 20 ml of water was added. Stirring was continued for 18 hours. After that the organic layer was separated, washed with brine and concentrated. The oily residue was triturated with cyclohexane to give a solid. A 2.3 g analytically pure sample was obtained by chromatography of 2.6 g of crude 3-pyridinecarboxylic acid, 5-[[(3-bromopropyl)amino]carbonyl]-6-(difluoromethyl)- 4-(2-methylpropyl)-2-(trifluoro-methyl)-, methyl ester on silica gel columns with 20% ethyl acetate/cyclohexane as eluting solvent, m.p. 107°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[CH2:13])=C[C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.[OH:16]/[N:17]=[C:18]1/[C@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][NH:21][CH2:22]/1.C[N:36](C=O)C>>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:21]1[CH2:22]/[C:18](=[N:17]\[OH:16])/[C@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:20]1)=[N:36][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: O=C(NC[C@@H]1CNC/C1=N\O)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)cc12
Reactant: CN(C)C=O
Product: COc1ccc2ncc(F)c(CCN3C/C(=N\O)[C@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
To 3-Fluoro-6-methoxy-4-vinyl-quinoline (0.554 g, 2.72 mmol) was added DMF (2.0 mL). Phenylmethyl {[(3S,4Z)-4-(hydroxyimino)-3-pyrrolidinyl]methyl}carbamate (0.66 g, 2.21 mmol) and TEA (0.76 mL, 5.44 mmol) were added to the mixture and the reaction was heated and stirred at 90 degrees C. for 18 hours. The solution was concentrated under reduced pressure and was chromatographed on silica gel to yield an oil (0.180 g, 18%). LCMS: m/z 468.4 (MH+).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:16]([NH2:17])=[C:15]([C:18]([CH3:20])=[CH2:19])[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)[CH3:3].C(O)(=O)C>C(O)C.[Pd].[Pt]>[CH:2]([C:4]1[C:16]([NH2:17])=[C:15]([CH:18]([CH3:20])[CH3:19])[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cc2c(sc3ccccc32)c(C(=C)C)c1N
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1cc2c(sc3ccccc32)c(C(C)C)c1N
Yield: 82.2 %

Procedure:
2,4-di(prop-1-en-2-yl)dibenzo[b,d]thiophen-3-amine (9 g, 32.2 mmol) was dissolved in ethanol (150 mL) and 9 mL of acetic acid was added. To the flask, 10% Pd/C (9.0 g) and 5% Pt/C (9.0 g) were added and hydrogenated at 40 psi of H2 for over night. GC indicated complete conversion of olefin to alkane. The reaction mixture was filtered through a Celite pad and washed with methylene chloride. The filtrate was concentrated to produce 7.5 g (82%) of desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:14][C:15](=O)[CH3:16].Cl>C(O)(=O)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:15]([CH3:16])[CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(C2CCNCC2)nc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
5-Bromo-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl (6.7 g, 18.9 mmol) was dissolved in 2% acetic acid in MeOH (40 ml). Propanone (8 mL, 113 mmol) and Na(CN)BH3 (3.6 g, 57 mmol) were added. The reaction mixture was stirred at RT over night. LC-MS showed only product. The reaction mixture was added 1N HCl filtered and evaporated in vacuo. The compound was dissolved in water pH was adjusted to PH=12 extracted with DCM (3×200 mL). The DCM phase was dried with Na2CO3 filtered and evaporation gave 4.4 g (82%) white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C([O-])(=O)C>[CH2:16]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: C(#Cc1ccc(-c2cccs2)s1)CCOCc1ccccc1
Reaction time: 8 h

Procedure:
0.8 g of 5-(4-hydroxy-1-butynyl)-2,2 '-bithiophene was dissolved in 8 ml of pyridine. 1 ml of benzoyl chloride was added at room temperature, stirred for few minutes and kept overnight. The reaction mixture was treated as in acetate example 81. Slightly yellowish crystal was then obtained and the melting point thereof was 61° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:26]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:26][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br
Reactant: CB(O)O
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: O
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate (1.26 g, 2.96 mmol), methylboronic acid (CAS number 13061-96-6; 0.532 g, 8.88 mmol), tetrakis(triphenylphosphine)palladium (0.342 g, 0.296 mmol) and potassium carbonate (1.303 g, 9.43 mmol) in 1,4-dioxane (10 ml) and water (1.5 ml) was sealed, evacuated and purged with nitrogen and subjected to microwave irradiation at 140° C. for 1 hour. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organics were extracted with ethyl acetate (2×20 ml). The combined organics were washed with brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][C:8]([OH:10])=O)=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.CCN(CC)CC.C(Cl)(=O)C(C)(C)C.O1CCNC1=O.[Li]CCCC.[CH2:40]([C@H:47]1[CH2:51][O:50][C:49](=[O:52])[NH:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.C(Cl)(Cl)Cl>[S:1]1[C:5]([CH2:6][CH2:7][C:8]([N:48]2[C@@H:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:51][O:50][C:49]2=[O:52])=[O:10])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCc1cc2ccccc2s1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCc1cc2ccccc2s1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of benzo[b]thiophene-2-propanoic acid (1.10 g, 5.33 mmol) and Et3N (0.89 mL, 6.4 mmol) in dry THF (22 mL) at -78° C. was added dropwise pivaloyl chloride (0.66 mL, 5.4 mmol). After the resultant white suspension was stirred for 10 min at -78° C. and 30 min at 0° C., it was recooled to -78° C. and a precooled (-78° C.) solution of metallated oxazolidinone, prepared by addition of n-BuLi (1.6M in hexane, 3.66 mL, 5.85 mmol) to a -78° C. solution of (S)-(-)-4-benzyl-2-oxazolidinone (1.05 g, 5.87 mmol) in THF (22 mL), was added via a cannula. The reaction mixture was stirred for an additional 1 h and then was quenched by addition of saturated aq. NH4Cl (36 mL). The mixture was concentrated and the residue was extracted with CH2Cl2 (3×100 mL). The combined organic phases were washed with saturated aq. NaHCO3 (85 mL), dried (Na2SO4) and concentrated to dryness. The crude solid (2.31 g) was purified by flash chromatography, eluting with EtOAc-hexane (1:2.5) to give (S)-3-[3-(benzo[b]thien-2-yl)-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone (1.82 g, 4.98 mmol) in 93% yield as a solid, mp 119°-122° C. [α]25D +54.9° (c 0.55, CHCl3).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][C:37]([CH3:42])([CH3:41])[CH2:36]1)(=[O:34])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][N:35]([S:32]([CH3:31])(=[O:33])=[O:34])[CH2:40][CH2:39][N:38]1[C:18]([C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2)=[O:19]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(S(C)(=O)=O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (117 mg, 0.26 mmol), 1-methanesulfonyl-3,3-dimethylpiperazine (51 mg, 0.26 mmol) and HATU (100 mg, 0.26 mmol) in DMF (1 mL) was added NEt3 (720 μL, 5.18 mmol). The resulting mixture was allowed to stir at r.t. for 16 h then partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%). The resulting solid was recrystallised from EtOAc and Et2O affording 715 (50 mg, 33%). LCMS (method I): RT 3.68 min, [M+H]+ 582.2. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.03 (1 H, m), 7.76-7.75 (1 H, m), 7.31-7.27 (2 H, m), 4.35 (4 H, brd s), 4.03 (2 H, t, J=5.39 Hz), 3.95 (3 H, s), 3.87 (4 H, t, J=4.70 Hz), 3.50 (2 H, t, J=5.40 Hz), 3.37 (2 H, q, J=7.47 Hz), 3.31 (2 H, s), 2.90 (3 H, s), 1.68 (6 H, s), 1.45 (3 H, t, J=7.47 Hz)
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:44][O:45][C:46](=[O:51])[C@H:47]([CH2:49][OH:50])[NH2:48]>CN(C=O)C>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:48][C@H:47]([C:46]([O:45][CH3:44])=[O:51])[CH2:49][OH:50])=[O:17])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)[C@H](CO)NC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A stirred solution of 4-[(1H-benzoimidazol-1-yl)methyl]benzoic acid (4 g, 15.87 mmol) in DMF at 0° C. is treated sequentially with EDC (3.6 g, 19 mmol), HOBt (2.5 g, 19 mmol), DIPEA (5.1 g, 39.5 mmol, 2.5 eq) and serine methyl ester hydrochloride (2.9 g, 19 mol), stirred at room temperature overnight and evaporated to dryness. The resultant residue is dissolved in EtOAc and water. The layers are separated and the organic layer is washed successively with 1M HCl, water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give the title product in 64% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.23-8.26 (m, 2H); 7.9 (s, 2H); 7.87 (d, J=7.6 Hz, 2H); 7.70 (d, J=6 Hz, 1H); 7.33 (m, 3H); 7.20 (m, 2H); 5.54 (s, 2H); 4.90 (t, J=4 Hz, 1H); 4.60 (m, 1H); 3.84-3.90 (m, 2H); 3.70 (s, 3H). LCMS (ESI+) 354 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15]Cl)=[O:8].[C-:25]#[N:26].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][CH:6]([CH2:19][CH3:20])[C:7]([NH:9][C:10]([CH3:18])([CH3:17])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:25]#[N:26])=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCCl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCC#N
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(3,5-dichlorophenoxy)-N-(1-chloro-6-methylhept-4-yn-6-yl) butyramide (3.91) in dry N,N-dimethylformamide (35 ml) containing potassium cyanide (0.78 g) was heated to 95° C. for 6 hours, cooled to ambient temperature then stored for 18 hours. The mixture was poured into water, extracted with diethyl ether (three times) and the extracts were combined, washed with water (three times), dried over magnesium sulphate then evaporated under reduced pressure to give the required product as a yellow oil, 3.42 g. A portion of this material was fractionated by chromatography (silica; hexane/ethyl acetate 3:1 by volume) to give a pure sample of 2-(3,5-dichlorophenoxy)-N-(1-cyano-6-methylhept-4-yn-6-yl) butyramide as a yellow gum, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.58(3H, s); 1.60(3H, s); 1.82-1.88(2H, m); 1.92-1.98(2H, m); 2.36-2.40(2H, t); 2.48-2.56(2H, m); 4.38-4.42(1H, t); 6.26(1H, s); 6.84(2H, s); 7.04(1H, s).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:46])(=[O:45])[NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:56][NH:57][CH2:58][CH2:59][CH2:60][CH3:61].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:45])(=[O:46])[NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[N:57]([CH2:58][CH2:59][CH2:60][CH3:61])[CH3:56])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC
Reactant: CCCCc1nn(-c2cc(C(=O)O)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nn(-c2cc(C(=O)N(C)CCCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A solution of 40 mg (0.0589 mmole) of 5-n-butyl-2-(5-carboxy-2-chlorophenyl)-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) and 51.3 μL (38.1 mg, 0.295 mmole) of N,N-diisopropylethylamine in 1 mL of CH2Cl2 and 0.3 μL of DMF was stirred at 0° C. under protection from moisture as 27.9 mL (20.5 mg, 0.236 mmole) of N-methylbutylamine was added, followed by 52.1 mg (0.118 mmole) of BOP reagent. The solution was stirred at 0° C. overnight and then concentrated. The residue was reconcentrated twice from toluene. It was then taken up in CH2Cl2 and washed successively twice with 5% citric acid (aqueous), twice with 5% NaHCO3 (aqueous), and then with brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was flash chromatographed on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) and then further purified by HPLC on a semi-preparative Zorbax C8 reverse phase column (elution with 60:40 acetonitrile-H2O) to give a 36% yield of the title compound as a colorless, glassy solid, mp >90° C. (gradual); mass spectrum (FAB) m/e 748 (M+1)+. By NMR the material appeared to exist as a mixture of amide rotamers in a ratio of approximately 1:1.
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.[CH2:53]([N:55]=[C:56]=[O:57])[CH3:54].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:53]([NH:55][C:56](=[O:57])[O:52][C:43]1[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=[C:41]([CH2:40][N:7]([C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:31]([Cl:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=3[Cl:36])=[CH:24][CH:25]=2)[CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:18])[CH:4]2[CH2:6][CH2:5]2)[CH:42]=1)[CH3:54]
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Oc1cc(CCCOC)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.08 M) was added ethyl isocyanate (3 eq.), triethylamine (3 eq.) and a few crystals of DMAP. The resulting solution was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and directly subjected to purification by way of column chromatography (SiO2, 3:2 (v/v) Hex:EtOAc→2:3 (v/v) Hex:EtOAc). The title compound was isolated as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:23]2[O:27][C:26]([CH3:29])(C)C(C)(C)[O:24]2)=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N+:33]([O-:35])=[O:34].Cl>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:23]([OH:24])[O:27][CH:26]([CH2:29][N+:33]([O-:35])=[O:34])[C:17]=2[CH:20]=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2c(C=O)cccc2OCCCOCc2ccccc2)OC1(C)C
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
NaOH aq. (NaOH (3.64 g, 83 mmol) was added to 3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (36 g, 91 mmol) in H2O (180 mL), and THF (50 mL) at rt, and the reaction mixture was stirred at rt for 5 min. MeNO2 (16.6 g, 273 mmol) was added dropwise and the mixture was stirred at rt for 16 h. The reaction mixture was acidified with 2 N HCl and extracted with EtOAc. The organic fraction was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. Purification was accomplished by flash chromatography (1:1 hexane/EtOAc) to give 15.9 g of the title compound as a light yellow oil (yield 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.05 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.70 (dd, J=9.4, 2.3 Hz, 1H), 5.29 (dd, J=13.7, 2.7 Hz, 1H), 4.53 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.04-1.91 (m, 2H); MS (ESI): m/z=356 (M−1, negative); HPLC purity: 99.35% (MaxPlot 200-400 nm), 97.32% (220 nm).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1cc(Nc2ccc(CCC(=O)O)cc2)cc(C(C)(C)C)c1O
Yield: 77.1 %

Procedure:
A mixture of 4.0 g of 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, 200 ml of ethanol of 0.1 g of 10% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogen uptake was complete after 30 minutes. Under a nitrogen atmosphere, the reaction mixture was filtered to remove catalyst The filtrate was evaporated to give an oil which was coevaporated with hexane to remove all traces of ethanol and then triturated with hexane to give a light orange crystalline solid. This solid was recrystallized from a mixture of ethanol and water to give 3.1 g 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-4-aminophenyl]propionic acid, m.p. 140°-142° C. Analysis: Calculated for C23H31NO3 : %C, 74.8; %H. 8.5; %N. 3.8; Found: %C, 74.7; %H, 8.3; %N, 3.9.