Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@@H:24]([OH:51])[C@@H:25]([O:43][Si](CC)(CC)CC)[C@@H:26]([O:39]CCF)[C@H:27](N2C=C(C)C(N)=NC2=O)[CH2:28][OH:29])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(OC(=O)C1C=CC=CC=1)(=[O:61])C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([OH:22])[C@H:24]([C@@H:25]([C@@H:26]([C@@H:27]([CH2:28][OH:29])[OH:61])[OH:39])[OH:43])[OH:51]
Reactant: CC[Si](CC)(CC)O[C@@H]([C@@H](OCCF)[C@@H](CO)n1cc(C)c(N)nc1=O)[C@H](O)COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 434 %

Procedure:
Compound 9 (1.92 g, 2.58 mmol) was dissolved in anhydrous DMF (11.9 mL) and benzoic anhydride (0.87 g, 3.85 mmol) was added with stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and the resulting organic phase was washed with a saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue obtained was purified by flash silica gel column chromatography and eluted with 60% ethyl acetate in hexane to yield 6-O-(4,4′-dimethoxytrityl)-3-O-(2-fluoroethyl)-4-O-(triethylsilyl)-2-deoxy-244-N-benzoyl-5-methylcytosin-1yl)-D-altro-hexitol (2.04 g, 93.2%). In a 100 mL round bottom flask, triethylamine trihydrofluoride (2.04 mL, 12.55 mmol) was dissolved in anhydrous THF (23.2 mL). Triethylamine (0.87 mL, 6.28 mmol) was added to this solution, and the mixture was quickly poured onto 6-O-(4,4′-dimethoxytrityl)-3-O-(2-fluoroethyl)-4-O-(triethylsilyl)-2-deoxy-2-(4-N-benzoyl-5-methylcytosin-1yl)-D-altro-hexitol (2.04 g, 2.44 mmol). The resulting mixture was stirred at room temperature for 6 hours and then poured into ethyl acetate (80 mL). The organic phase was washed sequentially with water (50 mL), 5% aqueous NaHCO3 (50 mL) and brine (50 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum under reduced pressure. The residue obtained was purified by silica gel column chromatography (30% ethyl acetate in hexanes) to afford compound 10 (1.66 g, 87.94%) as a white foam. MS (ES) m/z 724.3 [M+H]+.
Reaction SMILES: [Li].C([Li])(CC)C.C=CC=C.C=CC1C=CC=CC=1.C1(N[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)C=CC=CC=1>CCCCCC.O>[CH:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=1[CH:34]=[CH2:35])=[CH2:26]
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Agent: C=CC=C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: O
Solvent: C=Cc1ccccc1
Solvent: CCCCCC
Product: C=Cc1ccccc1C=C
Reaction time: 1 h

Procedure:
Still further, in a nitrogen atmosphere, 213 m mole as active lithium of sec-butyllithium was added to a 15 wt.% n-hexane solution of 9.5 kg of a monomer mixture comprising 1,3-butadiene and styrene in a weight ratio of 40:60, and the mixture was polymerized at 60° C. for 4 hours. After more than 99% of the monomers had been polymerized, the resulting active copolymer solution was further mixed with a 20 wt.% n-hexane solution of 19.0 kg of a monomer mixture comprising 1,3-butadiene and styrene in a weight ratio of 70:30, and the mixture was polymerized first at 70° C. for 4 hours and then at 85° C. for one hour. After substantially all of the monomer mixture had been copolymerized, the resulting final copolymer was inactivated by addition of a small amount of water. To the copolymer solution, 285 g of phenyl-β-naphthylamine was added. Thereafter, n-hexane was volatilized to obtain a non-divinylbenzene-incorporated thermoplastic elastomer in accordance with the present process (sample H), and the physical properties thereof were measured.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)[C:6]([NH2:22])=[CH:5][CH:4]=1.[CH2:23](OC(OCC)OCC)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:22]=[CH:23][N:9]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[C:7]=2[CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(N)c(NCc2ccc3nc(SC)oc3c2)c1
Solvent: O=CO
Product: COc1ccc2ncn(Cc3ccc4nc(SC)oc4c3)c2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 84.1 %

Procedure:
A mixture of 5-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (920 mg, 2.92 mmol), triethoxymethane (8.8 mL) and HCOOH (0.2 mL) was stirred at 90° C. for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:2 petroleum ether/ethyl acetate to give 6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light brown solid (799 mg, 84.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.33 (d, J=6.6 Hz, 1H), 7.15 (s, 1H), 6.80 (d, J=6.6 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:21]2[CH:22]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[OH:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2O)CC1
Temperature: 75 °C

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (4.03 g), 4-bromo-2-iodo-phenol (5.00 g), Pd(PPh3)2Cl2 (600 mg), copper iodide (500 mg), and triethylamine (2.35 mL) in N,N-dimethylformamide (30 mL) is heated under an argon atmosphere to 75° C. for 4 h. The reaction mixture is diluted with ice water after cooling to room temperature and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.32 min; Mass spectrum (ESI+): m/z=402, 404 [M+Na]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2].[N+](=[CH2:21])=[N-]>C(OCC)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([O:17][CH3:21])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc2cc(C(C)=O)ccc2c1

Procedure:
To a mixture of 24 g. of 6-acetyl-2-naphthyl-α-methylacetic acid and 200 ml. of diethyl ether are added 4.2 g. of diazomethane in 100 ml. of diethyl ether. The resulting mixture is evaporated to give methyl 6-acetyl-2-naphthyl-α-methylacetate. The product is added to 200 ml. of aqueous 20% sodium hypochlorite. The resulting mixture is allowed to stand for four hours at room temperature. The mixture is acidified by the addition of aqueous 1N hydrochloric acid and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-carboxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)#[N:2].FC(F)(F)C(O)=O.[ClH:27]>C(O)(=O)C.CO.[Pd]>[ClH:27].[ClH:27].[NH2:2][CH2:1][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 20 h

Procedure:
A mixture of 0.25 g of 9-cyano-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 10 ml of acetic acid, 10 ml of trifluoroacetic acid and 20 mg of 10% palladium-on-charcoal is hydrogenated in an autoclave under a pressure of 50 bar for 20 hours. The suspension is filtered and washed with acetic acid. The filtrate is concentrated to dryness under reduced pressure (15 mm Hg; 2 Kpa) at 40° C. The solid obtained is dissolved in a mixture of 50 ml of acetic acid and 10 ml of concentrated hydrochloric acid and then again concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue obtained, taken up in 25 ml of methanol, is filtered, then washed with two times 25 ml of isopropyl ether and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. 0.24 g of 9-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride is obtained in the form of a white solid melting above 260° C. (Analysis C14H14Cl2N4O; % Calculated C: 51.71, H: 4.34, N: 17.23; % Found C: 52.11, H: 4.53, N: 17.04).
Reaction SMILES: BrCC1C=CC2C(=CC=CC=2)C=1.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH:36]([CH2:37][O:38]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:35][N:34]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:33][CH:32]2[O:65][CH2:66][C:67]2[CH:76]=[CH:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH:68]=2)=[CH:27][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]2[CH:32]([O:65][CH2:66][C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[CH:68]=3)[CH2:33][N:34]([C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[CH2:35][CH:36]2[CH2:37][OH:38])=[CH:29][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: BrCc1ccc2ccccc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22 (h), by reacting tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate with triphenylchloromethane in pyridine there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 731 (M+NH4)+ ], as a colourless foam, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 62 (h) gave tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 871 (M+NH4)+ ], as a colourless foam. Subsequent selective cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) yielded tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 612 (M+H)+. Subsequent alkylation with methyl iodide analogously to Example 62 (h) gave tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 626 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12](OC)=NC4C([C:20]=3[Cl:21])=CC(Br)=CC=4C)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.O=P(Cl)(Cl)[Cl:39]>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:20]([Cl:21])=[N:33][C:32]4[C:34]([C:12]=3[Cl:39])=[CH:35][C:29]([Br:28])=[CH:30][C:31]=4[F:36])=[CH:26][CH:27]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (4 g, 15.37 mmol, Intermediate 6: step b) and 4-bromo-2-fluoroaniline (2.7 g, 13.973 mmol) in POCl3 (20 mL) was heated at 105° C. for 3 hours, cooled to room temperature and evaporated in vacuo to remove excess POCl3. The residue was poured into ice H2O and treated with aqueous NH4OH to pH 8-9 (temperature of the aqueous mixture was kept cold during addition). The precipitates were collected, rinsed with H2O and dried under reduced pressure. The solids were diluted with DCM and insoluble solids filtered off. The filtrate was evaporated to dryness to provide product as a tan solid.
Reaction SMILES: [C:1]1([C:11]([O:13]CC)=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CCO>[CH2:9]([O:8][C:6]([C:1]1([C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.5 %

Procedure:
To a solution of diethyl 1,1-cyclopentane dicarboxylate (2.5 g, 11.68 mmol) in EtOH (10 ml) was added dropwise a solution of KOH (654 mg, 11.68 mmol) in EtOH (10 ml) over 1/2 hour. The resulting mixture was stirred at room temperature for 96 hr, concentrated under vacuum, and partitioned between H2O and EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc. The EtOAc extracts were washed (brine), dried (Na2SO4), filtered, and concentrated under vacuum to give the product (1.73 g) as a clear oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.[C-:26]#[N:27].[K+]>C1COCC1.O>[N:12]1([CH:24]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:26]#[N:27])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=Cc1ccncc1
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(c1ccncc1)N1CCOCC1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
p-Toluenesulphonic acid (1.91 g, 10.1 mmol) in THF (10 mL) was treated portionwise with morpholine (1.75 g, 1.76 mL, 20.1 mmol) and 4-pyridinecarbox-aldehyde (1 g, 9.3 mmol) was added with stirring. The reaction mixture was heated at 100° C. for 2 h. After cooling to room temperature potassium cyanide (0.82 g, 12.6 mmol) was added as a slurry in water (1.5 mL) and the reaction mixture heated for 18 h at reflux. After cooling to room temperature the THF was removed in vacuo and the residue extracted with DCM, dried over sodium sulphate, concentrated, dissolved in ethyl acetate, then filtered through a pad of silica eluting with ethyl acetate. The residue was chromatographed on silica in DCM/ethyl acetate (0-100% gradient) to give the title compound (1.5 g). δH (DMSO-d6) 8.68-8.64 (2H, m), 7.49-7.46 (2H, m), 5.53 (1H, s), 3.66-3.60 (4H, m), 2.59-2.51 (2H, m), 2.43-2.35 (2H, m).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1.Cl.[C:19]([C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:20]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:24]2[CH2:25][CH2:26][C:21]([C:19]#[N:20])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)=[S:17])=[CH:11][CH:10]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1(c2ccccc2)CCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added to a suspension of 4-chlorophenyl isothiocyanate (1.69 g, 10 mmol) and 4-cyano-4-phenylpiperidine hydrochloride (2.22 g, 10 mmol) in dichloromethane (100 mL), and the reaction was then stirred at room temperature for 20 minutes. The mixture was washed with 2N hydrochloric acid, then brine, it was dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a white solid, 3.62 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[C:8](=[O:13])([O:11]C)[O:9][CH3:10].[C:14](=O)=O>CO>[CH3:10][O:9][C:8](=[O:11])[O-:13].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH3:14])[C:3]=1[CH3:7]
Reactant: O=C=O
Reactant: COC(=O)OC
Reactant: Cc1nccn1C
Solvent: CO
Product: COC(=O)[O-]
Product: Cc1n(C)cc[n+]1C
Temperature: 130 °C
Reaction time: 60 h

Procedure:
96 parts of 1,2-dimethylimidazole (CUREZOL 1.2DMZ manufactured by Shikoku Chemicals Corporation), 135 parts of dimethyl carbonate and 192 parts of methanol were put into an autoclave made of a stainless steel equipped with a cooling condenser and mixed homogenously. After nitrogen substitution, the temperature was then raised to 130° C. while being sealed, so as to initiate a reaction. At the beginning, the pressure was approximately at 4.5 Kg/cm2, but it was gradually raised due to generation of carbon dioxide, so that the gasses were appropriately released from the upper part of the cooling condenser, adjusted at a pressure of about 7 Kg/cm2 or less. After 60 hours, they were cooled at 30° C., and the result of the reacted solution by means of 1H-NMR showed that 1,2-dimethylimidazole was disappeared and 1,2,3-trimethylimidazolium monomethyl carbonate was produced approximately under a quantitative theory. Into 415 parts of the resultant solution of 1,2,3-trimethylimidazolium monomethyl carbonate, methanol and dimethyl carbonate, 205 parts of an aqueous solution of fluoroboric acid at a concentration of 42 wt % was gradually put in drops while stirring at a temperature of 25° C. over a period of about 30 minutes. As putting it in drops, bubbles of carbon dioxide were generated. Finishing the dropping and the generation of the bubbles, all the solvents were removed at a pressure of 20 Torr and at a temperature of 150° C., so as to obtain 194 parts of a white solid (3). The examinations of 1H-NMR, 19F-NMR, 13C-NMR and HPLC of the white solid (3) resulted in showing that 98 mol % of 1,2,3-trimethylimidazolium tetrafluoroborate (which is hereinafter shortened as “TMI.BF4”), 2 mol %, in total, of 1,2,3-trimethyl-4-carboxylate imidazolium and 1,2,3-trimethyl-4-carboxy-5-carboxylate imidazolium.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[Br-:1].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCBr
Reactant: Brc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCn1cc[n+](-c2ccc(Br)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 1.62 mmol (0.361 g) 1-(4-bromophenyl)imidazole and 1.78 mmol (0.319 g, 0.28 ml) 1-bromoheptane are dissolved in 5 ml THF and heated for 2.5 h to 100° C.
Reaction SMILES: S(CCCN1CCN(CCCS(O)(=O)=O)CC1)(O)(=O)=[O:2].CCN(CCO)CC.CC[CH:31]([CH2:34][O:35][C:36]([C:49]([N:51](CC[NH+](C)C)C)=O)(C1C=CC=CC=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)CC.[Cl-]>>[CH3:31][C:34]([O:35][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:51][CH:49]=1)=[O:2]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)CCCN1CCN(CCCS(=O)(=O)O)CC1
Agent: CCN(CC)CCO
Agent: [Cl-]
Product: CC(=O)Oc1c[nH]c2ccccc12

Procedure:
In accordance with the procedures described previously, 10 mg of eel cholinesterase (Code ECH, Worthington Biochemical Company, approximately 100 units/mg) is dissolved in 30 ml of the 0.5 M, pH 8.0, "TRITON X-100"-containing 1,4-bis(3-sulfopropyl) piperazine buffer solution described previously. Then 30 microliters of the resulting buffered eel cholinesterase solution (i.e. 1.0 unit of the enzyme) were impregnated into 12.7 mm discs of DE81 (diethylaminoethyl ion exchange paper, 3.5 microequivalents per cm2) paper (DEAE) discs, allowed to air-dry for 3 hours at room temperature, placed in uncapped glass vials and allowed to dry for 12 hours at 0.01 mm Hg, at 25° C. in a vacuum desiccator. Indoxyl acetate discs were prepared from the following solution and 9.0 cm Whatman No. 1 filter paper circles.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-])=O.[K+].[K+].ClCCCO[C:28]1[CH:29]=[C:30]([C:36]2(C=O)[CH:41]=[CH:40][CH:39]=[CH:38][CH2:37]2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:2][CH2:3][CH2:4][O:8][C:29]4[CH:28]=[C:33]([O:34][CH3:35])[CH:32]=[CH:31][C:30]=4[C:36]4[CH:37]=[C:38]([CH:17]=[O:20])[CH:39]=[CH:40][CH:41]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc(C=O)c2)c(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01 g; 9.13 mmol), K2CO3 (2.0 g), and 1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenylmethanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4 then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2, 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-4-methoxyphenyl]-phenylmethanone as white crystals, 3.07 g (63%), m.p.=140°-141 ° C.
Reaction SMILES: C[CH2:2][O:3][CH2:4][CH3:5].ClC([O-])=[O:8].[SH:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14]>C(=O)(O)[O-].[Na+]>[CH2:4]([O:3][C:2]([S:10][CH2:11][CH2:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])=[O:8])[CH3:5]
Reactant: CCOCC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: O=C([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
Ether chloroformate (1.2 g.) is added to a solution of 3-mercaptopropanoyl-L-proline [2.03 g.) in normal sodium bicarbonate (30 ml.) and the mixture is stirred vigorously at 5° for one hour, and for two hours at room temperature. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and concentrated to dryness to yield 1-[3-[[(ethoxy)carbonyl]thio]propanoyl]-L-proline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:28]1([NH:32][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:10][NH:11]3)=[CH:16][CH:15]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCC1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCC1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 125.6 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), cyclobutylamine (18.2 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 43.2 mg (92%) of the title compound as a TFA salt (1.5 H2O, 1.1 TFA, effective MW=561.92). 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.72 (2H, m), 8.13 (4H, m), 7.70 (1H, d, J=7.1), 7.58 (2H, m), 7.41 (2H, m), 7.27 (1H, s), 6.89 (1H, t, J=4.2), 2.84 (1H, m), 0.72 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 396.1.