Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[NH:10][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cccc(COc2ccc(Nc3ncnc4cc(-c5ccco5)[nH]c34)cc2Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (122 mg).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:5](COCC[Si](C)(C)C)[CH:6]=1.Cl.O>CCO>[Br:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[NH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)nc1-c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2nc(Br)c[nH]2)cc1

Procedure:
4-Bromo-2-(4-fluorophenyl)-1-(2-trimethylsilanyl-ethoxymethyl)imidazole (3.4 g; 9 mmol) is dissolved in EtOH (34 ml) and HCl conc. (37%; 34 ml) and heated to 55 C for 1 h. Water is added to the reaction mixture and the aqueous phase extracted three times with ethyl acetate. The combined organic phases are washed with 2N Na2CO3 and saturated NaCl-solution, dried over Na2SO4, filtered and evaporated to dryness to yiled the title compound as colorless crystals (2.1 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:18])(=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.[H-].[Na+].I[CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:18])(=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([O:16][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:9][CH:8]=3
Reactant: O=S1(=O)c2ccc(O)cc2Oc2cc(F)ccc21
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccc(F)cc2Oc2cc(OCC(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
Solid 3-fluoro-7-hydroxyphenoxathiin 10,10-dioxide (Example 64) (1.092 g, 4.10 mmoles) was added to an ice-bath cooled, stirred mixture of sodium hydride (60% dispersion in mineral oil) (Aldrich) (0.164 g, 4.10 mmole) in N,N-dimethylformamide (20 mL). After 10 minutes, within which effervescence ceased, 2-iodo-1,1,1-trifluoroethaane (4.993 g, 23.78 mmoles) was added and the solution was heated with stirring at 100° C. for 24 hours. The reaction was cooled and added in portions to 100 mL of vigorously stirred ice-water to give a solid, which was collected by suction filtration and washed with water. The solid which was two equal size spots on tlc (silica gel, ethyl acetate-hexanes:1-4) dissolved in dichloromethane (50 mL), absorbed on silica gel 60 and purified by flash column chromatography on silica gel 60. The column was eluted with ethyl acetate-hexanes:1-6 (1 L) and ethyl acetate-hexanes:1-3 (1 L), and the fractions that contained product (the higher Rf spot on tlc) were combined and spin evaporated in vacuo to give 0.731 g (51% yield) of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide as a white powder, m.p. 160-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Oc2c(Br)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.1 g, 6.17 mmol) in THF 201 mL) at room temperature was added N-bromosuccinimide (1.208 g, 6.79 mmol). The resulting solution was stirred vigorously at room temperature for 2 h after which time the reaction was quenched by addition of sat. aq. Sodium Thiosulfate solution and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.4 g, 5.72 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (d, J=16.0 Hz, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 6.91 (dd, J=8.8, 2.2 Hz, 1H), 6.31 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), LC/MS (m/7, MH+): 420.9.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH:18]([N:13]1[C:12]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:29])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1c2c(nn1C(C)C)CCNCC2
Yield: 61.3 %

Procedure:
The title compound (80 mg) was prepared according to Example 189 using 207 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 198 mg of 2-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19. found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.40 (m, 2H), 7.36-7.33 (m, 1H), 7.19-7.18 (m, 1H), 4.66 (br s, 2H), 4.10 (m, 1H), 4.00-3.66 (m, 2H), 2.76-2.61 (m, 2H), 2.13 (s, 3H), 1.45-1.29 (m, 6H).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=1.[CH2:22](O)[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:23]3[CH:22]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:4]=3)=[CH:17][N:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: C[Si](C)(C)c1cccc(B(O)O)c1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cccc(-c2ccc(-c3cccc([Si](C)(C)C)c3)nc2)c1
Yield: 94 %

Procedure:
A solution of (22) (5.70 g, 29.4 mmol) and 2,5-dibromopyridine (2.32 g, 9.8 mmol) in a mixture of toluene (120 cm3), ethanol (40 cm3) and aqueous sodium carbonate (2 M, 40 cm3) was deoxygenated with argon. Tetrakis(triphenylphosphine)palladium(0) (566 mg, 0.49 mmol) was added, and the solution was deoxygenated with argon again, then heated at reflux for 16 hours. Water (200 cm3) and dichloromethane (200 cm3) were added, and the layers were separated. The aqueous layer was extracted with dichloromethane (3×50 cm3). The combined organic extracts were washed with brine (500 cm3) and dried over magnesium sulfate, and the solvent was removed to leave a black oil. The crude product was purified by column chromatography using dichloromethane: light petroleum (1:1) as eluent, to give (23) as a white solid (3.48 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[C:6]2=[CH:7][N:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:11][CH2:10][NH:9][C:6]2=[CH:7][N:8]=1
Reactant: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cn1)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To 500 mg of tert-butyl 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate was added 1.5 mL of trifluoroacetic acid, followed by stirring at room temperature for 0.5 hours. The reaction mixture was poured into ice water, neutralized with a 1 M aqueous sodium hydroxide solution, and then chloroform was added to the mixture. The aqueous layer was separated, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 262 mg of 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20]OS(C)(=O)=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]([OH:31])(=[S:30])[CH3:29]>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20][S:30][C:28](=[O:31])[CH3:29])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)=S
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CC(=O)SCC(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Thioacetic acid S-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propyl]ester was prepared by an analogous procedure as described in example 26 ii) starting from 6.19 g (15.9 mmol) methanesulfonic acid 2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propyl ester and 2.1 ml (1.8 equiv.) thioacetic acid. Purification by flash chromatography on silica gel (eluent: CH2Cl2) gave pure thioacetic acid S-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propyl]ester as yellow oil. Yield: 1.87 g MS (ES+): m/e=370.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH:12]([CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57]([NH:11][CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:35])=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Nc1nc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)N2CCOCC2)C(=O)O)cs1
Reactant: CC(C)CC(O)C(O)C(N)CC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC(O)C(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Temperature: 25 °C

Procedure:
1-N-Hydroxybenzotriazole, 190.6 g, 395.0 g of [2S (2R*,3S*,4R*)]-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol (U.S. Pat. No. 4,680,284 and 4,845,079), 682.4 g (1.62 mol) of N-(4-morpholinyl-sulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine and 20 L of ethyl acetate are charged into a 50 L reactor and the slurry is stirred. Triethylamine, 107.1 g with 0.5 L of ethyl acetate, is added to the mixture and stirred for 1 hour at 30° C. A solution of 300.0 g of dicyclohexylcarbodiimide dissolved in 2.5 L of ethyl acetate is added to the reaction mixture over 15 to 30 minutes. The slurry is warmed to 35° to 40° C. and stirred at that temperature for 48 hours, cooled to 25° C., and the solids removed by filtration. The filtrate is washed with 0.5N aqueous hydrochloric acid solution (4 L), saturated sodium bicarbonate solution (4×4 L), and water (2 L). The solution is concentrated to a thick slurry under vacuum, chilled to 5° C., and the crude product solid collected by filtration and dried under vacuum at 40° C. The crude product and 4 L of isopropanol are charged into a 12 L reactor and the slurry is heated to 45° C. Water, 1 L, is added and heating continued to 60° C. The solution is cooled slowly to crystallize the product and then chilled to 10° C. The slurry is filtered and the cake is washed with cold isopropanol. After drying at 40° C. under vacuum, 770 g of [1S-(1R*,2S*,3R*)]-N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide is obtained as white needles of >99% purity by HPLC; mass spectrum (fast atom bombardment): 709.2 M+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.Cl.O>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Oc1nc(Cl)ncc1Br
Reactant: CSc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: CSc1ccc(Nc2ncc(Br)c(O)n2)cc1

Procedure:
9.8 g of 5-bromo-2-chloropyrimidin-4-ol is suspended in 200 ml of acetonitrile. After 7.2 g of 4-methylsulfanyl-phenylamine is added, 12 ml of a 4N solution of HCl in dioxane is added in drops while being stirred vigorously. After drop-by-drop addition of 5 ml of water, the mixture is stirred for 3 hours at 78° C. and for 2 days at room temperature. The mixture is cooled in an ice bath and suctioned off. The filter cake is washed twice with acetonitrile and dried. 15.2 g (92.7% of theory) of the product with a melting point of 238° C. (decomposition) is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5]/[N:6]=[C:7](/[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)\[CH2:8][NH2:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].O>ClCCl>[Cl:16][C:15]1[C:10](/[C:7](=[N:6]/[O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)/[CH2:8][NH:9][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[C:29]([F:28])([F:39])[F:40])=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Yield: 94.7 %

Procedure:
In a solution of 65 mg of (E)-2-amino-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanone-O-(cyclopropylmethyl)oxime and 32 mg of triethylamine in 2 ml of dichloromethane, 39 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 2 ml of water and extracted with dichloromethane (2 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 2:18 to 5:15) as the eluent to obtain 85 mg of the desired product as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[N-:17]=[N+:18]=[N-:19].[Na+].C(OCC)(=O)C>CN(C=O)C>[N:17]([CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(CN=[N+]=[N-])ccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 6chloromethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (10 g, 42.2 mmol, 1.00 mmol equiv.) in DMF (84 mL) is added sodium azide (13.7 g, 211.2 mmol, 5.00 mmol equiv.) at room temperature and the reaction contents are stirred overnight. The reaction is checked by TLC (5% ethyl acetate in hexanes). The reaction is terminated by pouring the reaction contents into water and extracting with ethyl acetate. The organic solvents are removed in vacuo and the crude product filtered through a plug of silica gel (ratio of 10:1) and eluted with hexanes. The solvent is removed in vacuo and stored under vacuo to afford 10 grams of the desired product 6-azidomethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (97% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:41])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28]COS(C3C=CC(C)=CC=3)(=O)=O)[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:43])([C@@H:17]([OH:42])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[OH:44][C@:45]1([C:72]#[C:73][CH3:74])[CH2:50][CH2:49][C@H:48]2[C@H:51]3[C:60]([C@@H:61]([C:63]4[CH:68]=[CH:67][C:66]([NH:69][CH3:70])=[CH:65][CH:64]=4)[CH2:62][C@:46]12[CH3:47])=[C:59]1[C:54](=[CH:55][C:56](=[O:71])[CH2:57][CH2:58]1)[CH2:53][CH2:52]3.[Na+].[I-].[CH:77](N(C(C)C)CC)(C)C>C(#N)C.CCCCCC.CCOC(C)=O>[OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:41])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:70][N:69]([C:66]3[CH:65]=[CH:64][C:63]([C@H:61]4[CH2:62][C@@:46]5([CH3:47])[C@@H:48]([CH2:49][CH2:50][C@:45]5([OH:44])[C:72]#[C:73][CH3:74])[C@H:51]5[C:60]4=[C:59]4[C:54]([CH2:53][CH2:52]5)=[CH:55][C:56](=[O:71])[CH2:57][CH2:58]4)=[CH:68][CH:67]=3)[CH3:77])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:43])([C@@H:17]([OH:42])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(NC)cc3)C[C@@]21C
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
The compound of Example 1C (15 g, 24.2 mmol) and the compound of Example 1H (11 g, 26.5 m mol), were combined with NaI (2.7 g), and diisopropylethylamine (3.12 g) in 400 mL of acetonitrile in a 1 liter pressure bottle. The solution was heated at 100° C. TLC (EtOAc:hexane, 60:40) or HPLC was checked for the completion of the reaction; no starting material was observed after 16 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite; the solvents were removed in vacuo. The crude material was diluted with EtOAc (500 mL) and washed with saturated ammonium chloride solution (2×100 ml). The solvent was removed in vacuo, and the crude material was loaded on silica gel column to elute with hexane/EtOAc (3:2-1:1-2:3). Pure fractions were collected and concentrated to provide 14.5 g (63.3%) of the titled compound.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH2:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O-:35])(=[O:3])=[O:2].[CH2:28]([N+:13]([CH3:20])([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCc1ccccc1
Reactant: CN(C)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[N+](C)(Cc1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 10 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
19.07 g (0.1 mol) of tosyl chloride, 12.12 g (0.1 mol) of N,N-dimethylaniline and 10.1 g (0.1 mol) of triethylamine were dissolved in 60 g of tetrahydrofuran, and, after cooling to 10° C., there was added 10.81 g (0.1 mol) of benzyl alcohol. While suppressing excessive elevation of the temperature, the reaction was allowed for 5 hours. After the completion of the reaction, the mixture was concentrated, and the precipitated white solid was washed with ether and dried to give N-benzyl-N,N-dimethylanilinium tosylate. Yield: 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3[N:12]=[N:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9]2)=[CH:4][CH:3]=1.C[C:23](N(C)C)=[O:24].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH2:33]>C1(C)C=CC=CC=1>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][NH:33][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:20](=[O:21])[C:11]3[N:12]=[N:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9]2)=[CH:6][CH:7]=1)=[O:24]
Reactant: Nc1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Reactant: CC(=O)N(C)C
Reactant: CN(C)CCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCNC(=O)Nc1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
2-(4-aminophenyl)-1,2-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (44 mg, 0.16 mmol) was suspended in toluene under nitrogen atmosphere (0.5 ml) at 0-5° C. DMA (0.5 ml) was added followed by N,N′-carbonyldiimidazole (26 mg, 0.16 mmol). The mixture was stirred for 1 h at 0-5° C. before mixed with a solution of 3-dimethylaminopropylamine (18 mg, 0.18 mmol) in toluene (0.5 ml). Stirring was continued for 1 h and the product was purified by preparative HPLC. The title compound was isolated as a dark red powder (2.6 mg, 6 μmol, 4%). LCMS: m/z 406 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7]C(C=[CH:6]1)C[CH:2]2[OH:8].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>>[C:2]([O-:8])(=[O:13])[C:1]([CH3:7])=[CH2:6].[C:9]([OH:13])(=[O:8])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CC2C=CC1C2
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)[O-]

Procedure:
Methacrylate (36 g) obtained by condensation of 5-norbornene-2-ol and methacrylic acid chloride and 4 g of methacrylic acid were dissolved in 360 g of methyl ethyl ketone, and the solution was heated at 70° C. Then, 0.40 g of 2,2-azobis(2,4-dimethylvaleronitrile) was added thereto, followed by heating reaction for 8 hours. After cooled to room temperature, the resulting reaction solution was slowly added dropwise to 10 liters of water, and precipitated crystals were filtered, washed and dried, thereby obtaining 18.72 g (yield: 46.8%) of a copolymer having an average molecular weight of 56,000 which is composed of 83.3 mol % of repeating unit (III-2) and 16.7 mol % of methacrylic acid.