Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH3:24])[C:12]([OH:14])=O)#[N:8].[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32](=[N:34]O)[NH2:33])[CH:31]=1.CCN(C(C)C)C(C)C>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32]2[N:33]=[C:12]([C:11]3[CH:15]=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]4[CH3:24])=[C:9]([CH:10]=3)[C:7]#[N:8])[O:14][N:34]=2)[CH:31]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(C#N)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 36 (122 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 70/30) afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:14]=O>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:14]=[N:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(CN)OCC
Solvent: Cc1ccccc1
Product: CCOC(CN=Cc1cc(Cl)cc(Cl)c1)OCC
Temperature: 114 °C
Reaction time: 2.5 h

Procedure:
The 2,2-Diethoxy-ethylamine (1852.5 g; 1.00 equiv; 13.63 moles), 3,5-dichloro-benzaldehyde (2453 g; 1.00 equiv; 13.60 moles), and Toluene (12 L) is charged to a 22 L flask equipped with a Dean Stark trap, condenser, nitrogen inlet, overhead stirring, and thermocouple. The light yellow reaction is warmed to reflux. Solvent begins distilling at 88° C. A total of ˜650 mL distillate (˜240 mL of water) is collected. The temperature is increased to 114° C. during the distillation. NMR after 2 hr at reflux shows the product. The heat is shut off after 2.5 hr. The solution is gravity filtered into a carboy through fluted filter paper to remove a few particulates (including a small section of glass tubing, which is most likely from the 3,5-dichloro-benzaldehyde). The filtered solution is concentrated using Buchi flask with the water bath set at 45° C. Once the solvent stops coming over, the temperature is increased to 70° C. with full vacuum and held for ˜1.5 hr to remove any residual toluene. The weight of (3,5-Dichloro-benzylidene)-(2,2-diethoxy-ethyl)-amine is 4059.3 g (102.9% of theory). Mass Spectrum (LCMS) m/z=291.2) (M+H+)
Reaction SMILES: [C:1]([C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:24]>C(O)C.[Pd].CCOCC>[ClH:24].[CH2:1]([C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cnc2ccc(NCc3ccccn3)nn12
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCc1cnc2ccc(NCc3ccccn3)nn12
Reaction time: 24 h
Yield: 41 %

Procedure:
3-(Hex-1-ynyl)-N-(pyridin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine was dissolved in ethanol (5 mL) with 5% palladium on charcoal and placed under hydrogen (50 psi) in a Parr shaker. After 24 hr, the reaction mixture was filtered through celite and concentrated to provide the free-base. This was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (26 mg, 41%) as an orange solid; 1H NMR (300 MHz, CD3OD) δ 8.52 (d, J=5.0 Hz, 1H), 7.92 (d, J=9.8 Hz, 1H), 7.89-7.83 (dt, J=1.7, 9.4 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.37-7.35 (m, 1H), 7.31 (d, J=9.8 Hz, 1H), 4.73 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 1.55-1.48 (m, 2H), 1.29-1.25 (m, 6H), 0.98 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 158.2, 156.2, 148.8, 139.0, 132.9, 131.9, 123.6, 122.8, 121.0, 119.8, 118.2, 46.9, 32.0, 29.3, 27.1, 23.2, 23.0, 13.8; HPLC tR=9.26 min (Luna), 95.3%; ES-MS: (M+H)=310 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:45][CH2:44][CH2:43][N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][F:34])[CH2:42][CH2:41]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCN(CCF)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (202 mg, 0.96 mmol), (prepared as described for the starting material in Example 4), in methylene chloride (10 ml) was treated with triphenylphosphine (352 mg, 1.35 mmol), 3-[4-(2-fluoroethyl)piperazin-1-yl)propan-1-ol (200 mg, 1.06 mmol), (prepared as described for the starting material in Example 27), and diisopropyl azodicarboxylate (226 mg, 1.15 mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture was loaded onto a silica column and eluted using methylene chloride/methanol (95/5). The relevant fractions were combined and evaporated under vacuum to give 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (208 mg, 57%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: O=C(Cl)OCCCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)OCCCCCl)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 82 μl (2 molar equivalents) of 4-chlorobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product (formula shown hereinabove) were isolated as an orange powder (yield=85%) which was characterized as follows:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18]O)=[C:8]([O:22][CH2:23][CH2:24][NH:25][CH3:26])[CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][Cl:3])=[C:8]([CH:7]=1)[O:22][CH2:23][CH2:24][NH:25][CH3:26]
Reactant: O=S(Cl)Cl
Reactant: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCO
Solvent: Cc1ccccc1
Product: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCCl
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 15 ml of thionylchloride in 200 ml of toluene was added at room temperature to a solution of 20.1 g of 2-[4-chloro-2-[2-(methylamino)ethoxy]phenoxy]benzeneethanol in 400 ml of dry toluene. After 30 min of stirring the mixture was concentrated, dissolved in water and washed with diethyl ether. The aqueous layer was basified with 2N sodium hydroxide and extracted with diethyl ether. The ethereal layer was dried over sodium sulphate, concentrated in vacuo and purified by silica chromatography using toluene-ethanol (8:2) to obtain 12.9 g (61%) of 2-[5-chloro-2-[(2-chloroethyl)phenoxy]phenoxy]-N-methyl-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 10 g (51 mmol) of 1-(4-chlorophenyl)butane-1,3-dione (commercially available) dissolved in dimethyl sulfoxide was slowly added dropwise to 2.237 g (56 mmol) of sodium hydride in 200 ml of dimethyl sulfoxide such that the temperature did not exceed 30° C. The mixture was stirred at 20° C. for another 30 minutes. 8.558 g (56 mmol) of methyl bromoacetate in a little dimethyl sulfoxide were then slowly added dropwise at 0° C. The mixture was stirred at 20° C. for 4 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phase was repeatedly washed with water. Drying of the combined organic phases, removal of the solvent under reduced pressure and chromatography of the residue gave 7.750 g of product (56.7% of theory); NMR (CDCl3, 400 MHz): 2.19 (s, 3H); 2.99 (d, 1H); 3.03 (d, 1H); 3.69 (s, 3H); 4.95 (dd, 1H); 7.49 (d, 2H); 7.98 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][N:9](CC)[C:10](=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNOCc1ccccc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
151 (616 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 152 as an oil (324 mg, 88%). 1H NMR (DMSO): δ 0.99 (t, 3H, J=7.3 Hz), 2.82 (m, 2H), 4.61 (s, 2H), 6.50 (t, 1H, J=5.8 Hz), 7.32 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][CH:14]([F:17])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:13][CH:14]([F:17])[CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: OCC(F)F
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40% solution in toluene) at 0° C. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (18:1) to give 1.9 g (90% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[S:29][C:30]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:31]=2[N:32]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:35]=[CH:36][C:30]6[S:29][C:28]([CH3:27])=[N:32][C:31]=6[CH:33]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1nc2cc(B(O)O)ccc2s1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6sc(C)nc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzothiazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.91 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.Cl>CCCCO>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=3[N:6]=2)=[C:15]([F:20])[CH:14]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1cccc2sc(Cl)nc12
Agent: Cl
Solvent: CCCCO
Product: Cc1cccc2sc(Nc3ccc(Br)cc3F)nc12
Temperature: 90 °C
Yield: 89.4 %

Procedure:
To a solution of 2-chloro-4-methyl-1,3-benzothiazole (0.25 g, 1.36 mmol) in n-BuOH (8 mL) was added 4-bromo-2-fluoroaniline (0.52 g, 2.72 mmol) and HCl (4.0 M in dioxane, 0.5 mL). The reaction was heated at 90° C. overnight. Solvent was removed by rotary evaporation and 1 N aqueous HCl was added. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was brought up in MeOH and the precipitate was collected by filtration, washed with MeOH, and dried in a vacuum oven to give N-(4-bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine (0.41 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.07 (t, 1H), 7.15 (d, 1H), 7.36 (m, 2H), 7.51 (d, 1H), 8.72 (t, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16].N1C=CC=CC=1>ClCCl>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[O:16])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 16 h
Yield: 121.4 %

Procedure:
tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (1.10 g, 5.91 mmol) was dissolved in dichloromethane (50 mL), and thereafter, 4-nitrophenyl chloroformate (1.19 g, 5.91 mmol) and pyridine (0.47 g, 5.91 mmol) were added to the obtained solution. The obtained mixture was stirred for 16 hours. Thereafter, the reaction solution was concentrated in vacuo to obtain tert-butyl 3-((((4-nitrophenoxy)carbonyl)amino)methyl)azetidine-1-carboxylate (2.52 g, quant) in the form of a white solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]([CH3:12])=[CH2:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16]OC(OC)N(C)C>>[CH3:14][N:6]1[C:5](=[O:15])[C:4]2=[CH:16][NH:2][N:1]=[C:3]2[N:8]([CH2:9][C:10]([CH3:12])=[CH2:11])[C:7]1=[O:13]
Reactant: COC(OC)N(C)C
Reactant: C=C(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: C=C(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Temperature: 90 °C

Procedure:
A mixture of 6-hydrazino-3-methyl-1-(2-methyl-2-propenyl)pyrimidine-2,4[1H,3H]-dione (0.575 g) and dimethylformamide dimethylacetal (0.73 ml) was heated at 90° C. for 20 minutes. The mixture was allowed to cool and was directly purified by column chromatography over silica eluting with ethyl acetate: hexane (2:1) and then recrystallisation from ethyl acetate/hexane to give the subtitle compound (0.063 g). Melting point: 232-233° C. MS (EI) 220 (M+) 1H NMR (CDCl3 /DMSO-d6) δ 1.80 (3H, s); 3.39 (3H, s); 4.60 (2H, s); 4.75 (1H, s), 4.89 (1H, s); 8.04 (1H, s); 13.04 (1H, s, br).
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]1)#[CH:2].[CH3:11][CH2:12][NH:13][C:14]([C@H:16]1[O:20][C@@H:19]([N:21]2[C:25]3[N:26]=[C:27](I)[N:28]=[C:29]([NH2:30])[C:24]=3[N:23]=[CH:22]2)[CH:18]([OH:32])[C@H:17]1[OH:33])=[O:15]>>[CH2:12]([NH:13][C:14]([CH:16]1[CH:17]([OH:33])[CH:18]([OH:32])[CH:19]([N:21]2[CH:22]=[N:23][C:24]3[C:25]2=[N:26][C:27]([C:2]#[C:1][C:3]2([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]2)=[N:28][C:29]=3[NH2:30])[O:20]1)=[O:15])[CH3:11]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)C(O)[C@H]1O
Reactant: C#CC1(O)CCCC(C)C1
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CC4(O)CCCC(C)C4)nc32)C(O)C1O

Procedure:
The reaction of 1-Ethynyl-3-methyl-cyclohexanol (JR3149B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3179 (15.0 mg, 59%) as a white solid after purification by a silica plug and RP-HPLC. 1H NMR (CD3OD-d4) δ 8.49 (s, 1H), 6.06 (d, J=6.9 Hz, 1H), 4.75 (dd, J=6.4 Hz, J=4.9 Hz, 1H), 4.46 (d, J=1.9 Hz, 1H), 4.34 (dd, J=4.9 Hz, J=2.1 Hz, 1H), 3.42 (m, 2H), 2.09 (d, J=12.3 Hz, 2H), 1.73 (m, 4H), 1.46 (m, 1H), 1.23 (m, 1H), 1.16 9 (t, J=7.1 Hz, 3H), 0.95 (d, J=6.2 Hz, 3H), 0.89 (m, 1H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4 (40), 254.4 (4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[C:10]([NH:29]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[C:10]([NH:29][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3)c2)cn1

Procedure:
The compound was prepared from the compound of Example 53 using the procedures of Example 54 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.1 (br s, 1H), 8.26 (s, 1H), 8.01 (d, 2H), 7.84-7.81 (m, 2H), 7.74-7.71 (m, 3H), 7.59 (s, 2H), 7.39 (t, 2H), 3.89 (s, 3H), 2.91-2.89 (m, 1H), 1.03 (d, 4H); LC-MS (ESI): Calculated mass: 487.55; Observed mass: 488.1 [M+H]+ (rt: 1.42 min).
Reaction SMILES: [C:1]([O:11]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Cl-].[Cl-].[Cl-].[Al+3].ClCCl>C(N(CC)CC)C>[CH3:9][O:8][C:6]([CH:5]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:11])=[O:7]
Reactant: COC(=O)CCCCC(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCCC1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
8.7 g (50 mmol) of dimethyl adipate, anhydrous aluminum trichloride (20 g) and 100 ml of dry dichloromethane were cooled to 0° C. under an ice bath. At 0° C., triethylamine (dried with sodium hydroxide, 45 ml) was added dropwise and slowly. After addition, the ice bath was removed and the reaction was carried out at room temperature for 4 hours, being monitored with TLC. After the reaction was completed, the reaction liquid was poured into an ice-water mixture slowly, which was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml×2). The organic layers were combined and washed with water and then with saturated NaCl, dried with anhydrous magnesium sulfate, and filtrated. The solvent was distilled off under reduced pressure to give 5.1 g of 2-oxocyclopentanecarboxylate methyl ester. The yield was 71.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14][OH:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:32](=[O:33])([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)[O:15][CH2:14][C:13](=[C:11]1[CH2:12][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:10]1)[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 320 mg (0.717 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethanol (Example 31) and 175 mg (1.43 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was added 217 mg (1.076 mmol) of 4-nitrophenyl chloroformate, and the reaction mixture was stirred for 4 h at rt. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=12:1 to afford the title compound as a white solid; Mass Spectrum m/e=613 (M+1 35Cl, 35Cl) and 615 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([C:8]1([O:13][C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18](OC)=[O:19])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:29]1([P:35](=[CH:48][C:49]#[N:50])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:49]([C:48](=[P:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:18]([C@@H:17]([NH:16][C:14](=[O:15])[O:13][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])#[N:50]
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)OC
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To 1.31 g (3.77 mmol) of methyl(2S)-2-({[(1-benzylcyclopentyl)oxy]carbonyl}amino)hexanoate in 12 mL of tetrahydrofuran:water (1:1) was added 221.5 mg (5.28 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with ethyl acetate. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 19 mL of dichloromethane, then 23.0 mg (188.5 μmol) of 4-dimethylaminopyridine was added. To this solution was added 1.19 g (3.96 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 799.2 mg (4.15 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 19 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 789.8 mg (34%) of 1-benzylcyclopentyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.31 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.76-7.66 (m, 3H), 7.64-7.54 (m, 12H), 7.20-7.14 (m, 5H), 6.90 (d, J=8 Hz, 1H), 4.58-4.50 (m, 1H), 3.24 (ABq, JAB=14 Hz, ΔνAB=31 Hz, 2H), 1.88-1.66 (m, 4H), 1.64-1.44 (m, 6H),1.42-1.14 (m, 4H), 0.89 (t, J=7 Hz, 3H); ES-LCMS m/z 617 (M+H).