Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:13]([O:15]C(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([NH2:9])=[O:8])=[O:4].Cl.C(OCC)C.Cl.C[O-].[Na+].C1C=CC2N(O)N=NC=2C=1.[NH:40]([C:70]([O:72][CH2:73][CH:74]1[C:86]2[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=2)[C:80]2[C:75]1=[CH:76][CH:77]=[CH:78][CH:79]=2)=[O:71])[C@H:41](C(O)=O)[CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:66])[NH:47][S:48]([C:51]1[C:64]([CH3:65])=[C:62]([CH3:63])[C:61]2[O:60][C:57]([CH3:59])([CH3:58])[CH2:56][CH2:55][C:54]=2[C:52]=1[CH3:53])(=[O:50])=[O:49].CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.C1COCC1.C(OCC)C>[NH:40]([C:70]([O:72][CH2:73][CH:74]1[C:86]2[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=2)[C:80]2[C:75]1=[CH:76][CH:77]=[CH:78][CH:79]=2)=[O:71])[C@H:41]([C:13]([N:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([NH2:9])=[O:8])=[O:4])=[O:15])[CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:66])[NH:47][S:48]([C:51]1[C:64]([CH3:65])=[C:62]([CH3:63])[C:61]2[O:60][C:57]([CH3:58])([CH3:59])[CH2:56][CH2:55][C:54]=2[C:52]=1[CH3:53])(=[O:50])=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Agent: CCN=C=NCCCN(C)C
Agent: C[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCC[C@H]2C(=O)NCC(N)=O)c(C)c2c1OC(C)(C)CC2
Temperature: -10 °C
Reaction time: 15 h
Yield: 93.5 %

Procedure:
(See SEQUENCE ID NO: 10) 540 mg (2.0 mmol) of Boc-Pro-Gly-NH2 are dissolved in 5 ml abs. THF and mixed while stirring with 3 ml HCl/diethyl ether (abs. diethyl ether is for this saturated with hydrogen chloride at 0° C.). After 0.5 hours the solvent is removed under vacuum and co-evaporated three times with 5 ml toluene on each occasion. 110 mg (2.0 mmol) NaOMe are added to 5 ml abs. THF and after 5 min 5 ml DMF, 300 mg (2.0 mmol) HOBT and 1.32 g Fmoc-Arg(Pmc)-OH. Cooling to -10° C. takes place, 600 mg (3 mmol) EDCI are added and a pH of 7.0 is set with 0.33 ml NMM. After 15 hours of stirring the solvent is removed under vacuum, the resulting syrup absorbed in 150 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and H2O respectively. The organic phase is dried with MgSO4, the solvent distilled off under vacuum and the product precipitated from hexane. 1.52 g (93%) of thin-layer chromatographically identical Fmoc-Arg(Pmc)-Pro-Gly-NH2 are obtained as a colourless powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:21][O:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH2:24][CH2:23][O:22][CH3:21])[N:14]=2)=[CH:9][CH:8]=1
Reactant: O=c1[nH]nc(-c2ccc(OCCCC(F)(F)F)cc2)o1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1nc(-c2ccc(OCCCC(F)(F)F)cc2)oc1=O
Temperature: 100 °C
Yield: 83.2 %

Procedure:
1.8 g of 5-[4-(4,4,4-trifluorobutoxy)phenyl]-1,3,4-oxadiazol-2(3H)-one, 0.77 g of 2-chloroethyl methyl ether and a solution of 2.15 g of potassium carbonate in 20 ml of dimethylformamide are introduced into a 25 ml three-necked flask. The mixture is heated to 100° C. for 1 h 45 min and is then cooled and poured into 100 ml of water. The precipitate formed is drained, washed with 3 times 50 ml of water and then dissolved in ethyl acetate. The solution is dried over sodium sulphate and filtered, and the solvent is evaporated off. 1.8 g of product are obtained, which product is recrystallized in 10 ml of 96 % ethanol. 1.5 g of product are finally obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1.[N-:20]=[C:21]=[O:22].[K+]>O>[NH:3]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)[C:21]([NH2:20])=[O:22]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)c1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)c1
Yield: 44.1 %

Procedure:
A solution of 4-(3-aminomethylphenyl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.5 g) and potassium isocyanate (0.76 g) in water (30 ml) was stirred at room temperature for 8.5 hours. The resulting precipitate was collected by filtration and then suspended in water (50 ml). The mixture was alkalilied with an aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(3-ureidomethylphenyl)-2-(diaminomethyleneamino)thiazole (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@H:17]([C:18]([O:20]CC)=[O:19])[C@@H:16]3[CH2:23][C@H:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@H:17]([C:18]([OH:20])=[O:19])[C@@H:16]3[CH2:23][C@H:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2[C@@H]3CC[C@@H](C3)[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl (1R, 3S, 4S)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.04 g, 3.06 mmol) in tetrahydrofuran (20 ml)-methanol(15 ml) was added 1N sodium hydroxide (17 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, to give (1R, 3S, 4S)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O.[CH3:20][NH:21][CH3:22].C(Cl)Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:20][N:21]([CH3:22])[C:17](=[O:19])[CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[I:7]
Reactant: CNC
Reactant: COc1ccc(I)c(CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(I)c(CC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 16.7 g (0.19 mole) sample of oxalyl chloride was added dropwise at 0° C. to a solution of 50.0 g (0.17 mole) of 2-iodo-5-methoxybenzeneacetic acid in 310 ml dry toluene and 31.7 ml of DMF. The mixture was allowed to warm to room temperature and stir for 16 hours. The solution was cooled to 0° C. and dimethylamine gas was admitted until the mixture was strongly basic. The mixture was allowed to warm to room temperature and stir for three hours and methylene chloride was added. The organic layer was washed with water, dilute hydrochloric acid, and sodium hydroxide. The organic layer was dried with MgSO4 and evaporated in vacuo to give 54.2 g of N,N-dimethyl-2-iodo-5-methoxybenzeneacetamide, mp 86°-89° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:24]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH:24]([CH3:26])[CH3:25])=[CH:29][CH:30]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(OC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A suspension of 140 g of methoxymethyl-triphenylphosphonium chloride in 400 ml of tert.-butyl methyl ether is treated with 45 g of potassium tert.-butylate within 5 minutes at 0° C. while gassing with nitrogen and the mixture is stirred for a further 10 minutes. Then, a solution of 41 g of 4-(isopropyloxy)-benzaldehyde in 100 ml of tert.-butyl methyl ether is added dropwise at 0° C. within 30 minutes. The reaction mixture is stirred at room temperature for a further 16 hours and then poured into 750 ml of 0.8N sodium hydrogen carbonate solution. The aqueous phase is separated and back-extracted with diethyl ether. The organic phase is washed neutral with water, dried over magnesium sulphate and concentrated. The residue is suspended in 800 ml of hexane. After cooling to 0° C. the triphenylphosphine oxide is filtered off and the filtrate is concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gives 45 g of pure 1-methoxy-2-(4-[isopropoxy]phenyl)ethene.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH2:23][CH2:22]1>CN(C)C=O>[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Reaction time: 6 h
Yield: 60 %

Procedure:
In 30 ml of dimethylformamide were dissolved 2.6 g of 5-fluorouracil, 2.66 g of anhydrous aluminum chloride and 7.0 ml of triethylamine. The reaction was carried out at 130° C. for 6 hours while adding 3.0 ml of 2,3-dihydrofuran to the solution. The reaction liquid was treated in the same manner as described in Example 13 to obtain 2.4 g of (1-(2-tetrahydrofuryl)-5-fluorouracil. The yield was 60%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[CH2:27][O:26]2)[CH:22]=[CH:23][CH:24]=1>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]([OH:26])[CH2:27][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([S:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[CH:8][CH:9]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: NCCc1ccc(Sc2ccc(O)cc2)cc1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CCO
Product: Oc1ccc(Sc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Yield: 32.2 %

Procedure:
4-[[4-(2-Aminoethyl)phenyl]thio]phenol (295 mg) and (2R)-2-(3-chlorophenyl)oxirane (186 mg) in ethanol (3.5 ml) was refluxed for 6 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel (chloroform/methanol=100/3) to give 4-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]phenol (155 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:13]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1ccc(CO)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution N-hydroxyphthalimide (2.45 g), 4-pentyloxybenzyl alcohol (Aldrich, 2.92 g) and triphenylphosphine (4.72 g) in THF was added drop-wise diethyl azodicarboxylate (1.2 eq.). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (petroleum ether/EtOAc, 1/2, v/v) and gave 2-(4-pentyloxy-benzyloxy)-isoindole-1,3-dione. This phthalimide intermediate (4.35 g) was dissolved in dichloromethane and methyl-hydrazine (1.1 eq.) was added. The reaction mixture stirred at room temperature for 60 minutes and the formed solid material was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (petroleum ether/EtOAc, 5/1, v/v), and gave the title compound (2.55 g). 13C-NMR (CDCl3) δ 159.1, 130.1, 129.2, 114.5, 77.7, 68.0, 29.0, 28.2, 22.5, 14.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]N.O(CC)[C:11]([S-])=S.[K+].C(Cl)(Cl)=S>>[N:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:11]=1
Reactant: CCOC(=S)[S-]
Reactant: NNc1ccccc1N
Agent: S=C(Cl)Cl
Agent: [K+]
Product: c1ccc2[nH]cnc2c1

Procedure:
In the process (b) of the invention, a 2-aminophenylhydrazine derivative of the formula (IVb) is reacted with carbond disulfide, potassium ethyl xanthate or thiophosgene to give a benzimidazole derivative of the formula (Ie) according to the Reaction Scheme (C).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)=[C:5](\[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1.C(OC1C=CC(C(C2C=CC(OCCN(C)C)=CC=2)=C(C2C=CC(OCC3C=CC=CC=3)=CC=2)CCO)=CC=1)C1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][C:4]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:37]=1)=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Agent: CN(C)CCOc1ccc(C(=C(CCO)c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Product: CN(C)CCOc1ccc(C(=C(CCCl)c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 63 %

Procedure:
Z-4-chloro-1,2-bis (4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino)-ethoxy]phenyl]-1-butene isprepared from 4.14 g of 1,2-bis-(4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino) ethoxy]phenyl]-1-buten-4-ol according to the procedure described in Example 6(c). The product is purified by column chromatography giving 2.68g (63%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9].[CH:13]1[CH:18]=[C:17]2[C:19]([CH:22]=O)=[CH:20][S:21][C:16]2=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:22]([C:19]1[C:17]3[CH:18]=[CH:13][CH:14]=[CH:15][C:16]=3[S:21][CH:20]=1)[NH:10][C:8]2=[O:9]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: O=Cc1csc2ccccc12
Product: COc1ccc2nc(-c3csc4ccccc34)[nH]c(=O)c2c1

Procedure:
Compound 19 was synthesized from 5-methoxy-2-aminobenzamide (9) (1.2 g, 7.3 mmol) and thianaphthene-3-carboxaldehyde (16) (1.2 g, 7.3 mmol): yield 1.3 g (60%); brown crystals; mp 289 to 290° C.; 1H NMR (DMSO-d6) δ 3.89 (3H, s, OCH3), 7.43-7.57 (4H, m, 4×ArH), 7.76-7.80 (1H, m, 1×ArH), 8.07-8.11 (1H, m, 1×ArH), 8.73 (1H, s, 1×ArH), 8.98-9.01 (1H, m, 1×ArH), 12.49 (1H, br s, NH) ppm; MS (ESI) m/z 308; Anal. (C14H12N2O2S): C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([O:25][CH3:26])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)=[CH:3][C:4]=4[O:25][CH3:26])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: COc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Product: COc1cc(-c2ccc(F)cc2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Yield: 72 %

Procedure:
Following the procedure described in Example 76c using 4-[4-bromo-2-(methyloxy)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one and (4-fluorophenyl)boronic acid gave the title compound as a solid (60 mg, 0.137 mmol, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.27-9.05 (m, 1H), 7.58 (dd, J=5.3, 7.3 Hz, 2H), 7.34 (ddd, J=2.3, 4.0, 7.8 Hz, 1H), 7.28-7.11 (m, 3H), 4.02-3.87 (m, 3H), 3.80-3.67 (m, 1H), 3.62 (ddd, J=4.2, 8.0, 11.9 Hz, 1H), 3.49-2.96 (m, 1H), 2.77-2.36 (m, 2H), 2.32-1.99 (m, 1H), 1.88-1.67 (m, 1H), 1.59-1.50 (m, 1H), 1.09-0.92 (m, 2H), 0.84-0.67 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19]CC1C=CC=CC=1)[CH2:15][N:14]([S:27]([C:30]1[C:31]3[CH:32]=[CH:33][N:34]=[CH:35][C:36]=3[CH:37]=[CH:38][CH:39]=1)(=[O:29])=[O:28])[CH:13]([CH2:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:43][CH2:42]1)[CH2:12]2)C1C=CC=CC=1.C(S)CS.B(F)(F)F.C(OCC)C.C(=O)(O)[O-].[Na+]>>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[OH:19])[CH2:15][N:14]([S:27]([C:30]1[C:31]3[CH:32]=[CH:33][N:34]=[CH:35][C:36]=3[CH:37]=[CH:38][CH:39]=1)(=[O:29])=[O:28])[CH:13]([CH2:40][N:41]1[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:45][CH2:46]1)[CH2:12]2
Reactant: O=S(=O)(c1cccc2cnccc12)N1Cc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2CC1CN1CCN(c2ccccc2)CC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: SCCS
Solvent: CCOCC
Product: O=S(=O)(c1cccc2cnccc12)N1Cc2cc(O)c(O)cc2CC1CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
To 314 mg of the amorphous compound obtained in Example 9, were added 2 ml of 1,2-ethanedithiol and 1 ml of boron trifluoride/ethyl ether, and the mixture was stirred at a room temperature for 18 hours. After the addition of saturated sodium bicarbonate aqueous solution, the reaction mixture was extracted twice with a mixture of chloroform and methanol (1:1), and the extract was dried over magnesium sulfate and concentrated under a reduced pressure to obtain a residue, which was then applied to a silica gel column and eluted with chloroform/methanol (50:1 to 20:1) to obtain 213 mg of the title compound in a colorless amorphous form.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]([F:11])([F:24])[F:25])(=[O:22])=[O:21])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-trifluoromethoxybenzenesulfonyl chloride (2.35 g, 9.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (1.80 g, 57%). 1H-NMR (300 MHz, CDCl3) δ 7.96 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 5.04 (s, 1H); 2.23 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1COCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:29])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine (2.0 g, 8.7 mmol) and 4-nitrophenyl isocyanate (1.5 g, 8.8 mmol) in 150 mL of THF was heated to reflux for 2 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 100 mL of ethyl acetate and tritutrated to provide a precipitate which was collected filtration to provide the title compound (3.1 g, 91%). 1H NMR (300 MHz, DMSO-d6) ppm 1.64 (m, 4H), 2.45 (m, 4H), 2.86 (d, J=6.44, 2H), 4.48 (d, J=6.44, 2H), 7.37 (m, 1H), 7.63 (m, 1H), 7.70 (m, 2H), 7.90 (m, 1H), 7.99 (s, 1H), 8.19 (m, 2H), 8.89 (s, 1H), 9.43 (s, 1H); MS (DCI/NH3) m/z 395 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([CH2:14][P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1CCCCC1>[CH:16]1([P:15]([CH2:14][P:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: [H][H]
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Product: C1CCC(P(CP(C2CCCCC2)C2CCCCC2)C2CCCCC2)CC1
Temperature: 100 °C

Procedure:
A 300 ml. stainless steel high pressure reactor was charged, under a nitrogen atmosphere at atmospheric temperature, with a solution of ##STR1## hereinafter referred to as Nb(OC6H3Ph2 --2,6)2 (CH2C6H4 --4Me)3 (2.2 g., 2.5 mmol.) and bis(di-phenylphosphino)methane (25.0 g., 65.1 mmol.) in cyclohexane (55 ml.). The reactor was pressurized with hydrogen (1,200 psi) and heated at 100° C. for four days. During the course of the reaction the pressure dropped requiring the repressurization of the reactor four times. Thereupon, the reactor was cooled and the hydrogen gas vented. The cyclohexane was removed in vacuo and water (30 ml.) was added to the mixture. The mixture was extracted with diethyl ether (200 ml.) which extraction was repeated four times to yield a clear colorless solution. The ether was removed and the resultant solution was recrystallized from hot ethanol (120 ml.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]12[CH2:22][CH:19]([NH:20][CH2:21]1)[CH2:18][O:17]2>>[CH:16]12[CH2:22][CH:19]([NH:20][CH2:21]1)[CH:18]([C:13]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])[O:17]2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1OC2CNC1C2
Product: Cc1cccc2c(Cl)ncc(C(=O)C3OC4CNC3C4)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-5-azabicyclo[2.2.1]heptane by following the similar procedure as described for intermediate-11a.