Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[OH:21])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.00 g (5.29 mmol) of 2-bromo-5-fluorotoluene were dissolved in 10 ml of tetrahydrofuran at −78° C. Addition of 4.0 ml (6.35 mmol) of a 1.6N solution of n-butyllithium in hexane was followed by stirring for 15 min, and then 0.79 g (6.35 mmol) of p-fluorobenzaldehyde dissolved in 10 ml of tetrahydrofuran was added dropwise. The mixture was warmed to RT and stirred for 1 h. The reaction solution was mixed with water and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution. The solvents were removed in vacuo, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 0.56 g (43% of theory) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:36]3[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=3)[N:30]=[C:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])[N:28]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
A mixture of benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g, 0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at room temperature. After evaporating the solvent under reduced pressure, the solid was triturated with Et2O, dried under vacuum, and taken up in CH2Cl2 (10 mL). 2-(4-Chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60 mmol) was added to this solution, followed by the addition of triethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 and washed with water. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-40% EtOAc in hexanes gave benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate as a colorless oil (0.19 g, 68% yield). LC/MS: m/z 469.1 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Oc1nncc2ccc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2nc(Br)ccc2cnn1Cc1cccc(Cl)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-3,8-diazaisoquinoline (1.00 g, 4.46 mmol) using 3-Chlorobenzyl bromide (1.37 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Trituration with hexanes/ethyl acetate 10:1 will afford the desired product. Step 2): 2-(3-chlorobenzyl)-7-(3-phenylprop-1-ynyl)-2H-3,8-diazaisoquinolin-1-one
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[C:11]([F:16])([F:15])[CH:12]([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: FC(F)C(F)(F)I
Reactant: Oc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Temperature: 70 °C

Procedure:
To a solution of 3-bromo-5-fluorophenol (104 mmol crude) and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: 1.91 min, [M+1] No Ionizable peak (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.76 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 100%; NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, 1H, d, J=8.35 Hz; 5.88 ppm, 1H, tt; J=52.95 Hz and J=2.64 Hz.
Reaction SMILES: [F:1][CH:2]([F:26])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=O)[C:23]#[CH:24])[O:19][C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5]1.[NH2:27][NH2:28].Cl>C(O)C>[F:1][CH:2]([F:26])[CH2:3][N:4]1[CH2:21][CH:20]([C:22]2[CH:23]=[CH:24][NH:28][N:27]=2)[O:19][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1
Reactant: C#CC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: FC(F)CN1CC(c2cc[nH]n2)OC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 8-(2,2-difluoroethyl)-10-prop-2-ynoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (25 mg, 0.07 mmol), hydrazine (42 μL, 1.34 mmol) and ethanol (0.5 mL) was stirred for 1 hour at room temperature. The solution was concentrated in vacuo to give the crude pyrazole as a yellow oil. HCl (400 μL of 4 M in dioxane, 1.60 mmol) followed by ethanol (0.2 mL) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was concentrated in vacuo to give 8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane as a gummy yellow solid. ESI-MS m/z calc. 286.2. found 287.1 (M+1)+; Retention time: 0.32 minutes (3 min run).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Li+].C1(=O)[N:13](CC(=O)C)[C:12](=O)[C:11]2=CC=CC=[C:10]12.CCCCCCCCCCCCCCCCO.C[O-].[Na+]>CN(C=O)C.CO>[NH2:2][C:1]1[NH:13][CH:12]=[C:11]([CH3:10])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CCCCCCCCCCCCCCCCO
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c[nH]c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyanoacetamide (62 g, 1.5 eq) and powdered lithium hydroxide (18 g, 1.5 eq) were mixed in 500 ml DMF and it was stirred at room temperature for 30 min. To the mixture was added a solution of phthalimidoacetone (100 g, 0.49 mol, purchased from TCI America, Portland, Oreg., USA, or prepared according to Lei, et al, J. Am. Chem. Soc. 2004, 126, 1626) in DMF (200 ml) over 1 h at room temperature. Additional DMF (25 ml) was used as a rinse. After stirring at room temperature for 5 min, HPLC/MS showed formation of the adol compound (MS: MH+=222.1, MNa+=244.0). Methanol (50 ml) was added followed by 25% sodium methoxide solution (160 g, 1.5 eq) and methanol rinse (50 ml). This mixture was heated at 60-65° C. for 2 h to form 2-amino-4-methyl-1H-pyrrole-3-carboxamide. To this reaction mixture was added ethyl formate (100 ml, 2.5 eq) at 40-60° C. After stirring for 15 min, more methanol (50 ml) was added followed by simultaneous addition of ethyl formate (100 ml, 2.5 eq) and 25% sodium methoxide solution (266 g, 2.5 eq) over 30 min. Additional methanol (50 ml) was added as rinse. The resulting mixture was heated at 60° C. for 5 h. More 25% sodium methoxide solution (113 ml, 1 eq) was added, and heating continued for 1 h more to convert all of the pyrrole N-formyl intermediate (MS: MH+=151.1). Water (400 ml) was added and mixture was heated at 60° C. for 30 min. Solution assay indicated the final product was formed in 69% yield. The hydrolyzed reaction mixture was concentrated under vacuum and diluted with water (1000 ml). The pH was adjusted to about 7.6 with 6 N HCl at 60-65° C. The resulting slurry was heated at 60-65° C. for 15 min and cooled slowly to 10° C. The solids were filtered, washed with water, and dried at 50-60° C. under vacuum. The final product was obtained as a light purple solid (39.5 g, 54% yield, purity: 99.8% by HPLC area).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH:23]=[CH:22][C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OC
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1OC
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (26.8 g), t-butyl acrylate (62.5 ml), triethylamine (25 ml) in anhydrous dimethylformamide (100 ml) are added palladium acetate (0.4 g) and 1,3-bis(diphenylphosphino)propane (0.74 g) under argon atmosphere, and the mixture is heated with stirring at 75° C. for 16 hours. The reaction solution is concentrated under reduced pressure to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:5) to give t-butyl 3-methoxy-4-methoxycarbonylcinnamate (23.5 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[N+:22]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=4)=[O:33])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc([N+](=O)[O-])c4)ccc3C2=O)C(=O)N1
Reaction time: 12 h
Yield: 38.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.74 g, 2.00 mmol) and 3-nitropheny isocyanate (0.33 g, 2.00 mmol) in acetonitrile (20 mL) was added TEA (0.56 mL, 4.00 mmol) at RT under nitrogen. After 12 hrs, the solid was filtered and purified by preparative HPLC (gradient: CH3CN/H2O: 15/85 for 5 min, to 100/0 in 10 min, 100/0 for 5 min). After evaporation of the solvent, the residue was triturated in ether (20 mL) for 1 hr. The product was then isolated by filtration and dried in vacuo to give 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(3-nitrophenyl)urea as a yellow solid (0.34 g, 39% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:41][CH3:42])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[C:31]4[N:30]=[CH:29][N:28]=[CH:27][C:26]=4[NH:25][N:24]=3)=[O:22])=[CH:18][N:17]([CH:32]([CH3:40])[C:33]([O:35]C(C)(C)C)=[O:34])[N:16]=2)[CH:14]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:41][CH3:42])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[C:31]4[N:30]=[CH:29][N:28]=[CH:27][C:26]=4[NH:25][N:24]=3)=[O:22])=[CH:18][N:17]([CH:32]([CH3:40])[C:33]([OH:35])=[O:34])[N:16]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)OC(C)(C)C)cc1NC(=O)c1n[nH]c2cncnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (10 mL) was added dropwise to a solution of tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)propanoate (0.945 g, 1.90 mmol, 1 equiv) in dichloromethane (10 mL). After 2 h, the reaction mixture was concentrated in vacuo to afford crude product (quantitative) which was used without further purification. LCMS (ESI): M+H=441.1.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:17]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:17][N:5]([CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1ccc(CN(C)S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-[(methanesulfonamido)methyl]benzoate (5 g, 20.6 mmol) in MeOH (100 mL) at rt was added K2CO3 (2.9 g, 21 mmol). Methyl iodide (7 ml, 16 g, 112 mmol) was added and the mixture stirred overnight. The reaction was filtered and the solid washed with CHCl3/MeOH. The combined filtrates were evaporated and the residue was purified by flash chromatographyon eluting with 0-5% MeOH/CHCl3. The title compound was isolated as a white solid (4.9 g, 94%): 1H (CDCl3): d 8.08 (d, 2H); 7.48 (d,2H); 4.41 (s, 1H); 3.97 (s, 3H); 3.91 (s, 3H); 2.83 (s, 3H).
Reaction SMILES: C(P(C(C)(C)C)C1C(C)=C(C)C(C)C(C)(C(C)C)C=1C1C=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl[C:36]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][CH:39]=[CH:38][N:37]=1.[OH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:57]([CH3:58])[C:56](=[O:59])[N:55]([CH2:60][O:61][CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])[C:54](=[O:68])[C:53]=2[CH3:69])=[C:48]([CH3:70])[CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:42]1([C:41]2[C:36]([O:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]4[N:57]([CH3:58])[C:56](=[O:59])[N:55]([CH2:60][O:61][CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])[C:54](=[O:68])[C:53]=4[CH3:69])=[C:48]([CH3:70])[CH:47]=3)=[N:37][CH:38]=[CH:39][CH:40]=2)[CH2:44][CH2:43]1
Reactant: Clc1ncccc1C1CC1
Reactant: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1=C(C)C(C)C(C)(C(C)C)C(c2ccc(C(C)C)cc2C(C)C)=C1P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ncccc2C2CC2)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Temperature: 120 °C
Reaction time: 5 h

Procedure:
Palladium(II) acetate (61 mg, 0.27 mmol) and di-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6-tri(propan-2-yl)biphenyl-2-yl]phosphane (130 mg, 0.27 mmol) were added to a mixture of C6 (615 mg, 4.00 mmol), C5 (1.0 g, 2.6 mmol) and cesium carbonate (2.6 g, 8.0 mmol) in 1,4-dioxane (25 mL). The reaction mixture was stirred at 120° C. under microwave irradiation for 5 hours, then diluted with ethyl acetate (50 mL) and filtered. After removal of solvents in vacuo, the residue was purified via silica gel chromatography (Gradient: 0% to 25% ethyl acetate in petroleum ether) to provide the product as a yellow gum. Yield: 900 mg, 1.8 mmol, 69%. LCMS m/z 494.1 [m+H]+. 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J=4.8, 1.8 Hz, 1H), 7.30 (dd, J=7.4, 1.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.08-7.10 (m, 2H), 7.01 (dd, J=7.5, 4.8 Hz, 1H), 5.51 (AB quartet, JAB=9.3 Hz, ΔνAB=3.8 Hz, 2H), 3.74-3.80 (m, 2H), 3.08 (5, 3H), 2.18 (5, 3H), 2.16-2.24 (m, 1H), 1.70 (5, 3H), 1.00-1.06 (m, 4H), 0.74-0.79 (m, 2H), 0.03 (5, 9H).
Reaction SMILES: [C:1]1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=C[CH:2]=1.N[C@H](C(OCC)=O)CCC(OCC)=O.C([C:34]1[CH:55]=[CH:54][CH:53]=[CH:52][C:35]=1[C:36]([NH:38][C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:37])#C.[K+].[Br-]>C(Cl)Cl.CO>[C:1]([C:54]1[CH:55]=[CH:34][C:35]([C:36]([NH:38][C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:37])=[CH:52][CH:53]=1)#[CH:2]
Reactant: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Reactant: C#Cc1ccccc1C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC
Agent: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.55 g of 4-ethynylbenzoic acid (obtained from tert.-butyl 4-ethynylbenzoate in 84% yield by hydrolysis with trifluoroacetic acid) in 50 ml of anhydrous ether and 25 ml of anhydrous tetrahydrofuran is added 1.58 ml of triethylamine. This is followed by 1.00 g of phenyl N-phenylphosphoramidochloridate. After stirring the reaction mixture at room temperature under nitrogen for 0.5 hour, 0.90 g of diethyl L-glutamate is added in one portion. The mixture is allowed to stir for another 8 hrs. After a workup, the residue is subjected to column chromatography using a 1% methanol:methylene chloride mixture as the eluent. The major fraction isolated from the column contained 0.68 g (54%) of diethyl N-(ethynylbenzoyl)-L-glutamate as an oil which slowly solidified: NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11-2.60 (m, 4H), 3.23 (s, 1H), 4.09 (q, 2H, J=6.9 Hz), 4.27 (l, 2H, J=6.9 Hz), 4.80 (m, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4 Hz); IR (KBr) 3330, 3280, 2990, 1735, 1640, 1520, 1380, 1200, 1105, 1020, 855, and 770 cm- 1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH2:14])[CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][N:6]([C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:7][CH2:8]1
Reactant: COC1CCN([C@@H]2CCC[C@H]2N)CC1
Reactant: COc1cc(C(=O)Cl)ccc1Cl
Product: COc1cc(C(=O)N[C@@H]2CCC[C@H]2N2CCC(OC)CC2)ccc1Cl

Procedure:
Following the procedure of Example 1b, using trans-N-[2-(4-methoxy-1-piperidinyl)cyclopentyl]amine and 3-methoxy-4-chlorobenzoyl chloride there is obtained as product trans-N-[2-(4-methoxy-1-piperidinyl)cyclopentyl]- 3-methoxy-4-chlorobenzamide.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:26][N:27]1[C:31]([NH2:32])=[CH:30][C:29]([CH3:33])=[N:28]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:32][C:31]4[N:27]([CH3:26])[N:28]=[C:29]([CH3:33])[CH:30]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
To a solution of 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (121 mg, 0.358 mmol) in N,N-dimethylformamide (5.0 mL) were added 1,3-dimethyl-1H-pyrazol-5-amine (47.8 mg, 0.43 mmol), 1-hydroxybenzotriazole (58 mg, 0.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.4 mg, 0.43 mmol) and triethylamine (45 mg, 0.43 mmol), and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10, then methanol/ethyl acetate=0/100→15/85), and precipitated from ethyl acetate/hexane to give the title compound (116 mg, 75%) as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].[CH:11]#[CH:12]>CS(C)=O>[CH:11]([O:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:8])([CH3:7])[CH3:1])=[CH2:12]
Reactant: C[Si](C)(C)CCCO
Reactant: C#C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=COCCC[Si](C)(C)C
Yield: 96 %

Procedure:
In a similar manner to Example 1, 25 g (0.19 mol) of 3-(trimethylsilyl)propanol, 2.5 g of KOH and 25 g of DMSO were reacted at 80° C. with acetylene. 3-(Trimethylsilyl)propyl vinyl ether was obtained in 96% yield.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.O>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1)[C:5]#[CH:6]
Reactant: O=Cc1ccc(O)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilylacetylene (1.00 g, 10 mmol) (Aldrich) in dry THF (100 mL) under argon at −78° C. was added n-butyllithium (4.4 mL, 11 mmol, 2.5 M solution in hexanes) (Aldrich) dropwise. The reaction was stirred for 30 min at −78° C., after which time 4-hydroxybenzaldehyde (0.50 g, 4 mmol) (Aldrich) was added and the reaction was allowed to slowly warm to room temperature. A saturated solution of ammonium chloride (5 mL) was then added and the reaction was stirred at room temperature for 2 h. The solution was then diluted by the addition of 30 mL water, and THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne which was used directly, without further purification. (Yield 501 mg, 84%).
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7](=[O:21])[CH2:8][S:9]/[C:10](=[C:12]1/[C@H:13]2[C@@H:15]([CH2:16][C:17]/1=O)[C:14]2([CH3:20])[CH3:19])/[CH3:11])[CH3:5]>[OH-].[Na+]>[CH2:4]([O:6][C:7]([C:8]1[S:9][C:10]([CH3:11])=[C:12]2[C:17]=1[CH2:16][C@H:15]1[C:14]([CH3:20])([CH3:19])[C@H:13]12)=[O:21])[CH3:5]
Reactant: CCOC(=O)CS/C(C)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
A solution of Na (1.70 g, 74.8 mmol) in abs. ethanol (75 mL) is heated to 60° C. before it is treated with a solution of crude {1-[(1S,5R)-6,6-dimethyl-3-oxo-bicyclo[3.1.0]hex-(2Z)-ylidene]-ethylsulfanyl}-acetic acid ethyl ester (18.2 g, 68.0 mmol) in abs. ethanol (200 mL). The mixture is stirred at 75° C. for 20 min, then cooled to rt, diluted with 0.5 M aq. NaOH (500 mL) and extracted with DCM (450+200 mL). The combined extracts are dried over Na2SO4, filtered and the solvent is removed in vacuo. This yields crude (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (10.5 g) as a yellow oil of 87% purity (LC-MS, UV 280 nm). LC-MS: tR=1.11 min, [M+1]+=251.14; 1H NMR (CDCl3): δ 4.26 (q, J=7.0 Hz, 2H), 2.95 (dp, Jd=18.8 Hz, Jp=3.5 Hz, 1H), 2.79 (d, J=19.3, 1H), 2.37 (s, 3H), 1.89-1.84 (m, 2H), 1.34 (t, J=7.0 Hz, 3H), 1.12 (s, 3H), 0.72 (s, 3H).