Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)=[CH:2][CH2:3][CH2:4][CH3:5].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([C:32]#[N:33])=[C:27]([F:34])[CH:26]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1>C1COCC1>[F:34][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C@H:12]3[CH2:13][CH2:14][Si@H:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH:30]=[C:29]([F:31])[C:28]=1[C:32]#[N:33]
Reactant: CCCC=C[Mg]Cl
Reactant: N#Cc1c(F)cc(CCCC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3cc(F)c(C#N)c(F)c3)CC2)CC1

Procedure:
50 ml (0.13 mols) of a THF solution of 2.5M of pentenylmagnesium chloride was dropped in a mixed solution of 41.0 g (0.1 mol) of 1-chloro-4-(trans-4-(4-(3,5-difluoro-4-cyanophenyl)butyl)cyclohexyl)-1-silacyclohexane and 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 40.1 g (yield: 90%) of the intended trans isomer product.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[C:11]([N:28](C(O)C)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:28]([CH2:2][CH:1]=[O:5])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (12.24 ml) and methylene chloride (50 mL) at −35 to −45° C. was added DMSO (14.75 g) in methylene chloride (25 mL) over 20 minutes. The reaction mixture was stirred for 10 minutes at −35 to −45° C. A solution of N-Fmoc-decylaminoethanol (20.0 g) in methylene chloride (70 mL) was added over 25 minutes and then stirred 40 minutes at −35 to −45° C. Triethylamine (21.49 g) was then added and the mixture stirred for 30 minutes at −10 to −20° C. The reaction mixture was quenched with water (120 mL) followed by concentrated sulfuric acid (20.0 g) while maintaining the internal temperature at 0-5° C. The organic layer was isolated and washed with 2% sulfuric acid (100 mL) followed by water (2×100 mL). The organic solution was distilled under vacuum at 60° C. to about 100 mL. Heptane (100 mL) was added, the temperature of the oil bath raised to 80° C. and the distillation was continued until the residual volume was 100 mL. More heptane (100 mL) was added and the distillation repeated to a volume of 100 mL. The heating bath was replaced with a cold water bath at 15° C. The bath was cooled slowly to 5° C. over 20 minutes to start the precipitation of the product. The slurry was then cooled to −5 to −10° C. and the slurry was stirred for 2 hours. The solid was then collected on a Buchner funnel and washed with cold (−5° C.) heptane (2×15 mL). The wet solid was dried in vacuo to yield the aldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH:25]([C:27]1[C:32]([CH3:33])=[C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]([CH3:42])=[C:29]([CH3:43])[C:28]=1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.CCCCCC.C(OC(=O)C)C>C1C=CC=CC=1>[CH2:45]([O:44][C:28]1[C:29]([CH3:43])=[C:30]([CH3:42])[C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([CH3:33])[C:27]=1[CH:25]=[CH:24][CH2:23][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(C(O)CCc2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(C)c1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1c(C)c(OCc2ccccc2)c(C=CCc2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
2.39 g(3.46 mmol) of 3-(2,4-dibenzyloxy-phenyl)-1-(2,5-dibenzyloxy-3,4,6-trimethyl-phenyl)-propan-1-ol was diluted with 100 ml of dry benzene and 30 mg of p-toluenesulfonic acid was added thereto. The mixture was stirred for 4 hours while refluxing to eliminate water. The solution thus produced was cooled down to room temperature and washed once(×1) with saturated aqueous sodium hydrogen carbonate solution. The washings was extracted with dichloromethane and the extract was combined with the original organic layer. Then, the combined mixture was dried, distilled under reduced pressure and subjected to a silica gel column chromatography(eluent: n-hexane/ethylacetate=10/1, v/v) to obtain 2.1 g(Yield 90%) of 4-[3-(2,5-dibenzyloxy-3,4,6-trimethylphenyl)-allyl]-1,3-dibenzyloxy-benzene. 2.1 g(3.12 mmol) of the compound thus obtained was diluted with 30 ml of ethylacetate, to which was slowly added 45 mg of 10% palladium catalyst. The resulting solution was stirred for 72 hours under hydrogen atmosphere of 60 psi, diluted with 50 ml of ethylacetate and then filtered. The filtrate was distilled under reduced pressure and subjected to a silical gel column chromatography(eluent: n-hexane/ethylacetate=1/1, v/v) to obtain 0.74 g (Yield 79%) of the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][C:36]1=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][C:36]3=[O:42])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CN1CCN(CCCO)C(=O)C1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Di-tert-butylazodicarboxylate (393 mg, 1.71 mmol) was added portionwise, at room temperature, to a stirred suspension of 4-chloro-6-methoxyquinazolin-7-ol, (300 mg, 1.42 mmol), 1-(3-hydroxypropyl)-4-methylpiperazin-2-one (270 mg, 1.57 mmol) and triphenylphosphine (522 mg, 1.99 mmol) in dichloromethane (10 ml). The reaction was stirred 1 hr before adding further di-tert-butylazodicarboxylate (393 mg) and triphenylphosphine (522 mg) and stirring for a further 1 hr. The resulting reaction solution was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (260 mg, 50%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.06 (quintet, 2H), 2.20 (s, 3H), 2.60 (t, 2H), 2.91 (s, 2H), 3.33 (t, 2H), 3.48 (t, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 7.40 (s, 1H), 7.41 (s, 1H), 8.87 (s, 1H); Mass Spectrum: M+H+ 365/367.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[S:37]1[CH2:41][C:40](=[O:42])[NH:39][C:38]1=[O:43].N1CCCCC1>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:41]4/[C:40](=[O:42])[NH:39][C:38](=[O:43])[S:37]/4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 85.3 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.10 g), 1,3-thiazolidine-2,4-dione (0.27 g), piperidine (0.04 g) and ethanol (30 mL) was heated under reflux for 3 hrs. The reaction mixture was concentrated, and the obtained crystals were washed with ethanol to give (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-1,3-thiazolidine-2,4-dione as yellow crystals (1.13 g, yield 84%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 252-253° C.
Reaction SMILES: CO[CH:3]([O:11]C)[CH2:4][C:5]1([OH:10])[CH2:9][CH:8]=[CH:7][CH2:6]1.CC1C=C(C)C=C(C)N=1.FC(F)(F)S(O[Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])(=O)=O.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O>C(Cl)Cl.O>[Si:28]([O:10][C:5]1([CH2:4][CH:3]=[O:11])[CH2:6][CH:7]=[CH:8][CH2:9]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(CC1(O)CC=CC1)OC
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(CC=O)CC=CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(2,2-dimethoxyethyl)cyclopent-3-enol (13.5 g, 78 mmol) was dissolved in DCM (250 mL). This was chilled to 0° C. under nitrogen and 2,4,6-trimethylpyridine (42 mL, 314 mmol) was added dropwise over 10 minutes. Tert-butyldimethylsilyl trifluoromethanesulfonate (18 mL, 78 mmol) was added dropwise via syringe very slowly over 20 minutes keeping the internal temperature below 5° C. The reaction was allowed to come to RT. By TLC (20% EtOAc/hexanes; KMnO4 stain), the starting material was completely consumed (˜2 hours). The reaction was then chilled back to 0° C. and triethylsilyl trifluoromethanesulfonate (35 mL, 157 mmol) was added in dropwise over a 10 minute period. This was allowed to stir at 0° C. for 1 hour before adding water (250 mL). The ice bath was removed and this mixture was stirred vigorously for ˜18 hours. The reaction was poured into a seperatory funnel and the DCM layer was separated. The organic was washed with dilute aqueous HCl, brine, dried over sodium sulfate, filtered and concentrated to afford a yellow oil which was flashed on silica by gradient eluting with hexanes to 20% EtOAc/hexanes over a 40 minute period. Product fractions were combined to afford the title compound.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[C:29]3[C:30]([OH:34])=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH:26]=2)=[CH:19][CH:18]=1)#[N:16].Cl>C(OCC)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[C:29]3[C:30]([OH:34])=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH:26]=2)=[CH:21][CH:22]=1)(=[NH:3])[NH2:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1ccc(CCc2coc3cccc(O)c23)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(CCc2coc3cccc(O)c23)cc1
Reaction time: 0.17 h

Procedure:
A suspension of 3-[2-(4-bromophenyl)ethyl]-4-hydroxybenzofuran (0.5 g), sodium cyanide (0.23 g), tetrakis(triphenylphosphine)palladium (0) (91 mg) and copper (I) iodide (30 mg) in acetonitrile (5 mL) was heated for reflux for three days. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.14 g). To a solution of hexamethyldisilazane (0.35 mL) in diethyl ether (2 mL) was added n-butyl lithium (2.46 mol/L n-hexane solution 0.7 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a solution of the 3-[2-(4-cyanophenyl)ethyl]-4-hydroxybenzofuran (0.13 g) in diethyl ether (3 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was washed with diethyl ether twice. The aqueous layer was basified by addition of 2 mol/L aqueous sodium hydroxide solution, and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with a mixed solvent of dichlorometane and methanol (5/1) (three times), and the extract was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[2-(4-carbamimidoylphenyl)ethyl]-4-hydroxybenzofuran (0.11 g). This material was dissolved in 1,4-dioxane (5 mL)-1 mol/L aqueous sodium hydroxide solution (5 mL). To the solution was added benzyl chloroformate (0.1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid (5 mL), and the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (35 mg).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([O:12]C)[CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([OH:12])[CH:11]=1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A 1M solution of boron tribromide in methylene chloride (400 mL, 0.40 mole) was cooled to -20° C. A solution of 37.5 g (0.20 mole) of 5-chloro-2-nitroanisole in 200 mL of methylene chloride was added slowly to the first solution. Upon completion of addition, the mixture was allowed to warm to ambient temperature at which it stirred for about 16 hours. At the conclusion of this period the reaction mixture was poured into ice water. The organic layer was separated from the aqueous layer and was evaporated under reduced pressure, leaving 31.40 g of 5-chloro-2-nitrophenol as a solid residue, m.p. 38°-39° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.CO.[NH3:15].N.CO>C(Cl)Cl>[NH2:15][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(CBr)ccc1C#N
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(CN)ccc1C#N
Reaction time: 2 h

Procedure:
2.5 g of the bromide (b) were introduced into 10 ml of MeOH, and NH3 was passed in during dropwise addition of 38 ml of conc. ammonia/MeOH 1:1. After 2 h, the solvent was stripped off, the product was taken up in DCM and washed with water, and the organic phase was dried over Na2SO4. The product was precipitated as hydrochloride with ethereal HCl. 1H-NMR (DMSO-d6, δ in ppm): 8.6 (broad signal, NH3+), 7.79 (1H), 7.55 (1H), 7.20 (1H), 4.10 (s, 2H), 3.93 (s, 3H)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11]([OH:13])=O>CN(C)C=O>[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11]([Cl:3])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: Cc1oncc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1oncc1C(=O)Cl

Procedure:
Thionyl chloride (118 g) was added to 5-methylisoxazol-4-yl carboxylic acid (42 g) and stirred at room temperature as dimethylformamide (0.2 ml) was added. The solution was heated under reflux for 2 hours with stirring. Excess thionyl chloride was removed in vacuo at 50° C., then the residue was distilled through a 15 cm Vigreaux column at reduced pressure to give an oil, b.p. 32°-34° C./0.1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14](=[CH2:20])[CH2:15][CH2:16][N:17]=[N+]=[N-])[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4](I)[CH:3]=1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1C=CC=CC=1>[CH3:12][S:9]([N:8]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2([CH2:15][CH2:16][NH:17][CH2:20]2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: C=C(CCN=[N+]=[N-])CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: c1ccccc1
Product: CS(=O)(=O)N1CC2(CCNC2)c2cc(Cl)ccc21
Yield: 85.3 %

Procedure:
A degassed solution of N-(4-Chloro-2-iodo-phenyl)-N-(4-azido-2-methylene-butyl)-methanesulfonamide (1.38 g) in benzene (200 ml) was heated to reflux under argon. Tris(trimethylsilyl)silane (1.32 ml) was added dropwise followed by 1,1′-azobis(cyclohexane carbonitrile) (110 mg). The reaction mixture was stirred at reflux for 20 hours then concentrated in vacuo. The residue was dissolved in ethyl acetate (60 ml), extracted with HCl 2N (3×60 ml). The aqueous layer was basified with 2N sodium hydroxide (250 ml) then extracted with ethyl acetate (3×150 ml). The combined organic layers were dried over sodium sulfate and the solvent evaporated in vacuo to afford 1-methanesulfonyl-5-chloro-spiro[indoline-3,3′-pyrrolidine] (766 mg) which was used as such for the next step.
Reaction SMILES: C[N:2]([C:11](=[O:33])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][C:13]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].[Li+].[OH-]>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:33])=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH:14]=2)[CH:21]=1
Reactant: CSCC[C@@H](C(=O)O)N(C)C(=O)c1ccc(C#Cc2cccnc2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(C#Cc2cccnc2)cc1-c1ccccc1C)C(=O)O
Reaction time: 18 h
Yield: 87.5 %

Procedure:
Methyl N-[4-(2-pyrid-3-ylethyn-1-yl)-2-(2-methylphenyl)benzoyl]methionine (43 mg, 0.09 mmol) was dissolved in MeOH (2 mL) and treated with excess 1 M LiOH. After 18 h at room temperature, the reaction was evaporated, and partitioned between ether and water. The aqueous layer was acidified with 1 M HCl and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated to provide 35 mg of the title compound. MS m/e 445 (M+H)+. 1H NMR (CDCl3, 300 MHz) 1.62 (m, 1H), 1.96 (m, 1H), 2.1 (m, 8H), 4.62 (m, 1H), 6.02 (m, 1H), 7.37 (m, 6H), 7.63 (m, 1H), 7.88 (m, 1H), 7.99 (m, 1H), 8.59 (m, 1H), 8.79 (m, 1H).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH:40]1[CH2:58][CH2:57][CH2:56][C@H:41]1[C:42]([NH:44][C@H:45]([C:53]([NH2:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43]>C(OCC)(=O)C.CC(N(C)C)=O>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([N:40]1[CH2:58][CH2:57][CH2:56][C@H:41]1[C:42]([NH:44][C@H:45]([C:53]([NH2:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 2 h

Procedure:
The mixed anhydride prepared by reacting Boc-Asp(OBzl) (5.82 g, 18 mmoles), N-methylmorpholine (1.98 mL, 18 mmoles) and isobutyl chloroformate (2.34 mL, 18 mmoles) in ethyl acetate (200 mL) at -15° C., was treated with the solution of HCl.Pro-Phe-NH2 (obtained above) and N-methylmorpholine (1.98 mL, 18 mmoles) in dimethylacetamide (40 mL). The reaction was allowed to proceed for 30 minutes at -15° C. and 2 hours at room temperature. The product was worked up as described earlier and reprecipitated from ethyl acetate-hexane.
Reaction SMILES: FC1C=CC=C(F)C=1C(Cl)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)[NH2:29].C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:23]([NH:22][C:20](=[O:21])[C:14]2[C:13]([F:12])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[S:24])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1c(F)cccc1F
Agent: O=C(N=C=S)c1c(F)cccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(F)cccc4F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,6-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,6-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (59 mg, yield 74%). 1H-NMR (DMSO-d6, 400 MHz): δ 3.94 (s, 3H), 3.96 (s, 3H), 6.57 (d, J=4.64 Hz, 1H), 7.11–7.51 (m, 4H), 7.62–7.64 (m, 1H), 7.80–7.83 (m, 2H), 8.08 (m, 1H), 8.52 (d, J=5.12 Hz, 1H), 12.16 (s, 1H), 12.28 (s, 1H) Mass spectrometry value (ESI-MS, m/z): 530 (M++1)
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.[CH3:13][C:14]([CH3:24])([C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:15]>O1CCCC1.CCCCCC>[CH3:15][C:14]([CH3:24])([C:16]([OH:23])([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:13]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: C#CCCCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a solution of hept-1-yne (3.9 g, 0.041 mol) in dry tetrahydrofuran (30 mls) at -70° C. under nitrogen was added n-butyl lithium (30 mls of a 1.55M solution in hexane) and the resulting mixture stirred for 1 hour. To this mixture was added a solution of 2,2-dimethyl-4-(1,2,-4-triazol-1-yl)-butane-3-one (6.8 g, 0.041 mol) in dry tetrahydrofuran (50 mls), and the resulting mixture was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous HCl (1.0M). The aqueous was further extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate solution and brine, dried (anhydrous MgSO4) and then concentrated in-vacuo to give a yellow oil. Chromatography on silica using gradient elution (diethyl ether 20-80% in petrol) gave the title compound (2.87 g) as a yellow crystalline solid melting point 76°-78° C.).