Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:48]([O:50]C)=[O:49])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]1[C:10]([C:48]([OH:50])=[O:49])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][NH:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(N2CCN(C(=O)CCCCOc3cc(F)ccc3CNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)N1CCN(c2nc(C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
Methyl 8-(benzyloxy)-5-(4-(5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoyl)piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 5.1; 1.1 mmol) was dissolved in a mixture of THF (6 ml), methanol (6 ml) and water (6 ml). Sodium hydroxide (7.5 mmol) was added and stirred for 2 days. The organic solvent was removed under vacuum, and the residue washed with diethyl ether. The aqueous residue was acidified with 1 N HCl to pH=8-9. The mixture was washed with ethyl acetate. The aqueous phase was acidified with 1N HCl to pH 3-4. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed under vacuum to afford the title compound (0.4 gr) that was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[C:6]=2[CH:30]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:23]5[O:24][CH2:25][CH2:26][O:27][C:22]=5[CH:21]=4)[CH2:16][CH2:15]3)[C:6]=2[CH:30]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2ncn(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Product: CC(=O)Nc1ccc2ncn(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
Analogously to Example 6, reaction of 6-[4-(4-(6-aminobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane ("D") with acetyl chloride gives 6-[4-(4-(6-acetamidobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[N:5][N:4]=[N:3]1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A solution of 1,5-dimethyltetrazole (20 g; 0.204 mole) in dry THF (200 mL) was cooled to -78° C. and treated with n-butyllithium (91 mL of 2.5 molar solution in hexane; 0.227 mole) and the mixture stirred at -78° C. for 30 minutes. Benzophenone (31.1 g; 0.171 mole) was added and the mixture stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. and stirred for 15 hours. The mixture was quenched with 2N HCl (100 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was crystallized from EtOAc-Hexane to afford the title compound as a white solid (10.5 g; 22%); m.p.=175°-176° C. (crystallized from EtOAc-hexane). MS (CI): m/e=281 for (M+H)+ ;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[F:12].[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:4][C:3]=1[F:12]
Reactant: Cc1n[nH]c2cc(Br)c(F)cc12
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(Br)c(F)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-fluoro-3-methyl-1H-indazole (130 mg, 0.284 mmol, 50% purity) in DMF (2 ml) was added NaH (60% oil dispersion, 18.16 mg, 0.454 mmol) at 0° C. The reaction mixture stirred for 15 minutes before the slow addition of a solution of 4-chloropyrimidin-2-amine (73.53 mg, 0.568 mmol) in DMF (2 mL). The resulting mixture was stirred at 60° C. for 16 hr. The reaction mixture was cooled and partitioned between water (15 ml) and EtOAc (15 ml). A precipitate formed and was collected by suction filtration. The filtrate was concentrated in vacuo and purified by flash chromatography (Isolute column, 1-2% methanol in DCM) to give the title intermediate as a yellow oil: 1H NMR (500 MHz, DMSO) delta 2.56 (3H, s), 7.00 (1H, s), 7.04-7.14 (2H, m), 7.92 (1H, d, J=8.35 Hz), 8.26 (1H, d, J=5.52 Hz), 9.22 (1H, d, J=5.99 Hz); LC-MS: m/z=+321.90, 323.80 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:49]=[CH:48][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[C:41]2=[O:47])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.[OH-].[Na+]>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[C:41]2=[O:47])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:48][CH:49]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCCN(C)C2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCCN(CCCCCOc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C(=O)O)cc2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
31.5 mg (750 μmol) of lithium hydroxide monohydrate are added to a solution of 47 mg (160 μmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(3-methyl-2-oxotetrahydro-pyrimidin-1(2H)-yl)pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate (Example 35A) in 1.0 ml of THF and 1.0 ml of 1 M aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 4.2 mg (7.0 μmol, 9.4% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH3:12])=[CH:5][C:4]=2[C:3]=1[NH2:13].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[F:1][C:2]1[C:3]([NH:13][C:23]([NH:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][C:15]([F:14])([F:28])[F:27])=[CH:26][CH:25]=2)=[O:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2
Reactant: Cc1cc2c(N)c(F)ccc2cn1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)c(F)ccc2cn1

Procedure:
Prepared from 6-fluoro-3-methylisoquinohn-5-amine (Description 79) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 394 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32])N>C(O)(=O)C>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH2:33])=[O:32])[N:2]=[CH:3][CH:4]=1
Reactant: NNc1cccc(C(N)=O)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 3-hydrazino-benzamide (2 eq) were dissolved in a sealed tube in acetic acid and irradiated in MW at 120° C. for 15 min. The solvent of the reaction mixture was removed and the crude product was purified by preparative HPLC yielding the desired product.
Reaction SMILES: C(Cl)(Cl)=O.C(N(CC)CC)C.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[C:29]([C:38]1C=CC(O)=C[CH:39]=1)([C:32]1C=CC=[CH:34][CH:33]=1)(C)C>O.C(Cl)Cl>[C:19]1([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)([C:16]2[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:17]=2)[C:21]2[C:33](=[CH:32][CH:29]=[CH:38][CH:39]=2)[CH2:34][CH2:20]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: O=C(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1ccc(C2(c3ccc(O)cc3)CCc3ccccc32)cc1

Procedure:
A solution of 4,4′-(2,3-dihydro-1H-indene-1,1-diyl)diphenol (“IBP”) was prepared by dissolving 8.33 g (0.0275 moles) of IBP monomer (prepared according to Example 9) in 33% aqueous caustic (15 g) and water (30 ml). To a 2 L glass reactor equipped with a pH probe, condenser, agitator, phosgene inlet, and caustic scrubber was added methylene chloride (500 ml), deionized water (140 ml), triethylamine (0.17 ml, 0.0012 moles), bisphenol-A (7.67 g, 0.0337 moles), p-cumylphenol (0.39 g, 0.0018 moles), and IBP solution. The batch was phosgenated in excess at a rate of 2 grams per min for 4 minutes, maintaining the pH between 9 and 10 with concomitant caustic addition (33% w/w). At the completion of the phosgenation, the reactor was purged with nitrogen to remove excess phosgene and the reaction mixture extracted with dilute acid (1N HCl) and deionized water. The final product IBP-BPA Copolymer (PL-11-058) was isolated as a white powder by exposing the polymer solution (in methylene chloride) to hot water, evaporating the solvent and providing a white powder. Characterization data for the IBP-BPA Copolymer (PL-11-058) is provided in Table 1, shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH:11]=1)[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Br)ccc1OCc1cccs1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1cc(Br)ccc1OCc1cccs1
Temperature: -50 °C

Procedure:
A solution of methyl 5-bromo-2-(2-thienylmethoxy)benzoate (1.6 g, 4.9 mmol) in dichloromethane (20 ml) was cooled to -85° C. A solution of DIBAL (5.8 ml, 1N in CH2Cl2) was added dropwise. The temperature was maintained below -75° C. for 30 minutes and then warmed to -50° C. over 21/2% hours. The reaction mixture was quenched with 1N HCl, washed with aqueous sodium hydrogen carbonate solution, dried (MgSO4) and evaporated. The product was purified by chromatography (eluant: diethyl ether/hexane) to give 5-bromo-2-(2-thienylmethoxy)benzyl alcohol a colourless gum (0.53 g, 36.4%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[N:20]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[N:20]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1nc(-c2cccs2)no1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: c1csc(-c2noc(COc3ccc(CCCCn4ccnc4)cc3)n2)c1
Yield: 29 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with 5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole to obtain 5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-3-(2-thienyl)-1,2,4-oxadiazole. The yield was 29%. Recrystallization from a ethyl acetate-MeOH gave colorless prisms, mp 94-95° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.C(Cl)Cl>CO.[Pd]>[CH3:1][CH:2]([CH3:35])[CH:3]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: CC(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 93.8 %

Procedure:
To a stirred solution of 4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (87 mg) at r.t. in methanol (4 ml) and CH2Cl2 (1 ml) under an argon atmosphere was added the 10% Pd/C (10 mg). The mixture was then stirred at r.t. under a hydrogen atmosphere for 38 hours. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to leave 4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (82 mg) of an off-white sticky solid which was used in the next step without further purification. MS (ISP): 243.2 ([Trt]+)
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH2:23][C:24](O)=[O:25])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[N:40]1([C:45]([NH2:47])=[NH:46])[CH:44]=[CH:43][CH:42]=[N:41]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH2:23][C:24](=[O:25])[NH:47][C:45](=[NH:46])[N:40]3[CH:44]=[CH:43][CH:42]=[N:41]3)[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: N=C(N)n1cccn1
Reactant: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(=N)n2cccn2)cc1
Yield: 38.9 %

Procedure:
To 120 mg pyrrolyl acetic acid from Step 4 was added 97 mg (0.6 mmol, 5 equiv.) of carbonyldiimidazole and 2 mL CH2Cl2. The reaction was mixed at room temperature for one hour, upon which time was added 88 mg (5 equiv.) 1H-pyrazole-1-carboxamidine hydrochloride, 0.16 mL (10 equiv.) triethylamine, and a catalytic amount of 4-dimethylaminopyridine. The reaction was mixed at room temperature for one hour, filtered to remove any precipitates formed, and washed with water. The organic phase was separated from the aqueous phase and concentrated to afford 59 mg crude N-ethyl-4-(1-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-5-phenyl-1H-pyrrol-2-yl)-benzamide, which was used in the next step without purification.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(F)c(Cl)c2)CC1
Product: Fc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([C:14](OCC)=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].O>O1CCCC1.C(O)C>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccc(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a mixed solution of the compound (2.5 g, 8.0 mmol) obtained in Example 39a in tetrahydrofuran/ethanol (v/v=1/2, 36 mL) were added sodium tetrahydroborate (1.8 g, 48 mmol) and calcium chloride (5.4 g, 48 mmol), and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude title compound (1.4 g, 68%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[CH2:15]([N:17]([CH2:28][CH3:29])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:16].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CS(C)=O>[CH2:28]([N:17]([CH2:15][CH3:16])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:11]2[CH:12]=[CH:13][C:8]([S:5]([C:2]([F:4])([F:3])[F:1])(=[O:7])=[O:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:29]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: CCN(CC)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 100 °C
Yield: 88.2 %

Procedure:
To a solution of 4.6 g (0.0188 mole) of 4-chlorophenyl trifluoromethyl sulfone and 4.8 g (0.0210 mole) of N,N-diethyl-4-hydroxybenzenesulfonamide in 80 ml of DMSO was added 2.9 g (0.0210 mole) of K2CO3. The mixture was heated at 100° C. for 3.25 hrs and cooled. The mixture was poured into aqueous NaOH and the crystalline product collected by filtration, washed well with water and dried, which gave 7.25 g (88.2% yield) of product. Recrystallization from 2-propanol afforded purified N,N-diethyl-4-(4-((trifluoromethyl)sulfonyl)phenoxy)benzenesulfonamide, mp 83°-84° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:28][C:29]3[C:30]([CH2:35][OH:36])=[N:31][CH:32]=[CH:33][CH:34]=3)C(=O)OC(C)(C)C)[CH:17]=[CH:18][C:4]1=2)[CH3:2].Cl>C(O)C>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:28][C:29]3[C:30]([CH2:35][OH:36])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3cccnc3CO)C(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3cccnc3CO)ccc21
Temperature: 50 °C
Reaction time: 7 h
Yield: 56.5 %

Procedure:
To a ethanol solution (20 ml) of tert-butyl (1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl((2-(hydroxymethyl)pyridin-3-yl)methyl)carbamate (0.82 g) was added 5 M HCl and the mixture was stirred at 50° C. for 7 hours. The resulting mixture was concentrated and then 5 M NaOH was added thereto. Organic materials were extracted with ethyl acetate twice and then dried over MgSO4. After evaporation, the residue was purified by column chromatography (methanol/ethyl acetate 1:9→1:1) to give the titled compound as pale yellow oil (0.37 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:4]=1[C:5]([NH2:7])=O>C(OCC)C.ClCCCl>[NH2:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:4]=1[C:5]#[N:7]
Reactant: Cc1ccc(Cl)c(N)c1C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: Cc1ccc(Cl)c(N)c1C#N
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1.18 g (0.033 mol) of hydrogen chloride, dissolved in 35 ml of diethyl ether, were added at 22 to 30° C. with stirring to a suspension of 5 g (0.027 mol) of the compound from example 3 in 50 ml of 1,2-dichloroethane and the mixture was then concentrated in vacuo. The residue was treated with 150 ml of phosphorus oxychloride and the mixture was stirred at 120° C. for 3 h. The reaction mixture was then concentrated in vacuo, the residue was dissolved in methylene chloride, and the solution was treated with water and neutralized using 2 N sodium hydroxide solution. After the phase separation, the organic phase was again washed with water, then with saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, 2.4 g (48% of theory) of the title compound were obtained as a yellowish powder of m.p. 77-80° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+:15]>C(Cl)Cl.C1COCC1>[N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([O-:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+:15]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([O-])c1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
A commercially available dinitrophenol (10.0 g, 54.3 mmol) was dissolved in 250 mL of methylenechloride, and water was removed on anhydrous magnesium sulfate. Solvent was removed by filtration under the reduced pressure. After the anhydrous dinitrophenol (10.0 g, 54.3 mmol) was dissolved in anhydrous THF (300 mL), NaH(0.782 g, 32.6 mmol) was added slowly. After all NaH was added, the solution was stirred for 3 hrs. Solvent was removed under reduced pressure to obtain 60 mol % sodium dinitrophenolate.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:30]=[CH:29][CH:28]=[CH:27][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](O)([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[O:14])[CH:7]=[CH:6][C:5]=12.C[Si]([C:35]#[N:36])(C)C.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].O.O.[F-].[K+]>ClCCl.O>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:30]=[CH:29][CH:28]=[CH:27][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([C:35]#[N:36])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[O:14])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a solution of 2-(benzo[2,1,3]oxadiazol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide (300 mg, 0.74 mmol) in dichloromethane (1.5 ml) cooled to 0° C. was added trimethylsilyl cyanide (1 ml, 7.4 mmol) followed by slow addition of tin tetrachloride (7 drops of a 1.0 M solution in dichloromethane). The reaction mixture was allowed to warm to room temperature overnight. Potassium carbonate (300 mg, 2.10 mmol) and potassium fluoride dihydrate (120 mg, 2.10 mmol) were added, followed by dropwise addition of water. The reaction mixture was stirred vigorously for 90 m., after which silica gel was (600 mg) added. The mixture was filtered and washed thoroughly with dichloromethane. The filtrate was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to give 124 mg of a pale yellow solid. Product was recrystallized from ethyl acetate/hexane to afford 96 mg (31% yield) of a pale yellow solid.