Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:18])[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([CH3:17])[C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N(C)C)N(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.78 g of the compound obtained in Step 79-1 in DMF (30 ml) was added 0.66 g of NaH under ice cooling. The solution was stirred at room temperature for one hour, then, 3.58 g of [(2-bromoethoxy)methyl]benzene was added. The solution was stirred at room temperature for two hours, then, water was added, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=2/3; v/v) to obtain 3.22 g of the title compound (pale yellow oil).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:23]1([CH2:29][CH2:30][CH2:31][CH:32]=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.7 g, 4.0 mmol) was added to a solution of benzenebutanol (0.5 g, 3.3 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a plug of silica gel, washing with dichloromethane, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (466 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 9.76 (1H, m), 7.31-27 (2H, m), 7.22-7.16 (3H, m), 2.66 (2H, t, J 73 Hz), 2.45 (2H, t, J 7.3 Hz), 1.97 (2H, quin, J 7.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1.[CH:18](O)=O>>[C:16]([C:14]1[CH:13]=[CH:12][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=3)[CH:18]=[N:1][C:2]=2[CH:15]=1)#[N:17]
Reactant: O=CO
Reactant: N#Cc1ccc(Nc2cccc(I)c2)c(N)c1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Temperature: 90 °C

Procedure:
A suspension of (30) (1.8 g, 5.36 mmol) in formic acid (20 ml) is heated to 80-100° C. for 1.5 hours. The hot reaction mixture is filtered through a cotton pad into ice-water (100 ml). The precipitate is filtered off, washed with water and dried. This crude product is dissolved in dichloromethane and is brought to precipitation by addition of petroleum ether. The product is filtered off and dried. Yield: 1.38 g (75%) of the title compound. Mp. 177-179° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][CH3:15])(=[O:13])[C:11]#[CH:12]>>[NH2:1]/[C:2](=[C:3](\[C:4]([O:6][CH2:7][CH3:8])=[O:5])/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])/[CH3:9]
Reactant: C#CC(=O)OC
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)C(/C=C/C(=O)OC)=C(/C)N
Temperature: 110 °C
Reaction time: 10 h
Yield: 93.8 %

Procedure:
Ethyl (2Z)-3-aminobut-2-enoate (6.46 g, 50.0 mmol) and methyl propiolate (4.20 g, 50.0 mmol) were mixed in one 100 mL flask, and the mixture was stirred at 110° C. for 10 hrs. The reaction mixture was cooled to room temperature and recrystallized with methanol to give 10 g (93% yield) of the pure product. LC-MS found: 214.2.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][N:9]=[C:8]1[CH:30]=O>C(O)C>[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][N:9]=[C:8]1[CH:30]=[N:2][OH:3]
Reactant: Cn1c(C=O)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C=NO)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A solution of hydroxylamine hydrochloride (0.13 g) in ethanol (10 ml) was treated with potassium hydroxide (0.11 g). A solution of 4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triazole-3-carboxaldehyde (0.54 g) in ethanol (10 ml) was added. The mixture was stirred at room temperature for 15 min and then filtered. The filtrate was evaporated and the residue was crystallised from a mixture of ethanol (5 ml) and ethyl acetate (5 ml) to give the title compound as a white crystalline solid (0.21 g) m.p. 187°-188°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=N[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.BrC1C=CC=[C:28]([F:32])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:28]([F:32])[CH:19]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Reactant: Fc1cccc(Br)c1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=341.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>ClCCl>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1CNCCN1
Solvent: ClCCl
Product: CC1CN(C(=O)OCc2ccccc2)CCN1
Reaction time: 1 h

Procedure:
A 4 g portion of 2-methylpiperazine was dissolved in 40 ml of dichloromethane, and 1.71 g of benzyl chloroformate was added dropwise thereto at −78° C. After 1 hour of stirring, the mixture was washed by adding water and dried and then the solvent was evaporated to obtain 2.0 g of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[Cl:8][CH2:9][CH2:10]O>>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:10][CH2:9][Cl:8])=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: OCCCl
Product: CC(C)(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-2-methylpropionate was prepared from 2-hydroxy-2-methylpropionic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 75°-77° C./6 mm Hg; 1H NMR δ 1.47 (s, 6H), δ 3.18 (s, 1H), δ 3.72 (t, 2H, J=5.6 Hz), δ 4.43 (t, 2H, J=5.6 Hz); 13C NMR 27.1, 41.2, 64.8, 72.1, 176.8 ppm; HRMS calcd for C5H7ClO3Tms (M--CH3) 223.0557, obsd 223.0577.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:33][O:34][CH2:35][CH3:36])[C:8]([NH:10][C@@H:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([O-:30])=[O:29])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:25][CH2:26][OH:27])[C:21]([NH2:24])=[CH:22][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[S:37](=[O:41])(=[O:40])([OH:39])[OH:38]>O>[S:37]([OH:41])([O-:40])(=[O:39])=[O:38].[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:33][O:34][CH2:35][CH3:36])[C:8]([NH:10][C@@H:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:25][CH2:26][OH:27])[C:21]([NH2:24])=[CH:22][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1nsc(N)n1
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1nsc(N)n1
Product: O=S(=O)([O-])O

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (5 g) in water (50 ml) was added 1M sulfuric acid (8 ml). The solution was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate sulfate (syn isomer) (5.2 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5](O)(=O)[CH3:6].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[NH:21]C(=N)C(Cl)(Cl)Cl>C(O)C>[CH2:5]([O:3][C:1]([C:2]1[NH:9][C:10]2[C:19]3[CH:18]=[CH:17][C:16]([F:20])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:21]=1)=[O:4])[CH3:6]
Reactant: CC(=O)O
Reactant: N=C(Nc1cnc2cc(F)ccc2c1N)C(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1nc2cnc3cc(F)ccc3c2[nH]1
Yield: 58.5 %

Procedure:
A solution of 1.15 g of 4-amino-7-fluoro-3-(trichloroacetimidoylamino)quinoline diacetate (VIII-1) in 120 ml of ethanol was heated under reflux for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to ice-water. After being basified with 2N aqueous ammonia, the mixture was extracted with chloroform. The extract was washed with water and brine, and then dried. The chloroform was removed by evaporation. The residue was chromatographed on a column of silica gel with chloroform-methanol (100:1 v/v), whereby 395 mg (yield: 59%) of the titled compound (I e-1) was obtained as crystals. These were recrystallized from chloroform-ethanol to give colorless crystals melting at 238°~240° C. (d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:17][CH2:13][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:7][C:2]=1[F:1]
Reactant: OCc1ccc(-n2cccn2)cc1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(-n2cccn2)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanol (0.71 g) in THF (15.0 mL) was added thionyl chloride (0.40 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate was added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.50 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH3:15]>C1COCC1.C(O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:15])(=[O:11])=[O:10]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To a solution of 2-(trifluoromethyl)benzenesulfonyl chloride (5 g; 20.44 mmol; 1.00 eq.) in anhydrous THF (5.00 ml) was added a solution of 71 ml Ammonia in Ethanol 2M under nitrogen at room temperature. The reaction mixture was shaken for 20 h at room temperature. The solvent was evaporated and the residue redissolved in EtOAc (150 mL) and then washed with NH4Cl saturated aqueous solution (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and the solvent evaporated to give the pure 2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (4.6 g, 89% yield, 98.6% HPLC purity). This compound was utilized as such for the next reaction.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=O)[CH:5]=[CH:4][N:3]1[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].[CH3:20][N:21]=[C:22]=[S:23]>CO.O>[SH:23][C:22]1[N:21]([CH3:20])[C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2](=[O:1])[CH:7]=2)=[N:10][N:11]=1
Reactant: CN=C=S
Reactant: C[Si](C)(C)CCOCn1ccc(C(=O)NN)cc1=O
Solvent: CO
Solvent: O
Product: Cn1c(S)nnc1-c1ccn(COCC[Si](C)(C)C)c(=O)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 105.8 %

Procedure:
The title compound of Example 20.1 (19.0 g, 67.0 mmol) was stirred in methanol (150 mL) and heated to 60° C. Methyl isothiocyanate (5.04 mL, 73.7 mmol) was then added via a syringe. After stirring for 40 minutes, a solution on NaOH (2.95 g, 73.7 mmol) in water (30 mL) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The aqueous residue was neutralized, extracted with chloroform, and the organic layer dried over sodium sulfate and concentrated. The residue was purified by silica gel using ethyl acetate to give the product (24.0 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11](SC)=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:32]1[CH:33]=[C:34](C=CC=1)[C:35](OO)=[O:36].[Na].[O-:43]CCCC.[Na+:48]>ClCCl.C(OCC)(=O)C.C(O)CCC>[O-:36][CH2:35][CH2:34][CH2:33][CH3:32].[Na+:48].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11]([OH:43])=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCCC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCO
Product: Oc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a cold (0° C.) solution of 4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (90 mg, 0.206 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (54 mg, 0.313 mmol). The reaction mixture was stirred 1.5 hours at 0° C. then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil. In a separate flask, a solution of sodium butoxide was prepared by reacting sodium (35 mg, 1.52 mmol) with n-butanol (2 mL). The sodium butoxide solution was added to the crude oil and the resulting solution was heated in a sealed tube at 120° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo. The resulting oil was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided a crude oil which was diluted with ethyl acetate (˜5 mL). Upon standing 7 hours, a solid had precipitated, which was collected on a filter to provide 2-(3-chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-ol (22 mg, 26%) as a pale yellow solid. 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.60 (s, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 6.24 (d, 1H), 4.19 (m, 1H), 1.99 (m, 2H), 1.78–1.42 (m, 6H); MS m/z 407 (M+1).
Reaction SMILES: [C:1]([C@@H:5]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2].[N-:21]=[N+:22]=[N-:23].[Li+]>CS(C)=O>[C:1]([C@@H:5]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:21]=[N+:22]=[N-:23])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CN=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Step A (13.52 g, 42.80 mmol) in 50 mL of dimethylsulfoxide under nitrogen was added lithium azide (2.3 g, 47.10 mmol). The solution was stirred for 2 h The reaction mixture was then partitioned with 300 mL of ethyl acetate and 200 mL of water. The ethyl acetate layer was washed with 125 mL of saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil. 1HNMR (300 MHz, CDCl3)δ 7.75 (2H, m), 7.47 (2H, m), 7.02 (1H, d, J=8 Hz), 4.94 (1H, q, J=5 Hz), 4.41 (2H, s), 3.80 (3H, s), 2.60 (2H, t, J=6 Hz), 2.30 (1H, m), 2.15 (1H,m), 2.11 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])=[O:4].[N-:34]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CC(C)=O.CCOCC>[NH2:34][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CN)c3C2=O)ccc1OC
Yield: 86.2 %

Procedure:
A mixture of 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide (0.30 g, 0.61 mmol) and sodium azide (90 mg, 1.38 mmol) in acetone (10 mL) was heated to reflux for 8 hours. To the solution was added triphenylphosphine (0.30 g, 1.1 mmol) and water (0.4 mL). The solution was heated to reflux for 5 more h. The solvent was removed in vacuo to give an oil. The oil was stirred in ether (10 mL) and water (10 mL) overnight to give a suspension. The suspension was filtered and washed with ether and water to give 2-amino-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide as a yellow solid (250 mg, 86% yield); mp, 111-112° C.; 1H NMR (CDCl3) δ 1.48 (t, J=6.9 Hz, 3H, CH3), 1.74 (brs, 2H, NH2), 2.86 (s, 3H, CH3), 3.57 (s, 2H, CH2), 3.77 (dd, J=4.6, 14.5 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.56 (dd, J=10.2, 14.2 Hz, 1H, CHH), 5.89 (dd, J=4.6, 10.2 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.12-7.15 (m, 2H, Ar), 7.52 (d, J=7.2 Hz, 1H, Ar), 7.67 (t, J=7.5 Hz, 1H, Ar), 8.86 (d, J=8.3 Hz, 1H, Ar), 11.21 (s, 1H, NH); 13C NMR (CDCl3) δ 14.68, 41.51, 48.65, 54.69, 55.88, 64.49, 111.45, 112.50, 115.81, 118.24, 120.37, 124.94, 129.38, 131.29, 135.90, 136.88, 148.55, 149.68, 167.64, 168.83, 172.41; Anal Calcd for C22H25N3O7S: C, 55.57; H, 5.30; N, 8.84. Found: C, 55.46; H, 5.33; N, 8.35.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:15])[CH2:13]Br)([CH3:10])([CH3:9])[CH3:8].[CH2:16]([C:18]1(OC)[C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)=[CH:21][NH:20][NH:19]1)[CH3:17]>CN(C)C=O>[C:7]([O:11][C:12](=[O:15])[CH2:13][N:19]1[C:18]([CH2:16][CH3:17])=[C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[C:21]([O:4][CH3:1])=[N:20]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC1(OC)NNC=C1Oc1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Potassium carbonate (306 mg, 2.22 mmol) and tert-butylbromoacetate (330 μl, 2.22 mmol) were added to a solution of the benzonitrile of Example 15 (270 mg, 1.11 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred overnight at 50° C. under nitrogen and then evaporated to dryness. The resulting residue was partitioned between dichloromethane (15 ml) and water (15 ml). The organic layer was separated, and the aqueous layer was extracted twice more with dichloromethane (2×10 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (4:1, by volume) to provide the title compound as a colourless oil (295 mg, 75%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9](OC)=[O:10])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[CH:2]=[CH2:3]
Reactant: C=CCOCCOCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOCCOCCO
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a stirred solution of ester (8) (9.77 g, 55.1 mmol, 1.0 equiv.) in THF (100 mL) was carefully added one portion of LAH (95%, 1.10 g, 27.5 mmol, 0.5 equiv.) at 0° C. After 30 min, another portion of LAH was carefully added and the reaction was stirred for an additional 30 min. The reaction was then carefully quenched with a Na2SO4-saturated aqueous solution. The resulting white aluminum salts were then filtered off over a short plug of Celite (EtOAc washings) and the filtrate was evaporated under reduced pressure. Purification was achieved by Kugelrohr distillation under reduced pressure and provided 7.99 g (99%) of alcohol (9) as a colorless oil; bp>200° C. (water tap vacuum). Spectroscopic data were consistent with those reported in the literature.26 1H NMR (400 MHz, CDCl3) δ 5.92 (m, 1H), 5.28 (m, 1H), 5.19 (m, 1H), 4.04 (m, 2H), 3.73 (m, 2H), 3.68 (m, 2H), 3.62 (m, 4H), 2.36 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[C:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[N+]([CH3:16])([O-])=O.N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:10]#[N:11])[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:16]1)=[O:12]
Reactant: COC(=O)C(C#N)=C1CCCC1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1(C#N)CC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of cyano-cyclopentylidene-acetic acid methyl ester (20.8 g, 126 mmol), in acetonitrile (500 mL) was added nitromethane (34 mL, 630 mmol, 5 eq) followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (18.8 mL, 126 mmol). The reaction solution turned orange upon the addition of DBU. The reaction mixture was stirred at room temperature for 16 hours. Another portion of DBU (1 mL) was added and stirred for 1 hour. The reaction mixture was partitioned between ether (1 L) and 1N HCl (400 mL) and the layers separated. The organic layer was washed with 1N HCl (2×300 mL), brine (2×200 mL), dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a wet-packed silica gel column eluting with 4-6% ethyl acetate/hexanes. The appropriate fractions were combined and evaporated to furnish 14.0 g (62%) of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 1.64 (d, J=5.0 Hz, 1H), 1.70-1.88 (m, 7H), 2.14 (d, J=5.0 Hz, 1H), 2.1-2.19 (m, 1H), 3.82 (s, 3H); MS (APCI) m/z 180 [M+H]+.