Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[C:8]([O:12][C:13]([NH:15][C@H:16]([CH:21]=O)[C@H:17]([CH2:19][CH3:20])[CH3:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl.CN(C=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][CH2:21][C@@H:16]([NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[C@@H:17]([CH3:18])[CH2:19][CH3:20]
Reactant: COC(=O)CN
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CNCC(=O)OC)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Glycine methyl ester hydrochloride (4.41 g, 0.035 mol) was dissolved in 1 ,2-dichloroethane (50 mL) and DMF (5 mL) and treated with 3A molecular sieves (10 g) and N-t-butoxycarbonyl-isoleucinal (6.3 g, 0.029 mol) with stirring at 0° C. Sodium triacetoxyborohydride (9.27 g, 0.044 mol) was added, and the pH of the mixture was adjusted to 6 with triethylamine (3 ml, 0.022 mol). After stirring for 18 h the mixture was filtered, concentrated and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and evaporation in vacuo afforded a residue which was purified by flash chromatography (SiO2, EtOAc:hexane, 1:3) to give the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:9]([CH3:17])[C:8]=3[CH:18]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([CH:12]([OH:16])[CH:13]([CH3:14])[CH3:15])=[C:9]([CH3:17])[C:8]=3[CH:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(C3CC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C(C)C)oc2ccc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
1-(5-Cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (0.80 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.34 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (0.4 g, 50%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(Cl)cc(S(=O)(=O)Cl)c1
Reactant: CC1CCCNC1
Solvent: ClCCl
Product: CC1CCCN(S(=O)(=O)c2cc(Cl)cc(C(=O)O)c2)C1

Procedure:
The procedure of Example 43 is repeated, starting with 5 g. (0.05 mole) of 3-methylpiperidine and 2.5 g. (0.01 mole) of 3-chloro-5-chlorosulfonylbenzoic acid in 15 ml. of methylene chloride, providing 2.7 g., m.p. 177°-179° C. of the crude product. Purification is effected by recrystallization from acetone-hexane, 1.2 g., m.p. 181°-183° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:22])[CH2:4][CH2:5][CH2:6][CH:7]1[C:11]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[Br:23]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CO>[ClH:1].[Br:23][C:20]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:2])[CH3:22])[C:8]=2[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)CCCC1c2ccccc2OC12CCCCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)CCCC1c2cc(Br)ccc2OC12CCCCCC2
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3.89 g of 3-(3-dimethylaminopropyl)-spiro[benzofuran-2(3H),1'-cycloheptane] hydrochloride in 35 ml of methanol at room temperature under nitrogen was added 2.24 g of N-bromosuccinimide. All solid dissolved rapidly as the pot temperature rose to 33° C. A TLC analysis after 20 minutes showed a complete reaction. The mixture was poured into water (175 ml), and 250 ml of saturated sodium bicarbonate solution was added with stirring. The mixture was then extracted with ether (2×250 ml). The combined organic extracts were washed with water (100 ml) and saturated sodium chloride solution (100 ml), dried briefly over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oil. This material was dissolved in 100 ml of ether and the solution was stirred and treated with hydrogen chloride-saturated ether solution until the liquid phase was acidic to a pH paper. After a few minutes, the salt was filtered off, washed with ether and dried to afford 4.52 g of a solid, m.p. 169°-172° C. This crude salt was combined with two other batches of previously prepared crude salt and recrystallized by dissolving the solids in 20 ml of absolute ethanol, filtering by gravity, and treating the stirred filtrate dropwise with ether (140 ml). After stirring for 30 minutes the recrystallized salt was filtered, triturated and washed with ethanol/ether (1:7) solution, then ether and finally hexane. Drying in vacuo afforded 5.08 g of crystalline solid, m.p. 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[CH2:11][C:10]3[S:15][C:16]([CH3:18])=[CH:17][C:9]2=3)=[CH:4][CH:3]=1.BrN1[C:24](=[O:25])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.CO.O>[CH3:24][O:25][CH2:18][C:16]1[S:15][C:10]2[CH2:11][N:12]([CH3:14])[CH2:13][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]=2[CH:17]=1
Reactant: Cc1cc2c(s1)CN(C)CC2c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COCc1cc2c(s1)CN(C)CC2c1ccc(Cl)cc1

Procedure:
2.79 gm (0.01-ol) of 4-(p-chloro-phenyl)-2,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine were dissolved in 50 ml of carbon tetrachloride, the solution was heated at its boiling point with 1.8 gm of N-bromo-succinimide and 0.1 gm of azo-bis-isobutyronitrile for several hours. The resulting succinimide was suction-filtered off, and the solvent was removed in a rotary evaporator. The residue was admixed with a solution of 0.01 mol of sodium methoxide in methanol, and the mixture was heated at its boiling point for a short time. Then, water was added, and the resulting mixture was extracted with ether. Upon addition of etheral hydrochloric acid to the extract, the hydrochloride of the title compound crystallized out.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].[N:17]1[C:22]2[NH:23][CH:24]=[CH:25][C:21]=2[CH:20]=[N:19][CH:18]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:25]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:22]=3[NH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Reactant: c1ncc2cc[nH]c2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncncc23)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (18.75 mg, 0.30 mmol) in 0.6 mL of methanol, 7H-pyrrolo[2,3-d]pyrimidine (6, 73 mg, 0.61 mmol) and potassium hydroxide (51 mg, 0.92 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (P-0005, 85 mg, 76%). MS(ESI) [M+H+]+=365.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([S:48](F)(=[O:50])=[O:49])[CH:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:43]=[C:42]([CH3:41])[CH:47]=[CH:46][N:45]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cc1ccnc(S(=O)(=O)F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 69.7 %

Procedure:
To a suspension (3 mL) of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (330 mg) and 4-methylpyridine-2-sulfonyl fluoride (343 mg) at room temperature, and the mixture was stirred at room temperature for 41 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 333 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[ClH:25].FC1C=C(N[C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:52])C=CC=1OC1C=CN=C2C=C(C(N3CCCC3)=O)SC=12>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:52])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: Cl
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Yield: 54 %

Procedure:
Starting from the compound 177 (scheme 35) and following the procedure described above for the synthesis of compound 305a, title compound 305c was obtained in 54% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.08 (s, 1H), 10.67 (s, 1H), 8.66 (d, 1H, J=6.2 Hz), 8.26 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.85(dd, 1H, J1=12.9 Hz, J2=2.5 Hz), 7.53(t, 1H, J=8.8 Hz), 7.65 (s, 1H), 7.48-7.45 (m, 1H), 7.35-7.30 (m, 4H), 7.28-7.24 (m, 1H), 6.94(d, 1H, J=6.1 Hz), 3.79 (s, 3H), 3.75 (s, 2H). MS (m/z): 502.1 (M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:33])[N:12](COCC[Si](C)(C)C)[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(S)(S)C.O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:33])[NH:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)n(COCC[Si](C)(C)C)n2)ccc1O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(-c2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)[nH]n2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70.7 mg of 6-(4-hydroxy-3-methoxy-phenyl)-3-oxo-2-(2-trimethylsilanylethoxymethyl)-2,3-dihydro-pyridazine-4-carboxylic acid 4-chloro-benzyl amide and 60 μl ethandithiol and 60 μl water were dissolved in 750 μl TFA and stirred at room temperature for 3 h. Afterwards, the solvent was distilled off and the raw product purified by HPLC (column 125×25, PurospherStar RP18 endcapped, 5 μm; solvent: A: water (0.05% HCOOH), B: acetonitrile (0.05% HCOOH)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:15]([O-])=O.O.Cl>C(O)C.CO>[NH2:15][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:12])[CH3:13])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CN(C)CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: CN(C)CC(=O)Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A solution of N1-(4-chloro-3-nitrophenyl)-N2,N2-dimethylglycinamide (1.0 g, 3.89 mmol), SnCL2×2 H2O (5.26 g, 23.3 mmol, Aldrich), and 1M HCl (2 mL, Aldrich) in absolute ethanol (100 mL) was allowed to stir at RT overnight. The reaction was diluted with methanol (100 mL) and quenched with saturated NaHCO3 (200 mL). After stirring 2 hrs at rt, the emulsion was filtered through a celite pad and filtrate evaporated. The residue was then resuspended in dichloromethane (200 mL), washed with water (200 mL), organic layer concentrated by rotary evaporation, and placed under high vacuum to provide N1-(3-amino-4-chlorophenyl)-N2,N2-dimethylglycinamide (0.9 g, 55%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 6 H) 2.99 (s, 2 H) 5.29 (s, 2 H) 6.68-6.74 (m, 1 H) 7.03 (d, J=8.61 Hz, 1 H) 7.22 (d, J=2.38 Hz, 1 H) 9.49 (s, 1 H). ESIMS (M+H)+=228.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH2:19][CH2:20]O)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>O>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH2:19][CH2:20][Br:1])=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: OCCNc1ccnc2cc(Cl)ccc12
Reactant: Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(NCCBr)ccnc2c1
Temperature: 165 °C
Yield: 55 %

Procedure:
Hydrobromic acid (22.5 ml, 414 mmol) and then sulphuric acid (7.5 ml, 140 mmol) are added dropwise onto the 7-chloro-4-(β-hydroxyethylamino)quinoline 5 (15 g, 67 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 165° C. for 3 h 30 min, and then poured into 300 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9) and the medium is then extracted at the reflux of toluene (300 ml) for 15 min. The organic phase is then collected and the product 6 is obtained by crystallization at −18° C. overnight, filtration, and then drying under vacuum: 10.55 g (yield=55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:13]=[CH:12][NH:11][C:10]1=[NH:14].[CH2:15](Br)[CH2:16]Br>Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:10]2=[N:14][CH2:15][CH2:16][N:11]2[CH:12]=[CH:13]1
Reactant: BrCCBr
Reactant: N=c1[nH]ccn1-c1c(Cl)cccc1Cl
Agent: Cl
Product: Clc1cccc(Cl)c1N1C=CN2CCN=C21
Temperature: 140 °C
Yield: 10.8 %

Procedure:
A mixture consisting of 4.56 gm (0.02 mol) of 1-(2,6-dichloro-phenyl)-2-imino-4-imidazoline and 2.6 ml of ethylene bromide (about 150% of the stoichiometrically required amount) was heated to 140° C. while stirring and was maintained at that temperature for 15 minutes. After cooling, the glassy mass was dissolved in about 1 N hydrochloric acid, and the solution was friactionally extracted with ether at stepwisely increasing pH-values (addition of 2 N sodium hydroxide). Those fractions which contained the reaction product in substantially pure form, as determined by thin-layer chromatography, were combined, dried over anhydrous calcium sulfate and evaporated in vacuo. The residue was further purified by stirring it with acetone and collecting the crystallized product by suction filtration. 0.55 gm (10.8% of theory) of pure 7-(2,6-dichloro-phenyl)-2,3-dihydro-imidazo[1,2-α]imidazole, m.p. 184°-187° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (2.29 g) in methanol (10 mL) was added dropwise 2M trimethylsilyldiazomethane solution in hexane (11.9 mL) under ice-cooling. The reaction mixture was concentrated, and to the residue was added hexane. The precipitated crystals were collected by filtration, and the filtrate was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate=9/1 to 7/3). The product and the crystals obtained above were combined to give methyl 1-(tert-butoxycarbonylamino)-cyclopentane-carboxylate (2.49 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.O1[CH2:12][CH2:11][CH2:10][CH2:9]1>N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC>[CH2:1]=[C:2]1[CH2:12][CH:11]2[CH2:4][CH:3]1[CH:9]=[CH:10]2.[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: C1CCOC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1C=CC(=O)O1
Solvent: CCCCCC
Product: C=C1CC2C=CC1C2
Yield: 183.7 %

Procedure:
This synthesis example is directed to the synthesis of polymer (1b) (illustrated below as chemical formulas 14 or 15), a γ-hydroxy carboxylic acid structure. 21.2 g of 5-ethylenebicyclo[2.2.1]hept-2-ene, 19.6 g of maleic anhydride, 2.56 g of 2,2'-azobisisobutyronitrile, and 240 g of tetrahydrofuran were placed in a 500-ml, three-necked flask equipped with a thermometer, a condenser pipe, and a nitrogen inlet pipe, and the mixture was heated under reflux at 70C while introducing nitrogen for 8 hr to conduct polymerization. After the completion of the polymerization, the reaction mixture was poured into 1000 ml of n-hexane to precipitate the resultant polymer, which was then dried to give 37.5 g of a 5-methylenebicyclo[2.2.1]hept-2-ene/maleic anhydride copolymer (1a) (yield 92%). The polymer was analyzed by various methods and was found to mainly have a structure represented by the following formula:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([F:30])=[CH:22][C:21]=1/[CH:31]=[CH:32]/[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33](=[O:34])/[CH:32]=[CH:31]/[C:21]3[CH:22]=[C:23]([F:30])[C:24]([C:26]([F:27])([F:29])[F:28])=[CH:25][C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cc(F)c(C(F)(F)F)cc1F
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cc(F)c(C(F)(F)F)cc3F)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,5-difluoro-4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.97 min; [M+H]+=440.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19](O)=[O:20])[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22].Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:22].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C:28]4[CH:27]=[C:26]([O:25][CH3:24])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=4)[CH2:31][CH2:32]3)=[O:20])[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(OCc5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Yield: 74.4 %

Procedure:
Using 7-benzyloxy-1,2-dihydro-3-naphthoic acid (0.4 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.76 g), triethylamine (0.6 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.75 ml), an amidation as that described in Example 6 is carried out. The reaction product is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(7-benzyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.6 g) as colorless crystals, m.p. 196°-199° C. (decomp.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.ClCCl.C(OCC)C>[ClH:24].[F:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (937 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (13.6 ml) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo to yield 4-(4-fluoro-benzenesulfonyl)-piperazine hydrochloride salt (819 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17](=[O:19])[NH:16][C:15]([C:20]3[CH:25]=[C:24]([S:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=3[O:36][CH2:37][CH3:38])=[N:14][C:13]=2[C:12]([CH2:39][CH2:40][CH3:41])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:42](O)CC>>[NH3:10].[CH2:3]([N:10]1[C:18]2[C:17](=[O:19])[NH:16][C:15]([C:20]3[CH:25]=[C:24]([S:26]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)(=[O:27])=[O:28])[CH:23]=[CH:22][C:21]=3[O:36][CH2:37][CH2:38][CH3:42])=[N:14][C:13]=2[C:12]([CH2:39][CH2:40][CH3:41])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCc1nn(Cc2ccccc2)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(Cc3ccccc3)c2c(=O)[nH]1
Product: N

Procedure:
A 60% w/w dispersion of sodium hydride in mineral oil (160 mg, 4 mmol) was added portionwise to stirred, ice-cooled propan-1-ol (20 ml). When the effervescence had ceased, the title compound of Example 41 (550 mg, 1 mmol) was added and the resulting mixture heated under reflux for 96 hours, then allowed to cool and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml), then the separated aqueous phase extracted with ethyl acetate (100 ml in total). The combined organic solutions were dried (Na2SO4) and evaporated under reduced pressure, then the residue purified by column chromatography on silica gel, using ethyl acetate:methanol:0.880 aqueous ammonia (95:5:0.5) as eluant, to provide the title compound (230 mg) as a colourless foam. Found: C, 61.65; H, 6.48; N, 14.53. C29H36N6O4S requires C, 61.68; H, 6.48; N, 14.88%. δ (CDCl3): 0.98 (3H, t), 1.15 (3H, t), 1.83 (2H, m), 2.01 (2H, m), 2.24 (3H, s), 2.46 (4H, m), 2.92 (2H, t), 3.08 (4H, m), 4.22 (2H, t), 5.73 (2H, s), 7.12 (1H, d), 7.27 (3H, m), 7.36 (2H, m), 7.80 (1H, d), 8.82 (1H, s), 11.84 (1H, s). LRMS: m/z 565 (M+1)+.