Azzindani/Open_Reaction_Data huggingface dataset:
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])[C:7]2=[O:22].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].C(N(CC)C(C)C)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3,4-dichlorophenyl isocyanate (0.56 g, 3.0 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) in pyridine (20 mL) was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was suspended in a biphasic mixture of CH2Cl2 (150 mL) and water (150 mL) and stirred for 2 hours. The solid was filtered, washed with additional water (50 mL), and dried. The resulting solid was stirred in methanol (200 mL) at room temperature for 1 hour, filtered, and dried. This material was refluxed in methanol (2×200 mL) for 3 hours, filtered, and dried. The resulting solid was chromatographed using a methanol-CH2Cl2 (with 0.1% of triethylamine) gradient, eluting 0.23 g of the product at 7:93 methanol-CH2Cl2 (with 0.1% of triethylamine), in 16% yield; mp 290-292° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 10.50 (97.00%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.56-2.62 (m, 2H), 2.82-2.94 (m, 1H), 4.47 (d, J=5.9 Hz, 2H), 5.15 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 7.05 (t, J=6.1 Hz, 1H), 7.29 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.77-7.91 (m, 4H), 9.11 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 42.7, 49.0, 117.9, 118.9, 121.7, 122.4, 123.5, 129.7, 130.4, 130.9, 131.6, 133.3, 140.6, 148.4, 155.0, 167.0, 167.2, 169.8, 172.7; Anal. Calcd for C21H16N4O5Cl2+0.25H2O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.22; H, 3.25; N, 11.56.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.B(F)(F)F.CCOCC>CCOC(C)=O>[CH:13]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1=CCCCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
Ethyl 4-hydroxybenzoate (1.0 g, 6.02 mmol) and cyclohexene (6.0 mL) were mixed together and boron trifluoride diethyl etherate (0.38 mL, 3.01 mmol) was then added. The mixture was heated under reflux for 2 h and then cooled to rt. EtOAc (20 mL) was added and the solution washed with 5% NaOH solution (3×40 mL) and with H2O (50 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated. The crude product was absorbed over silica gel and purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (from 100:0 to 90:10) to afford the title compound (1.17 g, 78%), as white solid. MS (ESI) m/z: 249 [M−H]+; 1H NMR (DMSO-d6): δ 1.29 (t, J=7.1 Hz, 3H), 1.33-1.49 (m, 5H), 1.50-1.59 (m, 1H), 1.63-1.79 (m, 2H), 1.89-1.98 (m, 2H), 4.26 (q, J=7.1 Hz, 2H), 4.41-4.49 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[NH:5][CH:4]=1)#[N:2].C(O)CCC.[O:22]([CH:26]([CH3:34])[CH2:27][C:28]([NH:30][CH2:31][CH2:32][NH2:33])=[O:29])[N+:23]([O-:25])=[O:24].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>CO>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[CH2:27][CH:26]([O:22][N+:23]([O-:25])=[O:24])[CH3:34])[NH:5][CH:4]=1)#[N:2]
Reactant: CC(CC(=O)NCCN)O[N+](=O)[O-]
Reactant: N#Cc1c[nH]c2cccc(OCC3CO3)c12
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCCCO
Product: CC(CC(=O)NCCNCC(O)COc1cccc2[nH]cc(C#N)c12)O[N+](=O)[O-]

Procedure:
4.2 g. 1-(3-cyanoindol-4-yloxy)-2,3-epoxypropane (see European patent specification No. 0,045,910) are suspended in 100 ml. n-butanol, mixed with 11.5 g. 2-(3-nitroxybutanoylamino)-ethylamine and stirred for 2 days at ambient temperature. After removal of the solvent, the residue is chromatographed on silica gel with methylene chloride/methanol (95:5 v/v) and methylene chloride/methanolic ammonia solution (95:5 v/v). From the appropriate fractions, after removal of the solvent, there are obtained 4.6 g. of base. By dissolving in methanol and adding the calculated amount of fumaric acid, there are obtained, after suction filtration, 3.9 g. (40% of theory) of the desired fumarate; m.p. 155°-156° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1C(F)(F)F

Procedure:
A suspension of 2-trifluoromethyl-4-fluorobenzoic acid (16.85 g, 81 mmol) in dichloromethane (150 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (8.5 mL, 97.4 mmol). After the gas evolution subsided, the reaction mixture was refluxed for an additional 10 minutes, and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.C([Li])(CC)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1>C1COCC1>[F:33][CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2COc2ccccc21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: FC=C1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 11-Bromomethylene-6,11-dihydro-dibenzo[b,e]oxepine (1 eq.) in dry THF (0.1 M). Cool the solution to −78 C in a dry ice/acetone bath. Slowly add s-butyl lithium (1.2 eq., 1.3 M in cyclohexane) to the above solution. Stir the dark brown solution at −78 C. for two hours. Add a solution of N-fluorobenzene sulfonimide (1.2 eq.) in dry THF (0.4 M) over 2 minutes. Remove the cold bath and allow the reaction mixture to warm to ambient temperature. Stir the reaction mixture at room temperature for 1 hour. Quench the reaction with water. Wash the resulting mixture with saturated aqueous NaHCO3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[OH-:12].[Na+]>O>[NH4+:3].[Cl:1][C:2]1[N:7]=[C:6]([OH:12])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: [OH-]
Reactant: CCc1nc(Cl)nc(Cl)c1F
Agent: [Na+]
Solvent: O
Product: CCc1nc(Cl)nc(O)c1F
Product: [NH4+]
Temperature: 90 °C

Procedure:
A mixture of the compound of part (ii) (40 kg) and water (10 kg) was heated to 90° C. and 4N aqueous sodium hydroxide solution (127 L) added.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[NH2:39][C:40]1[N:44]([CH3:45])[N:43]=[C:42]([CH:46]2[CH2:48][CH2:47]2)[CH:41]=1>C(#N)C>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:39][C:40]2[N:44]([CH3:45])[N:43]=[C:42]([CH:46]3[CH2:48][CH2:47]3)[CH:41]=2)=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:30])([F:31])[F:1])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: Cn1nc(C2CC2)cc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nc(C2CC2)cc1NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 41 h
Yield: 25.4 %

Procedure:
To a solution of 3-(3,5-bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 9, 0.6 mmol) in dry acetonitrile (1.0 ml), triethylamine (0.100 ml, 0.7 mmol) and 5-amino-3-cyclopropyl-1-methyl pyrazole (0.100 g, 0.7 mmol) were added. The reaction mixture was stirred for 41 h at 80° C. under nitrogen and then concentrated. The residue was worked up as described in Example 17,2) to give 90 mg (25%) of the title compound. 1H NMR (200 MHz, CDCl3): δ=0.7 (m, 2H), 0.9 (m, 2H), 1.85 (m, 1H), 3.5 (s, 3H), 5.3 (s, 1H), 5.4 (s, 1H), 5.85 (s, 1H), 7.28 (s, 2H), 7.53 (d, 2H), 7.63 (s, 1H), 7.8 (d, 2H); EI SP/MS: 589 (M+).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][C:7]1[C:8]([NH2:16])=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1.CCN(CC)CC>C1COCC1>[CH3:5][N:6]1[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[NH:16][C:1]1=[S:2]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of thiophosgene (2.3 ml, 30 mmol) in THF (300 ml) was added dropwise to a solution containing N1-Methyl-4-nitro-benzene-1,2-diamine (5.01 g, 30 mmol) and Et3N (9.2 ml, 66 mmol) in THF (300 ml) at 0° C. over 90 min. After stirring at 0° C. for another 1 hr, the mixture was allowed to warm to room temperature. The mixture was then concentrated to about 100 ml, water (200 ml) was added, the mix was stirred for 20 min, the product was collected by filtration and washed with small amount of cold CH2Cl2, after drying left 5.16 g as a mustard yellow solid: LC/MS (m/e) at 210.0 [M+H]+, Rt at 1.49 min.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:18]([NH2:20])[CH3:19])=[C:10]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[CH:11]=2)[CH:6]=[CH:5]1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[C:24]([S:31][CH3:32])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:9]2[N:8]=[C:7]3[CH:6]=[CH:5][N:4]([CH3:3])[C:12]3=[CH:11][C:10]=2[C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH3:19])[N:25]=[C:24]([S:31][CH3:32])[N:23]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1cscn1
Reactant: CSc1nc(N)c(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2cscn2)n1
Temperature: 120 °C
Yield: 8.6 %

Procedure:
(S)-1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine dihydrochloride (200 mg, 0.604 mmol), 4-amino-6-chloro-2-(methylthio)pyrimidine-5-carbonitrile (182 mg, 0.906 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.315 mL, 1.81 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by column chromatography eluting with 20-80% EtOAc in hexane over 60 minutes. The fractions containing the desired product were collected and concentrated to give the title compound (22 mg, 9%). ESI-MS m/z [M+H]+ calc'd for C19H18N8S2, 423; found 423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][C@@H:48]([NH2:50])[CH3:49])[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][C@@H:48]([NH:50][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:49])[C:39]([O:41][CH3:42])=[O:40]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (513 mg, 1.07 mmol), methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate (260 mg, 1.07 mmol) and Et3 N (220 μl, 1.58 mmol) in DMF (10 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc and the solution was washed with sat. NaHCO3, dried over Na2SO4, and evaporated. The residue was recrystallized from MeOH—CHCl3-EtOAc-n-hexane to give 400 mg (69%) methyl (S)-3-chloro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as pale brown crystalline powder. 1H-NMR (DMSO-d6) δ 1.21 (d, 3 H, J=6.4 Hz), 2.24 (s, 3 H), 3.37 (s, 2 H), 3.82(s, 3 H), 3.83 (s, 3 H), 4.04–4.12 (m, 3 H), 6.75–6.77 (m, 1 H), 6.91–6.95 (m, 2 H), 7.11–7.17 (m, 2 H), 7.29–7.31 (m, 1 H), 7.78–7.99 (m, 4 H), 8.12–8.13 (m, 1H), 8.46 (s, 1 H), 8.55 (s, 1 H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53](=[O:60])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:46][CH:45]=1>CN(C=O)C.O>[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:45]=[CH:46][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53]([N:54]2[CH2:55][CH2:56][N:57]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:21]=3[Br:20])[CH2:58][CH2:59]2)=[O:60])=[CH:48][CH:49]=1
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-bromo-5-fluorobenzoic acid (46 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 40 mg (37%) of N-biphenyl-4-yl-3-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 524.09 (M+1)+, 96%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 7H), 7.42 (t, 2H), 7.34 (t, 1H), 7.0 (m, 2H), 3.96 (m, 2H), 3.7 (m, 4H), 3.5 (d, 2H), 3.3 (m, 2H).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.COC(OC)[N:14]([CH3:16])C.O.[NH2:20]N>>[CH:1]1([C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:16][NH:14][N:20]=2)[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: COC(=O)CC(=O)C1CC1
Solvent: O
Product: COC(=O)c1c[nH]nc1C1CC1

Procedure:
Using methyl 3-cyclopropyl-3-oxopropanoate (2.8 g), dimethylformamide dimethylacetal (2.8 mL) and hydrazine monohydrate (1.1 mL) and in the same manner as in Example 1(3), a crude product of methyl 3-cyclopropyl-1H-pyrazole-4-carboxylate was obtained. This was dissolved in dimethylformamide (30 ml), potassium carbonate (4.2 g) and 2-chloro-5-trifluoromethylpyridine (3.6 g) were added, and the mixture was stirred at 100° C. for 2 hr. In the same manner as in Example 1(4), the title object compound (4.8 g, 77%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][O:6][CH:5]1[OH:9])[CH:2]=[CH2:3].[CH2:10]([O:12]C(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)C.[C:34]1([CH3:40])C=CC=C[CH:35]=1>>[OH:12][CH2:10][CH2:3][CH:2]([CH2:40][CH:34]=[CH2:35])/[CH:1]=[CH:4]/[C:5]([O:6][CH2:7][CH3:8])=[O:9]
Reactant: C=CCC1CCOC1O
Reactant: CCOC(=O)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: C=CCC(/C=C/C(=O)OCC)CCO

Procedure:
3-allyl-tetrahydrofuran-2-ol (18 g, 140 mmol) and ethoxycarbonyl triphenylphosphorane (35 g, 104 mmol) were stirred overnight in toluene (200 mL). The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (15.8 g, 61.1%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[C:26](O)=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ClCCl.CO>CN(C=O)C>[C:26]([CH:25]([O:29][CH2:30][CH3:31])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=2)=[CH:19][CH:20]=1)(=[O:27])[NH2:39]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
3-{4-[2-(4-tert-Butoxycarbonylamino phenyl}ethoxy]phenyl]-2-ethoxypropanoic acid (1.18 g, 2.75 mmole) and benzotriazol-1-yl-oxytri-pyrrolidinophosphoniumhexafluorophosphate (1.43 g, 2.75 mmole) were dissolved in dry DMF (20 ml). Ammonia gas was bubbled through the mixture for 5 minutes. After stirring at room temperature for 16 hours it was checked using HPLC that all the starting material was consumed. Water was added and extracted three times with ethyl acetate dried with magnesium sulfate and evaporated. The residue was redissolved in dichloromethane and chromatography on silica using a gradient system of dichloromethane:methanol (0-5%) gave 1.04 g (85% yield) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(C1N(C(C(OCC2C=CC=CC=2)=O)=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C(=O)C1)C=C.[C:57]1([SH:63])[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]([S:63][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:7]2[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:3]1
Reactant: O=C(OCc1ccccc1)C1=CCC2CC(=O)N12
Reactant: Sc1ccccc1
Agent: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1C(Sc2ccccc2)CC2CC(=O)N21

Procedure:
Crude benzyl 7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate prepared from an ethyl acetate solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one (1.00 g) by ozonolysis and cyclisation was dissolved in dry dimethylformamide (5 ml) treated successively with thiophenol (0.20 ml) and potassium carbonate (0.133 q) with stirring. After a period of 1 hour the solution was concentrated under reduced pressure and the residue treated with ethyl acetate. It was then washed with brine, dried over sodium sulphate and concentrated. Chromatography on silica gel 60 (<230 mesh) eluting with 60°-80° petroleum ether/ethyl acetate 7:3 grading to 6:4 gave two fractions containing diastereoisomers of the title compound. The least polar fraction (0.183 g) was an approximately 4:1 mixture of isomers A (5) and B (6); νmax (CHCl3) 3000, 1760 and 1740 (sh); τ(CDCl3) for major isomer A (5), 2.6-2.9 (10H, m, phenyls), 4.88 (2H, s, benzyl CH2), 5.26 (1H, d, J 7 Hz, C2-H), ca 5.90 (1H, br m, C5-H), 6.10 (1H, td, J9 and 7 Hz, C3-H), 6.69 (1H, dd, J16 and 5 Hz, C6-H), 7.32 (1H, dd, J16 and 21/2 Hz, C6-H), 7.73 (1H, dd, J9 and 7 Hz, C4-H) and 7.77 (1H, dd, J9 and 4 Hz, C4-H); minor isomer B (6) had 5.62 (d, J 5 Hz, C2-H); (M+ for mixture at m/e 353.1102. C20H19NO3S requires 353.1085). The more polar fraction (0.102 g) was isomer C (8) which could be crystallized from diethyl ether; m.p. 84°-85°; νmax (CHCl3) 3000, 1765 and d 1740 cm-1 ; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.81 (2H, s, benzyl CH2), 5.84 (1H, d, J 7 Hz, C2-H), 6.04 (1H, ddd, J12, 7 and 5 Hz, C3-H), 6.2-6.5 (1H, m, C5-H), 6.90 (1H, dd, J16 and 4 Hz, C6-H), 7.19 (1H, dd, J16 and 21/2 Hz, C6-H), 7.64 (1H, dt, J12 and 5 Hz, C4-H) and 7.95 (1H, td, J12 and 10 Hz, C4-H); (Found; C, 68.1; H, 5.6; N, 3.9% C20H19NO3S requires C, 68.0; H, 5.4 and N, 4.0%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]([F:13])([F:14])[F:15])=[C:3]([OH:2])[CH:8]=1)([O-:11])=[O:10]
Reactant: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a solution of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene (5.0 g, 22.6 mmol) in N,N-dimethylformamide (23 mL) was added lithium chloride (2.40 g, 56.5 mmol), and the mixture was stirred at 120° C. for 2 hr. The reaction temperature was heated to 155° C., and the mixture was further stirred for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL)/hexane (75 mL), and washed with 1% aqueous citric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL)/hexane (25 mL), and the combined organic layer was washed with water (100 mL) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→90/10). The obtained solution was concentrated under reduced pressure to give the title compound (2.22 g, 47%) as a yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH:12]([CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-])=O)=[CH:8][CH:9]=2)[CH2:4]1>CO>[ClH:1].[CH3:2][N:3]1[CH:12]([CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:14])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CC1Cc2ccc([N+](=O)[O-])cc2CN1C
Agent: Cl
Solvent: CO
Product: CC1Cc2ccc(N)cc2CN1C
Reaction time: 1 h

Procedure:
To 2,3-dimethyl-7-nitro-1,2,3,4tetrahydroisoquinoline hydrochloride (2.0 g, 8.24 mmol) in methanol (100 ml) was added a catalytic amount of 10% Pd--C. The mixture was hydrogenated at 50 psi for 1 h, filtered, and concentrated to a solid which was used immediately in the next reaction (1.6 g, 92%), m.p. 215-217° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:13]([CH2:15]C(O)=O)#[N:14].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[CH:15][C:13]#[N:14])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: N#CCC(=O)O
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CC(=CC#N)CC(=O)OC
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a solution of 3-oxo-pentanedioic acid dimethyl ester (523 g) in toluene (750 mL), cyanoacetic acid (511 g), NH4OAc (46.3 g) and acetic acid (90.1 g) were added and heated at reflux with dehydrating by Dean-Stark apparatus for 8 h. After cooling to room temperature, the reaction mixture was washed with water, saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give crude 3-cyanomethylene-pentanedioic acid dimethyl ester (403 g) as an oil. 1H NMR (200 MHz, CDCl3) δ ppm 3.39 (d, J=0.88 Hz, 2 H), 3.62 (s, 2 H), 3.72 (s, 3 H), 3.74 (s, 3 H), 5.51 (s, 1 H).