Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][CH:9]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:10][N:11]([CH3:13])[CH3:12].Cl[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1(C)C=CC=CC=1.O>[CH3:8][CH:9]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:22]=2)=[CH:17][CH:16]=1)[CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: CC(CN(C)C)Oc1ccc(-c2n[nH]c3ncccc23)cc1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cn1nc(-c2ccc(OC(C)CN(C)C)cc2)c2cccnc21
Reaction time: 0.25 h

Procedure:
In 40 ml of toluene was suspended 2.3 g of 60% sodium hydride, and 40 ml of dimethylformamide was added to the suspension under ice-cooling. Thereto was added in the two or three times divided manner 14.8 g of 3-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine. After the mixture was stirred for 15 minutes, a solution of 7.0 g of ethyl chloroacetate in 70 ml of toluene was added dropwise. The mixture was stirred at room temperature for 1 hour, and then it was stirred at 40° C. for 1 hour. After cooling, water was added. The toluene layer was separated, washed with water and dried. Toluene was distilled off. The residue was purified by chromatography to give ethyl 3-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-1H-pyrazolo[3,4-b]-pyridin-1-ylacetate in an oily form.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:10]2([CH2:13][NH:12][CH2:11]2)[CH2:9][O:8]1.CO.CN(C=O)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:12]2[CH2:13][C:10]3([CH2:9][O:8][CH2:7]3)[CH2:11]2)=[N:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1NCC12COC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC3(COC3)C2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
Potassium carbonate (78 mg) and 2-oxa-6-azaspiro[3.3]heptane (30 mg) were added to a methanol/DMF (1 ml/2 ml) solution containing 2-chloro-5-nitropyridine (30 mg), followed by stirring at 80° C. for 3 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1 to 1:4), and a white solid of 6-(5-nitropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (23 mg) was thus obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[N:35]=2)[N:32]=1>CN(C)C(=O)C.O1CCCC1>[C:37]([NH:36][C:34]1[N:35]=[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]3[CH:24]=[C:23]([NH:22][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:9])[CH:44]=[CH:43][CH:42]=3)=[N:32][N:31]2[CH:33]=1)(=[O:41])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)C(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(C)C)cn4n3)c2)n(C)n1
Yield: 72.5 %

Procedure:
Using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (108 mg, 0.77 mmol), tetrahydrofuran (3.2 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (134 μL, 1.54 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylpropanamide (200 mg, 0.64 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 119, the title compound (201 mg, 72%) was obtained as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]1[C:18](=[O:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].[BH4-].[Na+].C(Cl)Cl>C(O)C>[CH3:3][CH:2]([CH2:4][C@H:5]1[C@H:18]([OH:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:1]
Reactant: COc1cc2c(cc1OC)[C@H]1CC(=O)[C@H](CC(C)C)CN1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@H]1C[C@@H](O)[C@H](CC(C)C)CN1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0.11 M solution of (+)-TBZ (15) in ethanol at 0° C. was added NaBH4 (2.85 eq). The reaction mixture was allowed to stir for 60 min. at room temperature. The solvent was carefully removed under reduced pressure, and the residue was taken up in dichloromethane and washed with three portions of saturated aqueous K2CO3. The aqueous washings were back extracted with two portions of dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to provide a colorless oil that crystallized on standing under high vacuum. Purification of the crude product was achieved by chromatography on SiO2 (2.5-5% MeOH—CH2Cl2, elution was observed at 285 nm) UV active fractions were reanalyzed by TLC. Two products, 18 and 19, were isolated from this procedure. The major product 18 was a colorless solid 74%: [α]26D +48 (c 0.30, CH2Cl2) 1H NMR (CD2Cl2) δ 0.93 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.04 (ddd, J=14.6, 8.7, 4.3 Hz, 1H), 1.42 (dd, J=20.2, 11.4 Hz, 1H), 1.59 (ddd, J=13.7, 9.6, 3.3 Hz, 1H), 1.64-1.78 (m, 2H), 1.96 (apparent t, J=11.4 Hz, 1H), 2.27 (br s, 1H), 2.40-2.48 (m, 1H), 2.54 (ddd, J=12.3, 3.7, 2.3 Hz, 1H), 2.60-2.67 (m, 1H), 2.95-3.09 (m, 3H), 3.11 (apparent d, J=11.1 Hz, 1H), 3.35 (ddd, J=10.4, 10.4, 4.5 Hz, 1H), 3.80-3.81 (m, 6H), 6.60 (s, 1H), 6.69 (s, 1H); 13C NMR (CD2Cl2) δ 21.61, 24.02, 25.33, 29.30, 39.68, 40.81, 41.58, 51.83, 55.74, 55.91, 60.02, 60.92, 74.32, 108.42, 111.73, 126.68, 129.76, 147.35, 147.61; HRMS-(ESI+) calcd for (C19H29NO3+H) ([M+H]+ 320.2226, found 320.2242. The minor product 19 was a yellow oil 4%: 1H NMR (CD2Cl2) δ 0.94 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.13-1.20 (m, 1H), 1.24-1.34 (m, 2H), 1.60-1.77 (m, 2H), 1.89-2.00 (m, 1H) 2.36-2.44 (m, 2H), 2.53 (ddd, J=10.5, 10.5, 3.8 Hz, 1H), 2.58-2.70 (m, 2H), 2.91-2.98 (m, 1H), 2.98-3.09 (m, 1H), 3.48 (apparent d, J=11.6 Hz, 1H), 3.80-3.82 (apparent s, 6H), 4.07 (apparent d, J=3.1 Hz, 1H), 6.60 (s, 1H), 6.68 (s, 1H); 13C NMR (CD2Cl2) δ 22.74, 22.81, 24.87, 29.30, 37.83, 38.87, 39.42, 52.44, 55.76, 55.96, 56.32, 56.43, 67.88, 108.45, 111.78, 127.18, 130.38, 147.30, 147.54.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=3)[CH2:23]2)=[O:21])[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:29][N:28]=3)[CH2:25]2)=[O:21])[N:14]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(Br)cn2)C1
Reactant: COc1cccc(B(O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc(OC3CN(C(=O)Nc4cccnn4)C3)nc2)c1F
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A solution of 2-fluoro-3-methoxyphenyl boronic acid (0.065 g, 0.38 mmol) in THF/H2O (10:1; 2 mL) was added to a microwave vial containing 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (prepared in Step 1) (0.100 g, 0.25 mmol) and potassium carbonate (0.105 g, 0.76 mmol). Nitrogen gas was bubbled through the mixture for 5 mins then 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.020 g, 10 mole %) was added and the vial sealed and heated at 100° C. in microwave synthesiser for 30 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with sat. aqueous sodium carbonate solution (20 mL) then sat. sodium chloride solution (20 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a brown gum, which was purified by flash chromatography, eluting with a gradient of 80 to 100% ethyl acetate in hexane to a afford an off-white solid (0.079 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[CH:35](N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][N:23]([CH3:35])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CNC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C)C1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
The hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylazetidine-3-carboxamide (110 mg, 0.22 mmol Example 99), formaldehyde (54 μl of a 37% wt aqueous solution, 0.67 mmol) and diisopropylethylamine (78 μl, 0.45 mmol) were stirred at room temperature in 5% acetic acid in 1,2-dichloroethane (2 ml) with 3 Å molecular sieves. Sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added portionwise over 0.5 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and the residues purified preparative HPLC (standard basic conditions) to give the title product (68 mg, 65%) as a white powder. 1H NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.45 (m, 3H), 2.89 (s, 3H), 3.39 (brs, 2H), 3.60 (d, 2H), 3.95 (s, 2H), 3.98 (s, 3H), 7.17 (m, 2H), 7.25 (s, 1H), 7.44 (brs, 1H), 7.84 (brs, 1H), 8.00 (s, 1H), 8.51 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 473.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[C:14]1([C:20]2[N:21]=[C:22]([CH:31]([NH2:33])[CH3:32])[O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]1([C:20]2[N:21]=[C:22]([CH:31]([NH:33][CH:8]3[C:9]4[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)[CH3:32])[O:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(N)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1cccc2c1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (0.67 g), 1-(4,5-diphenyloxazol-2-yl)ethylamine (0.98 g) and p-toluenesulfonic acid (catalytic amount) in toluene (30 ml) was refluxed for 7 hours with Dean-stark equipment. The solution was evaporated in vacuo and methanol (MeOH) (10 ml) was added to the residue. To the MeOH solution, NaBH4 (0.21 g) was added at 0° C. After being stirred for 2 hours at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.73 g). MS (m/z): 425 (M+ +1) NMR (CDCl3, δ): 1.60 (3H, d, J=6.8 Hz), 1.60-2.08 (6H, m), 2.42-2.86 (2H, m), 3.80 (1.5H, s), 3.81 (0.5H, q, J=6.8 Hz), 3.82 (1.5H, s), 3.90 (0.5H, m), 4.29 (0.5H, q, J=6.8 Hz), 4.77 (0.5H, m), 6.73 (1H, m), 7.00-7.20 (2H, m), 7.33-7.39 (6H, m), 7.57-7.68 (4H, m)
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=4)[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)COc1ccc2c(c1)-c1nc(S)sc1CC2
Reactant: BrC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1ccc2c(c1)-c1nc(SC(c3ccccc3)c3ccccc3)sc1CC2
Yield: 90 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate and bromodiphenylmethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([OH:18])[N:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)O)[CH:23]=[CH:22][N:21]=[CH:20]1.FC1C=CC(CCC2C=CC(OC(C3C=CC(F)=CC=3)CC3N(C)C=NC=3)=CC=2C([O-])=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([O:18][CH:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:24][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: OC(Cn1ccnc1)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(O)nc1-c1ccc(F)cc1
Agent: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)[O-])c1)c1ccc(F)cc1
Product: COC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)nc1-c1ccc(F)cc1

Procedure:
Methyl 2-(4-fluorophenyl)-6-hydroxypyridin-3-carboxylate was reacted with 2-(imidazol-1-yl)-1-(4-fluorophenyl)ethanol by the procedure described for the preparation of 2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoate to give methyl 2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]pyridin-3-carboxylate.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:14]([C:15](=[O:24])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:12]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][N:10]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:17]([NH:16][C:15]([C:14]1[C:9]([O:8][CH2:7][C:6]([OH:35])=[O:5])=[N:10][CH:11]=[C:12]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:13]=1)=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)COc1ncc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)COc1ncc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1
Yield: 67.5 %

Procedure:
A solution of 0.25 g (0.53 mmol) (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl ester in 10 ml 50% trifluoroacetic acid in CHCl3 was stirred for 3 hours at room temperature. The reaction mixture was then concentrated at reduced pressure to obtain a solid. The solid was slurried in ethyl acetate, filtered, washed with ethyl acetate, and then dried at 55° C. at reduced pressure overnight. 0.15 g (68% yield) of the title compound. MS: m/z (APCI, AP+) 420 [M−]+. CHN Analysis: Calcd: C, 65.86; H, 5.05; N, 10.02. Found: C, 65.73; H, 5.08; N, 9.86.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 1-phenylpiperazine 2 (2.59 g, 15.98 mmol) was reacted with N-(2-bromoethyl)phthalimide (8.12 g, 31.96 mmol), Et3N (2.0 mL) and K2CO3 (8.0 g) in DMF (40 mL) and stirred at 70° C. under N2 overnight. After the reaction mixture was cooled down, water (100 mL) was added. The mixture was extracted with diethyl ether. The organic phase was combined and dried over Na2SO4. The solvent was removed under vacuo to give the crude product, which was purified by flash chromatography (Hexane/EtOac=1/1) to furnish 3a, 3.81 g (71%) 1HNMR (CDCl3) 2.68-2.72 (m, 6H, N(CH2)2, CONCH2), 3.12-3.15 (t, J=4.8 Hz, 4H, N(CH2)2), 3.84-3.89 (t, J=6.3 Hz, 2H), 6.80-6.82 (t, J=8.1 Hz, 1H, Ar—H), 6.88-6.91 (d, J=8.1 Hz, 2H, Ar—H), 7.21-7.26 (t, J=8.1 Hz, 2H, Ar—H), 7.69-7.86 (m, 4H, Ar—H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:16])[C:7]=2[CH:17]=1)#[N:2].S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([O:16][CH3:22])[C:7]=2[CH:17]=1)#[N:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1oc2ccc(C#N)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2ccc(C#N)cc2c1OC
Yield: 90.9 %

Procedure:
Ethyl 5-cyano-3-hydroxy-2-benzofurancarboxylate (200 mg, 0.866 mmol), dimethyl sulfate (131 mg, 1.04 mmol) and potassium carbonate (132 mg, 0.953 mmol) were added to acetone (140 ml), and the mixture was refluxed under heating for 1.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and water (200 ml) was added to the residue, which was followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 193 mg of ethyl 5-cyano-3-methoxy-2-benzofurancarboxylate (91%). The obtained compound (170 mg, 0.694 mmol) was dissolved in methanol (5 ml) and potassium hydroxide (160 mg, 2.86 mmol) was added, which was followed by refluxing under heating for 45 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure and IN hydrochloric acid was added to the residue to adjust the pH to 2-3. The resulting precipitate was collected by filtration to give 123 mg of 5-cyano-3-methoxy-2-benzofurancarboxylic acid as a colorless solid (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)cc1
Yield: 56.5 %

Procedure:
This product was prepared by a modification of the general procedure described in Diana et al. J.Med.Chem. 1995, 38, 1355. A mixture of 4-chlorobenzonitrile (5 g, 36.34 mmol), EtOH (90 mL), hydroxylamine hydrochloride (2.52 g, 36.34 mmol) and K2CO3 (2.51 g, 18.17 mmol) was refluxed for 20 h. The reaction mixture was concentrated, cold water was added, and it was filtered and dried to give 4-chlorobenzoamidoxime as a white solid (3.5 g, 56%). Next, this product (1.7 g, 10 mmol) was taken up in pyridine (34 mL) and treated with ethyl oxalyl chloride (2.22 mL, 20 mmol) at 0° C. The reaction mixture was stirred for 1 h, then poured into pH 7 phosphate buffer, concentrated and partitioned between CHCl3 and water. The organic phase was washed with 10% aqueous NaHCO3 solution, dried over Na2SO4, filtered, concentrated and purified by flash chromatography to give ethyl 3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carboxylate as an amorphous solid (2.14 g, 85%): 1H NMR (300 MHz, CDCl3) δ (TMS) 8.18 (dt, Jt =2.2, Jd =8.6, 2H, arom), 7.56 (dt, Jt =2.2, Jd =8.6, 2H, arom), 4.66 (q, J=7.1, 2H, OCH2), 1.57 (t, J=7.1, 3H, OCH2CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.O.NN>CCO.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Sc3ccccc3)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Sc3ccccc3)c(N)c2)CC1
Reaction time: 2 h
Yield: 102.4 %

Procedure:
To a solution of tert-butyl 4-[3-nitro-4-(phenylsulfanyl)phenyl]-1-piperazinecarboxylate (1.7 g, 3.8 mmol) in 42 mL of a 4:1 EtOH:THF solvent system is added Raney nickel (260 mg suspension in EtOH) followed by hydrazine monohydrate (0.92 mL, 19 mmol). The mixture is stirred vigorously for 2 h and then filtered through celite that is pretreated with water. The filtrate is concentrated, the residue crystallized from MeOH/EtOAc/hexane to give 1.5 g (92%) of the aniline as a white foam.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH:3]([OH:6])[CH2:4][CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH:2]([CH:3]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4][CH3:5])[CH3:1])(=[O:18])=[O:17]
Reactant: CCC(O)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Pentane-2,3-diol 1.04 g (10.0 mole) and triethylamine 2.23 g (22.0 mole) were dissolved in 40 mL of methylene chloride, and methanesulfonyl chloride 2.52 g (22.0 mole) was dropwise added thereto in a range of 0 to 5° C. and stirred at 0° C. for 30 minutes. After the raw materials were confirmed to be exhausted by gas chromatography analysis, the organic layer was washed with 20 ml of water and then 20 ml of a saturated salt solution. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was refined by column chromatography (Wako Gel C-200, hexane/ethyl acetate=2/1 eluted) to obtain 2.24 g of pentane-2,3-diyl dimethanesulfonate (pale orange liquid; novel compound) which was the targeted product (yield: 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[C:6]([NH2:15])[CH:5]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[C:6]([N:15]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])[CH:5]=1
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)c1cc(N)c(Cl)c(S(N)(=O)=O)c1
Solvent: CO
Product: COC(=O)c1cc(N2C(=O)CCC2=O)c(Cl)c(S(N)(=O)=O)c1
Reaction time: 6 h

Procedure:
25.4 g of 4-chloro-3-amino-5-sulphamylbenzoic acid methyl ester, m.p. 195°-196° C., are thoroughly mixed with 25 g of succinic acid anhydride and melted for 6 hours at 180° C. The melt is allowed to cool slowly and CH3OH is added carefully. The product crystallises. A small amount of water added completes the crystallisation.