Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH4+:5].[Cl-].[CH2:7]([O:14][C:15]([N:17]1[CH2:22][C@@H:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:20][C@H:19]([C:32](OC)=[O:33])[C@@H:18]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]([N:17]1[CH2:22][C@@H:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:20][C@H:19]([C:32](=[O:33])[NH2:5])[C@@H:18]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](C(N)=O)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Under an atmosphere of N2, a 2.0M solution of Me3Al in PhMe (Aldrich, 140 ml, 280 mmol) was added dropwise to a stirred and ice-cooled suspension of NH4Cl (14.92 g, 279 mmol) in dry PhMe (280 ml). After the addition was complete, the reaction mixture was allowed to stirr at room temperature for 30 minutes; at this point, solid NH4Cl disappeared completely, and the clear, homogeneous mixture resulted. To this was added a solution of (2R*,3S*,5S*)-1-benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (13.88 g, 27.89 mmol) in dry PhMe (30.0 ml) dropwise at room temperature: on the addition, the reaction mixture became turbid. This was stirred and heated at a bath temperature of 50 C. overnight (ca. 20 hours). The turbid white reaction mixture was ice-cooled; and H2O (80.0 ml, 4.40 mol) was added carefully, wherein H2 gas evolved violently. The resultant white precipitates were filtered off by the aid of Celite, and washed with AcOEt (80 ml×5). The combined filtrate and AcOEt washings were washed with sat. NaCl aq. solution (×2), dried (MgSO4), and concentrated in vacuo to give a viscous colorless oil (13.76 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 100 g). Elution with n-hexane-AcOEt (5:1/2:1/1:1) gave title compound (11.10 g, 82.4%) as a colorless syrup. IRmax (film): 3405(s), 3340(s), 3200(s), 3100(w), 3070(m), 3045(m), 1735(m), 1675(br., v.s), 1610(s), 1498(s), 1160(s), 1100(s), 836(s), 775(s), 737(s) cm-1 ; 1H-NMR δ: 7.42-7.18(m, 10H), 5.83(d, J=5.1 Hz, 1H), 5.67(br.s, 1H), 5.47(br.s, 1H), 5.20(d, J=12.5 Hz, 1H), 5.13(d, J=12.5 Hz, 1H), 3.91(br.d, J=13.9 Hz, 1H), 3.63(dd, J=10.0, 6.8 Hz, 1H), 3.53(dd, J=10.0, 7.7 Hz, 1H), 3.08(dd,J=13.9, 7.7 Hz, 1H), 2.98(ddd,J=17.6, 5.1, 4.8 Hz, 1H), 2.25-1.91(m, 3H), 0.87(s, 9H), 0.02(s, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[N+:19]([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH2:19]
Reactant: CCCc1noc(C=Cc2ccc(OC)c([N+](=O)[O-])c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1noc(C=Cc2ccc(OC)c(N)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[2-(4-Methoxy-3-nitro-phenyl)-vinyl]-3-propyl-[1,2,4]oxadiazole (compound of Example 7; 0.140 g, 0.48 mmol) was dissolved in ethyl acetate (10 mL) to which stannous chloride (0.43 g, 1.93 mmol) was added and the reaction mixture was stirred at room temperature. After 8 h, additional stannous chloride (0.32 g, 1.44 mmol) was added and the reaction mixture was stirred at room temperature for about 16-18 h. The pH of the reaction mixture was adjusted to 11 by addition of 10% sodium hydroxide and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20].[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:17]2[CH:18]=[CH:19][C:14]3[NH:13][C:12](=[O:20])[O:11][C:15]=3[CH:16]=2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: O=c1[nH]c2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
3.93 g (22.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 3.00 g (22.2 mmol) 2-benzoxazolinone and 14.8 g (111 mmol) aluminium trichloride were combined and heated for 3 h to 130° C. Then the mixture was combined with ice water and EtOAc, the solid was suction filtered and the phases were separated. The aqueous phase was extracted twice with EtOAc, the organic phases were combined, dried and evaporated down. The residue was triturated in DIPE, suction filtered and dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15](Cl)=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH:41]([O:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH2:40][CH2:39]1>O1CCCC1>[C:46]([CH2:45][O:44][CH:41]1[CH2:40][CH2:39][N:38]([C:15]([C:12]2[C:13](=[O:14])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]([CH3:30])[C:11]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:43][CH2:42]1)([OH:48])=[O:47]
Reactant: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Reactant: CCOC(=O)COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)N2CCC(OCC(=O)O)CC2)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
A mixture of 1.62 g of 1-(4-cyanophenyl)-4-chlorocarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one, 2.04 g of triethylamine, 20 ml of tetrahydrofuran and 1.35 g of ethyl 4-piperidinoxyacetate was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The insolubles were filtered off, and the solvent was removed by evaporation. The resulting residue was crystallized in chloroform-methanol-ethyl acetate to give 250 mg of the title compound as pale yellow crystals. The mother liquor was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent;ethyl acetate:methanol 9:1). The resulting crude crystals were recrystallized in chloroform-methanol-ethyl acetate to give 601 mg of the title compound as pale pink crystals.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:3]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[CH2:2]
Reactant: CS(=O)(=O)Nc1ccc(OC(=O)c2ccc(CCBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1ccc(C(=O)Oc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.7 %

Procedure:
A mixture of 10.0 g (0.02511 mol) of 4-(methanesulfonamido)phenyl 4-(2-bromoethyl)benzoate, 3.47 g (0.02511 mol) of potassium carbonate and 100 ml of acetone was stirred at room temperature for 48 hours. The resultant mixture was filtered and the filtrate was condensed to a solid. Recrystallization from 1:1 1,2-dichloroethane:hexane gave 4.2 g (52.7% of theory) of 4-(methanesulfonamido)phenyl 4-vinylbenzoate; mp=172°-3° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][N:12]=[N+]=[N-])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: [N-]=[N+]=NCc1ccc2c(N)n[nH]c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc2c(N)n[nH]c2n1
Reaction time: 64 h

Procedure:
A mixture of 3-amino-6-azidomethyl-7-azaindazole (60 mg, 0.317 mmol), triphenylphosphine (416 mg, 1.59 mmol) and water (86 mg, 4.76 mmol) in THF (10 mL) was stirred for 64 h. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica (chloroform/ammonia, methanol gradient, 5-10% methanol) to give the title compound as a yellow solid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[C:33]([F:44])([F:43])[F:32])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-trifluoromethylphenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.47 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.4 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 6.80-6.73 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 554.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Fe]>[CH:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12](=[O:14])[CH2:11][CH2:10][CH:7]2[CH2:6][CH2:5][CH:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCC(CCC(=O)O)CC1
Agent: [Fe]
Product: CC(C)C1CCC(CCC(=O)CCC2CCC(C(C)C)CC2)CC1
Temperature: 290 °C

Procedure:
3-(4-Isopropylcyclohexyl)propionic acid (39.7 g., 0.20 mole) and iron (hydrogen reduced, 6.15 g., 0.11 mole) is heated for 1.5 hours at 195° C. under a nitrogen atmosphere. After that time, the temperature is increased to 290° C. and maintained at that temperature for three hours. The cooled reaction mass is extracted well with ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residue is stripped under vacuum to leave the product, 17.3 g. (51%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N+:12]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])([O-])=[O:13]>C1(C)C=C(C)C=C(C)C=1>[CH:1]1([C:4]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:12][O:13][C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: C(#CC1CC1)c1ccccc1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1noc(-c2ccccc2)c1C1CC1

Procedure:
A solution of (cyclopropylethynyl)benzene (300 mg, 2.110 mmol) and dimethyl nitromalonate (0.854 mL, 6.33 mmol) in mesitylene (4 mL) was heated to 150° C. for 16 h. The reaction mixture was concentrated to yield a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to yield methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate. The compound was re-purified by preparative HPLC [Column: PHENOMENEX® S10 30×100 mm; Gradient time: 10 min; Flow rate=40 ml/min; Solvent A=10% MeOH−90% Water−0.1% TFA; Solvent B=90% MeOH−10% water−0.1% TFA; Start % B=20; Final % B=100] to yield methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate (170 mg). The compound had an HPLC ret. time=2.77 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=244+.
Reaction SMILES: [O:1]([C:8]1[S:12][C:11]([CH2:13][NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.CO.C(OCC)(=O)C.O>[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][CH2:13][C:11]2[S:12][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[O:21])=[CH:18][N:17]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: NCc1ccc(Oc2ccccc2)s1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Temperature: 60 °C
Reaction time: 0.58 h
Yield: 48.2 %

Procedure:
To a solution of C-(5-phenoxythiophen-2-yl)methylamine described in Preparation Example 24 (170 mg, 0.83 mmol) and 6-aminonicotinic acid (130 mg, 0.91 mmol) in N,N-dimethylformamide (10 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (400 mg, 0.91 mmol) and triethylamine (0.3 mL, 2.2 mmol), and the solution was stirred for 35 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=50:1), and the title compound (130 mg, 0.40 mmol, 48.2%) was obtained as a solid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH2:11].C(Cl)Cl.C[N+]1([O-])CCOCC1.C(#N)C>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.CCCCCC>[CH3:1][CH2:2][C:3](=[O:12])[CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH2:11]
Reactant: C=CC=CC=CCCC(O)CC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCCCCC
Product: C=CC=CC=CCCC(=O)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
In argon atmosphere, 6,8,10-undecatrien-3-ol (5) (1.80 g, 10.8 mmol), methylene chloride (45 mL), Molecular Sieves 4A (4.50 g), N-methylmorpholine N-oxide (NMO) (1.90 g, 16.2 mmol) and acetonitrile (5 mL) were added to a 100 mL flask, and further tetrapropylammonium perruthenate (TPAP) (190 mg, 0.541 mmol) was added, followed by stirring at room temperature for 4 h. TPAP (190 mg, 0.541 mmol) was added, followed by stirring for 2 h at room temperature. Then NMO (1.90 g, 16.2 mmol) was added, followed by stirring for 3 h at room temperature. Hexane was added to the reaction mixture which then was filtered, and the filtrate was concentrated under reduced pressure. Thus obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=50:1) to give 6,8,10-undecatrien-3-one (1-1) (476 mg, 2.90 mmol, yield 27%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23](COCC[Si](C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCN(C(=O)NCCO)CC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)NCCO)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-amide (as prepared in the previous step, 95 mg, 0.16 mmol) in 3 mL of DCM was added 0.10 mL of EtOH followed by 1.0 mL of TFA. The resulting solution was stirred at RT for 6 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-8% MeOH/DCM) gave 68 mg (92%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.09 (d, 1H, J=8.4 Hz), 8.00 (s, 1H), 7.15 (dd, 1H, J=8.4, 2.2 Hz), 5.79 (m, 1H), 4.15 (dd, 2H, J=13.3, 1.1Hz), 3.61 (t, 2H, J=5.9 Hz), 3.27-3.32 (m, 2H), 2.90 (ddd, 2H, J=13.0, 13.0, 2.5 Hz), 2.73 (dddd, 1H, J=12.1, 12.1, 2.6, 2.6 Hz), 2.26 (m, 4H), 1.73-1.88 (m, 6H), 1.62 (dddd, 2H, J=12.6, 12.6, 12.6, 4.0 Hz ). Mass spectrum (ESI, m/z): Calcd. for C25H30N6O3, 463.2 (M+H), found 463.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([O:31]C)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccnc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylate (430 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 235 mg (57%) of the acid. HR-MS: m/z Calculated for C22H22N2O6S 443.1271; Found 443.1270.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20](=[O:36])[NH:21][C@:22]3([C:27](=[O:35])[NH:28][S:29]([CH:32]4[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:24][C@H:23]3[CH2:25][CH3:26])[NH:17][CH2:16]1)=[O:13])[CH2:7]2.[C:37]([O:41][C:42]([C@@H:44]([CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)[C:45](O)=[O:46])=[O:43])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:32]1([S:29]([NH:28][C:27]([C@@:22]2([NH:21][C:20]([C@H:18]3[N:17]([C:45](=[O:46])[C@@H:44]([C:42]([O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:43])[CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]4)[CH2:16][C@H:15]([O:14][C:12]([N:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[CH:11][C:3]=5[Cl:2])[CH2:7]4)=[O:13])[CH2:19]3)=[O:36])[CH2:24][C@H:23]2[CH2:25][CH3:26])=[O:35])(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)[C@H](C(=O)O)C1CCCCC1
Reactant: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)[C@@H](C(=O)OC(C)(C)C)C1CCCCC1)C(=O)NS(=O)(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 10 mL round-bottomed flask was charged with (3R,5S)-5-(((1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropyl)carbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate hydrochloride (0.150 g, 0.267 mmol), (S)-2-(tert-butoxycarbonyl)-2-cyclohexylacetic acid (82 mg, 0.32 mmol) and HATU (122 mg, 0.321 mmol) and stirred in dry DMF (1.5 mL). The solution was cooled on an ice-water bath and then treated with DIEA (0.140 mL, 0.802 mmol) by dropwise addition. The mixture was stirred at 0° C. for 1 h, then allowed to warm up and stirred at room temperature for 16 h. The reaction mixture was diluted with water (5.0 mL) resulting in the separation of a precipitate. After stirring at room temperature for about 1 hour the precipitate was collected by filtration, washed with water and dried to a cream colored solid, (195 mg, 95%). MS m/e 664 (M+−Boc).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>CN(C)C=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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:20]=[CH2:21])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (3.0 g, 8.9 mmol), tributyl-vinyl-stannane (3.9 mL, 13.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (514 mg, 0.445 mmol) in N,N-dimethylformamide (10 mL) was stirred at 85° C. for 15 h. The mixture was cooled to 25° C., extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, hexanes to 15% ethyl acetate/hexanes) to afford 1-benzenesulfonyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine (2.2 g, 87%) as a white solid: LC/MS m/e calcd for C15H13N2SO2 [M+H]+ 285.34, observed 285.2; 1H NMR (400 MHz, CDCl3) δ ppm 5.32 (d, J=11.0 Hz, 1H), 5.78 (d, J=17.6 Hz, 1H), 6.59 (d, J=4.0 Hz, 1H), 6.77 (dd, J=11.0 Hz, J=17.6 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.74 (d, J=4.0 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 8.19 (m, 2H), 8.46 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[F:11])=[O:3].BrBr.S([O-])([O-])(=O)=[O:15].[Na+].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.ClCCl>[F:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[C:2](=[O:3])[CH:1]=[O:15]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)c1c(F)cccc1F
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC(=O)c1c(F)cccc1F
Temperature: 80 °C

Procedure:
5 g of 2,6-difluoroacetophenone are placed in 13.6 ml of DMSO, and 2.7 ml of bromine (8.8M in water) are added dropwise, the reaction temperature rising from room temperature to 40° C. When the addition of bromine is complete, the mixture is heated at 80° C. for 30 min. After cooling to room temperature, the reaction mixture is poured into 100 ml of dichloromethane; with stirring, sodium sulfate and solid sodium hydrogen carbonate are added to the solution, filtration is carried out and the reaction mixture is concentrated using a rotary evaporator. The crude product is subjected to flash chromatography with dichloromethane. In this way (2,6-difluorophenyl)-oxoacetaldehyde is obtained in the form of a colourless viscous oil.