Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].[NH:26]1[CH:30]=[N:29][C:28](S)=[N:27]1.N1C=NC=N1>>[N:26]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: N#Cc1cccc(OCCCCl)c1
Reactant: Sc1nc[nH]n1
Agent: N#Cc1cccc(OCCCl)c1
Agent: c1nc[nH]n1
Product: N#Cc1cccc(OCCCn2cncn2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 1H-1,2,4-triazole, the title compound was obtained as a colorless oil (750.0 mg, 32%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]=O)[C:11]=1[CH3:18].[CH:19]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[CH2:20].[O-]S(C(F)(F)F)(=O)=O.[Ca+2].[O-]S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>CO>[C:24]1([S:21]([CH:19]2[CH:16]([C:12]3[C:11]([CH3:18])=[C:10]([Br:9])[CH:15]=[CH:14][N:13]=3)[NH:1][C:2]3([CH2:6][CH2:5][N:4]([CH3:7])[C:3]3=[O:8])[CH2:20]2)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(Br)ccnc1C=O
Reactant: CN1CCC(N)C1=O
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1c(Br)ccnc1C1NC2(CCN(C)C2=O)CC1S(=O)(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 26.5 %

Procedure:
To a stirred solution of 3-amino-1-methyl-pyrrolidin-2-one (3258.49 mg, 28.55 mmol) in methanol (8 mL) was added 4-bromo-3-methyl-pyridine-2-carbaldehyde (which may be prepared as described in Description 7) (5710 mg, 28.55 mmol), phenyl vinyl sulfone (4801.68 mg, 28.55 mmol), and calcium triflate (482.74 mg, 1.43 mmol). The reaction was stirred for 5 minutes. Triethylamine (3.97 mL, 28.55 mmol) was then added [caution—slight exotherm observed], and the reaction was stirred for 15 minutes. A large amount of solid was observed to precipitate out of the reaction, this was sonicated and stirred for a further 15 minutes. The solid was then filtered off, and washed with additional methanol (approximately 10 mL). The pale cream solid was then washed with diethyl ether (10 mL), and air dried for 10 minutes to give a colourless solid, then dissolved in MeOH (8 mL), and treated with phenyl vinyl sulfone (4801.68 mg, 28.55 mmol), calcium triflate (482.74 mg, 1.43 mmol) and lastly triethylamine (3.97 mL, 28.55 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The solid was filtered off, and washed with Et2O (10 mL). The solid was then air dried for 15 minutes on the sinter to afford 7-(benzene-sulfonyl)-8-(4-bromo-3-methyl-2-pyridyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (D8) (3520 mg, 7.58 mmol, 26.5% yield);
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:35])[CH2:33]Cl.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:9]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]2[F:31])[CH:5]=[N:4][C:3]=1[C:32](=[O:35])[CH2:33][N:36]=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(C(=O)CCl)ncn1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N
Yield: 94 %

Procedure:
Compound (16) obtained in step (7) above (185 mg) was dissolved in N,N-dimethylformamide (3.7 ml), to which was then added sodium azide (37 mg), and the resultant mixture was stirred at room temperature for 1 hour to effect the desired reaction in order to convert the chloro group of compound (16) into azido group and thus to produce the titled compound (17). The reaction solution was concentrated and the residue obtained was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate and then concentrated to yield a yellow syrup. This syrup was purified by silica gel column chromatography (developer solvent:toluene-ethyl acetate, 1:1), to give the titled compound (17) as a colorless solid (176 mg). Yield: 94%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(I)c2cc(Br)cnc21
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CN1CCN(c2cn(C)c3ncc(Br)cc23)CC1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.445 mmol), 1-methylpiperazine (356.7 mg, 3.56 mmol), copper(I) iodide (84.8 mg, 0.445 mmol), K3PO4 (378 mg, 1.78 mmol), 1,2-ethanediol (138 mg, 2.225 mmol) in isopropyl alcohol (5 mL) in a sealed tubes was heated at 70° C. for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried and concentrated. Purification by flash chromatography afforded the title compound. LCMS-ESI+: calc'd for C13H17BrN4 309.1 (M+H+); Found: 309.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.[CH2:19]([N:21]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O.CN(C)C=O>[CH3:19][NH:21][C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)C=Cc1ccc(C(=O)O)cc1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of methyl 4-carboxycinnamate (160 mg) in methylene chloride was added methylamine hydrochloride (58 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (140 mg) at ambient temperature, and the mixture was stirred for 2 hours. To this suspension was added 1-hydroxybenzotriazole (137 mg) and dimethylformamide (2 ml), and the mixture was stirred for 14 hours at same temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give methyl 4-(methylcarbamoyl)cinnamate (82 mg) as a colorless powder.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.Cl.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:45]([NH2:48])=[N:44][C:42]([C:35]1[C:34]([NH2:33])=[N:39][C:38]([NH2:40])=[C:37]([Cl:41])[N:36]=1)=[O:43]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCCCCCCCCC(=O)Nc1ncc[nH]1
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCCCCCCCCC(=O)Nc1ncc[nH]1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
Diisopropylethylamine (0.26 mL, 1.49 mmol) was added to a solution of 12-aminododecanoic acid (1H-imidazol-2-yl)amide dihydrochloride (14) (0.056 mg, 0.16 mmol) in absolute ethanol (5 mL). A white precipitate formed and the reaction was stirred at 70° C. for 10 min, then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.087 g, 0.22 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 16 hours then cooled to room temperature. The solvent was removed by rotary evaporation and the resulting residue was dissolved in small volume of methanol and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography eluting with 1% to 10% of 9:1 methanol/ammonium hydroxide in dichloromethane to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecanoic acid (1H-imidazol-2-yl)amide 15 (0.034 g, 44%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 4H), 2.29 (t, 2H), 3.09 (m, 2H), 6.61 (m, 4H). m/z (ESI) 493 [C21H33ClN10O2+H]+. mp 102-104° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1cc(-c2ccc(C)cc2)nc(-n2ccc(C(F)(F)F)n2)n1
Yield: 75 %

Procedure:
4-Methoxy-6-(4-methyl-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307c was synthesized from compound 305 (1 g, 3.59 mmol) and (4-methyl-phenyl)-boronic acid 306c (732 mg, 5.39 mmol), according to the procedure as described for compound 307b, as a white solid in 75% yield. MS (ESI, EI+): m/z=335 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:25])([F:24])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[C:19](OCC)=[O:20].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[F:24][C:3]1([F:25])[CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6]2[C:19](=[O:20])[NH:1][CH2:2]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC(F)(F)CNC3=O
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of diethyl 1-(3-amino-2,2-difluoropropyl)-1H-indole-2,6-dicarboxylate (2.3 g) in ethanol (160 mL) are added triethylamine (2.7 mL, 19.0 mmol) and K2CO3 (1.3 g, 9.5 mmol). The mixture is heated at 80° C. for 16 h. Ethanol is removed under vacuum and water (100 mL) is added. The resulting light yellow solid is filtered and dried to afford the title compound (1.2 g, 70% for 3 steps).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(Cl)(Cl)Cl>[C:17]([N:7]1[CH2:8][CH2:9][CH2:10][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc2c(s1)CNCCC2
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCc2ccsc2C1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a mixture of 4 g of 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 4 g of pyridine in 20 ml of chloroform was added 4.1 g of acetic anhydride under ice-cooling and the mixture was stirred at room temperature for an hour. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried and concentrated to give 4 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:34])=[C:15]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=2)[CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:15]2[CH:16]=[C:11]([NH:10][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:8])[CH:12]=[CH:13][C:14]=2[CH3:34])=[O:33])[CH2:27][CH2:28]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1ccc(N)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccnc2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
Pyridine-3-carbonyl chloride (0.09 g) was added to a stirred mixture of N-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide (0.15 g), triethylamine (0.1 g) and methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was evaporated and the residue was triturated under a mixture of ethyl acetate and diethyl ether. There was thus obtained the title compound (0.056 g); Mass Spectrum: M+H+444.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O.Cl>N1C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:30])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][C@@H:14]2[OH:29])[C@:21]2([CH3:27])[C@H:20]([CH2:25][C@@H:24]([O:26][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:23][CH2:22]2)[CH2:19][C@H:18]3[OH:28])[CH2:11][CH2:10]1)[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of cholic acid methyl ester (25 g, 59.2 mmol) in pyridine (75 mL), stirring at 0° C., was added methanesulfonyl chloride (5.04 mL, 65.1 mmol) dropwise over 30 minutes. The reaction was allowed to warm to room temperature and stir for 6 hours. The reaction mixture was poured into a mixture of EtOAc (200 mL), 1 N HCl (200 mL), and ice. The layers were separated, and the organic layer was washed with 1N HCl (2×50 mL), dried (Na2SO4) and concentrated to provide a light yellow oil. The crude material was passed through a plug of silica eluting with 50% EtOAc/hexanes to provide 24.5 g (83%) of the title compound as a light yellow oil that foamed into a white, sticky foam when placed on the high vacuum pump.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13](Cl)(=[O:15])=[O:14])([O-:3])=[O:2].[C:17]1([N:23]2[C:27]([SH:28])=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[C:17]1([N:23]2[C:27]([S:28][S:13]([C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14])=[N:26][N:25]=[N:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Sc1nnnn1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Sc2nnnn2-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
In 100 ml of tetrahydrofuran were dissolved 10 g of 2,4-dinitrophenylsulfonyl chloride and 7.3 g of 1-phenyl-5-mercaptotetrazole and the solution obtiained was cooled to 0° C. Then, 4.1 g of triethylamine was gradually added dropwise to the solution. After one hour, the solvent was distilled off and the residue was crsytallized from a mixture of acetonitrile to provide 6.2 g of the desired product having a melting point of from 128° C. to 130° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12]>>[CH3:17][Si:15]([CH3:18])([C:11]([CH3:14])([CH3:13])[CH3:12])[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCCCCCO
Yield: 52.6 %

Procedure:
Using the procedure of Step A of Preparation 16, 8.12 g of sodium hydride at 50% in oil, 20 g of 1,6-hexane diol and 25.5 g of terbutyl dimethyl chloro silane were reacted to obtain after chromatography, 20.7 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH3:15])=[C:10]([C:11]([OH:14])([CH3:13])[CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23])([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[CH:36](I)([CH3:38])[CH3:37]>CN(C)C=O>[OH:14][C:11]([C:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:20]3[C:21]([C:22]([O:24][CH:36]([CH3:38])[CH3:37])=[O:23])=[CH:27][CH:28]=[CH:29][C:19]=3[N+:16]([O-:18])=[O:17])[C:7]=2[O:8][C:9]=1[CH3:15])([CH3:12])[CH3:13]
Reactant: Cc1oc2c(N)cccc2c1C(C)(C)O
Reactant: CC(C)I
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc2c(NC(=O)c3c(C(=O)OC(C)C)cccc3[N+](=O)[O-])cccc2c1C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A mixture of 7-amino-3-(1-hydroxy-l-methylethyl)-2-methylbenzo[b]furan (150 mg), 3-nitrophthalic anhydride (205 mg) and potassium carbonate (202 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 hours. Then, isopropyl iodide (280 mg) was added to the mixture and the mixture was stirred for 3 hours. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of 2-propanol and water to give 3-(1-hydroxy-1-methylethyl)-7-(6-isopropoxycarbonyl-2-nitrobenzoylamino)-2-methylbenzo[b]furan (136 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.C(O)C.[BH4-].[Na+]>CO>[CH3:1][CH:2]([CH3:3])[CH2:4][CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCC(=O)CCC(C)C
Reactant: NCCCCCCCN1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)CCC(CCC(C)C)NCCCCCCCN1CCCCC1

Procedure:
To a solution of 1.70 g of 2,8-dimethylnonan-5-one and 1.98 g of 1-(7-aminoheptyl)piperidine in 50 ml of methanol was added 6 N hydrochloric acid-ethanol to have a pH value of approx. 7 (pH test paper). To the resulting solution was added under cooling 1.26 g of sodium borohydride all at once. The resulting mixture was stirred under chilling with ice for one hour, and then stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was extracted with chloroform after addition of water and an aqueous sodium hydroxide solution. The chloroform portion was dried and evaporated under reduced pressure to remove the solvent, yielding an oily product. The oil product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1) to give the desired compound as a colorless oil.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([Cl:31])=[CH:33][CH:34]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)Nc2ccc(Cl)cc2)ccn1
Yield: 96.9 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 4-chloroaniline (25.12 mg, 0.196 mmol) and DMAP (21.65 mg, 0.17 mmol) in DMF was added PyBOP (92.22 mg, 0.17 mmol), and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(4-chloro-phenyl)-isonicotinamide as a colorless solid (49 mg, 98% yield).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:33]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2cccc(Cl)c2Cl)N1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2,3-dichlorophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to afford (4S)-2-(N-(3-pentyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline.
Reaction SMILES: [CH3:1][CH2:2][C:3](C)=[O:4].[C:6]([OH:11])(=[O:10])[C:7](C)=C.[CH3:12]C(N=NC(C#N)(C)C)(C#N)C>CO>[CH3:1][CH:2]([O:11][C:6]([CH3:7])=[O:10])[CH2:3][O:4][CH3:12]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCC(C)=O
Reactant: C=C(C)C(=O)O
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A monomer solution was prepared by placing 7000 g of MEK in a tank kept at a nitrogen atmosphere and dissolving 2220 g of (B) 5-methacryloyloxy-2,6-norbornanecarbolactone (hereinafter inscribed as “NLM”), 2480 g of EAM and 90 g of methacrylic acid. Also, a polymerization initiator was prepared by placing and dissolving 700 g of MEK and 80 g of AIBN in another container kept at the nitrogen atmosphere. Into a polymerization tank kept at the nitrogen atmosphere, 3300 g of MEK was put and the temperature was raised to 80° C. with stirring. Subsequently, the monomer solution and the polymerization initiator solution kept at the temperature of 25 to 30° C. were fed into the polymerization tank kept at 8.0° C. over 4 hours, respectively. After the completion of feed, the polymerized solution was matured for 2 hours with keeping the polymerization temperature at 80° C., then cooled to room temperature and taken out. Polymer was precipitated from the resulting polymerized solution by dropping in 80 kg of aqueous methanol and filtrated. The resultant wet cake was washed with 80 kg of methanol, filtrated subsequently dissolved in MEK again, and passed through a filter 40QSH supplied from Cuno Incorporated to remove a trace amount of metals. Then, the solvent was replaced by PGMEA with removing MEK by heating under reduced pressure to prepare PGMEA solution containing 15% polymer. The features of the resultant polymer, the content of high polymer and the evaluation results of storage stability of PGMEA solution are shown in Table 1.