Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[CH:18]=[O:19].[H-].[Na+].Cl>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:17]([CH:18]=[O:19])[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: O=C(O)Cc1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
3-Hydroxyphenylacetic acid (3 g, 19.7 mmol) and 5-bromo-2-fluorobenzaldehyde (2.34 mL, 19.7 mmol) were combined in DMF (60 mL). Sodium hydride (60% in mineral oil; 1.58 g, 39.4 mmol) was added portionwise, and the reaction was stirred at 70° C. for 3 hours. Additional 5-bromo-2-fluorobenzaldehyde (2.34 mL, 19.7 mmol) and sodium hydride (60% in mineral oil; 0.79 g, 19.7 mmol) were added, and the reaction was stirred at 70° C. for 3 hours. The mixture was acidified with 1N aqueous HCl to pH 3-4 and extracted with EtOAc, and the combined organic layers were washed three times with H2O, dried and concentrated. The residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the desired product (2.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[F:12][C:13]1[CH:14]=[C:15]([S:27](Cl)(=[O:29])=[O:28])[CH:16]=[C:17]([N+:24]([O-:26])=[O:25])[C:18]=1[O:19][C:20]([F:23])([F:22])[F:21]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:27]([C:15]2[CH:16]=[C:17]([N+:24]([O-:26])=[O:25])[C:18]([O:19][C:20]([F:21])([F:22])[F:23])=[C:13]([F:12])[CH:14]=2)(=[O:29])=[O:28])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)cc(F)c1OC(F)(F)F
Reactant: COc1ccc(N)cc1OC
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2cc(F)c(OC(F)(F)F)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,4-Dimethoxyaniline (1.53 g, 10 mmol) is added to a solution of 3-fluoro-5-nitro-4-trifluoromethoxyphenylsulfonyl chloride (2.87 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After stirring at room temperature for 15 min, the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provides the title compound.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[OH:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])=[O:18]
Reactant: COC(=O)c1ccccc1O
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (5.0 g, 27.0 mmol), methyl 2-hydroxybenzoate (4.11 g, 27.0 mmol) and Cs2CO3 (18.49 g, 56.7 mmol) were dissolved in acetonitrile (100 mL) and stirred at 80° C. for 3 h. The reaction mixture was diluted with AcOEt and washed with 1M HCl and water. The organic layer was separated, dried with Na2SO4, filtered and concentrated via rotary evaporation to afford the title compound 545 (7.55 g, 88%) as a light yellow foam.
Reaction SMILES: [CH3:1][NH2:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:17][S:18]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:20])=[O:19].[OH-].[Na+]>CC#N>[CH3:1][NH:2][CH:24]1[CH2:25][CH2:26][N:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CNC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1-Methylsuylfonyl-4-piperidone (40.00 g, 0.226 mol), CH3CN (240 ml) and 40% CH3NH2 (20.4 ml, 0.263 mol) were added to a round bottom flask, and the mixture was stirred at room temperature for 1 hour. To another round bottom flask, NaBH(OAc)3 (60.00 g, 0.283 mol) and 120 ml of CH3CN were added. This solution was stirred at −10° C., to which the first mixture (derived from 1-methylsulfonyl-4-piperidone) was added slowly via an additional funnel. After the addition, the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentarted to a small volume, to which 1N aq. NaOH (282 ml) was added. This resulting solution was extracted with CH2Cl2 (3×500 ml) followed by extraction with toluene until no product remained in the extraction solution. The combined organic layers were dried over Na2SO4. After filtration, the solution was concentrated in vacuo to give the product (29.0 g, 63%). 1H NMR (CDCl3) δ 3.66 (m, 2H), 2.84 (m, 2H), 2.76 (s, 3H), 2.52 (m, 1H), 2.42 (s, 3H), 1.96 (m, 2H), 1.45 (m, 2H). MS m/e 193 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:19]=[C:20]([NH:21]C(=O)C(F)(F)F)[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.C(N(CC)CC)C>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:19]=[C:20]([NH2:21])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a suspension of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2,2,2-trifluoro-acetamide (106.65 mmol) in methanol (500 mL), triethylamine (150 mL) was added and the mixture was refluxed for 36 hours and then evaporated to dryness. The crude was treated with a mixture of diethylether (400 mL) and methanol (100 mL), stirred at room temperature for 30 min., filtered and washed with diethylether. After drying in vacuo the title compound was obtained as white solid (50.5 g, 86%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([C:18]=2[CH:20]=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH:16]1[C:17]2[C:12](=[CH:11][C:10]3[C:19]([C:18]=2[CH2:20][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCCNCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred solution of 3-amino -1-propanol, 15a (0.87 g, 11.65 mmol) in 25% MeOH/CH2Cl2 (20 mL), was added a solution of aldehyde 8 (2.00 g, 9.7 mmol) in 25% MeOH/CH2Cl2 (15 mL) under N2. The mixture was stirred at room temperature overnight until the imine formation was complete (monitored by NMR). The solvent was removed in vacuo, the solid residue dissolved in 50% MeOH/CH2Cl2 (40 mL) and the solution was cooled to 0° C. NaBH4 (29.1 mmol) was added in small portions to the solution and the mixture was stirred at rt overnight. The solvent was removed in vacuo, the solid residue dissolved in CH2Cl2 (40 mL) and washed with 10% aq. Na2CO3 solution (3×30 mL). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and removed in vacuo to give an oily residue. The oil was purified by flash column chromatography (6% MeOH/CHCl3) to yield the product 14a as a pale yellow thick oil (78%), Rf=0.3 (6% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.27 (d, 2H), 7.99 (d, 2H), 7.52 (m, 2H), 7.45 (m, 2H), 4.71 (s, 2H), 3.79 (t, 2H), 3.09 (t, 2H), 1.74 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]#[N:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]3[NH:24][N:25]=[N:26][N:22]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)ccc1-c1cc(C#N)sc1-c1ccc(Cl)cc1C
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1cc(Cl)ccc1-c1cc(-c2nnn[nH]2)sc1-c1ccc(Cl)cc1C
Temperature: 110 °C
Yield: 90 %

Procedure:
A round-bottomed flask was charged with 4,5-bis(4-chloro-2-methylphenyl)thiophene-2-carbonitrile (600 mg, 1.67 mmol), zinc bromide (945 mg, 4.20 mmol) and sodium azide (273 mg, 4.20 mmol). After degassed, DMF (5 mL) was added. The reaction mixture was heated to 110° C. and stirred at this temperature until complete. The reaction was cooled to rt, and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 603 mg (90%) of product was obtained as a white solid, 1H NMR (DMSO, 500 MHz) δ 7.82 (s, 1H), 7.36 (d, J=2.04 Hz, 1H), 7.34 (d, J=1.94 Hz, 1H), 7.31 (d, J=8.25 Hz, 1H), 7.28 (dd, J1=8.26 Hz, J2=1.99 Hz, 1H), 7.17 (dd, J1=8.20 Hz, J2=2.05 Hz, 1H), 7.02 (d, J=8.28 Hz, 1H), 2.17 (s, 3H), 2.03 (s, 3H); 13C NMR (DMSO, 125 MHz) δ 140.58, 139.14, 139.12, 138.19, 133.59, 133.39, 132.94, 132.47, 131.71, 131.17, 130.57, 130.17, 130.11, 126.00, 125.80, 19.69, 19.57.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].[BH4-].[Na+]>ClCCCl.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH3:14])[OH:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)N1CCc2cc(C(C)O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
1-Acetyl-2,3-dihydro-1H-indole (16.1 g, 0.1 mol) in 1,2-dichloroethane (60 ml) was added dropwise to refluxing mixture of acetyl chloride (21.33 ml, 23.55 g, 0.3 mol) and aluminum chloride (40.0 g, 0.3 mol) in 1,2-dichloroethane (40 ml). The mixture was heated under reflux for 2 hours, cooled and poured onto crushed ice (1 Kg). The mixture was extracted with dichloromethane (3×500 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. Ethanol (400 ml) was added and the mixture was cooled in a water bath. Sodium borohydride (7.57 g, 0.2 mol) was added and the mixture was stirred for 1 hour. Water (100 ml) was added and the ethanol was evaporated under reduced pressure. Water (500 ml) was added and the mixture was extracted with dichloromethane (3×500 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the alcohol as an off-white solid (18.43 g, 90%).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>ClCCl>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 1.5 g of triethylamine in 20 ml of dichloromethane is added a solution of 2.11 g of 6-chloropyridine-3-carbonyl chloride in 5 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature diluted with 20 ml of dichloromethane and washed with 30 ml of 1N NaOH. The organic layer is washed twice with 20 ml of 1N NaOH, dried (Na2SO4) and the solvent removed. The residue is triturated with ether to give 3 g of solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1)=[O:16].O>CN(C=O)C>[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=3[CH:11]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: CNC(=O)c1cc(Cl)ccn1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2)ccn1
Temperature: 70 °C
Yield: 61.4 %

Procedure:
To the solution of 2-methylsulfanyl-benzothiazol-6-ol (3.76 g, 19.08 mmol, 1.0 eq) in DMF (25 mL), was added CsCO3 (15.54 g, 47.70 mmol, 2.5 eq) at room temperature. After stirring for a while, 4-chloro-pyridine-2-carboxylic acid methylamide (4.86 g, 28.62 mmol, 1.5 eq) was added to the mixture and the mixture was stirred at 70° C. under reflux condenser overnight. After cooling the reaction mixture in ice bath, water (100 mL) was added and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified using 20 g of ISCO Silica Gel column (0%-50%-80%-100% ethyl acetate-hexane mixture over 45 min 40 mL/min run) to yield 4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (3.88 g, 62%) as a white solid. M+H=332.1
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Cl.[I-].[Na+]>CN(C)C=O>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3Cc3ccccn3)c2c1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a stirred solution of 5-(2-ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation 5; 150 mg, 0.47 mmol) in dry dimethylformamide (4 ml) at room temperature under nitrogen were added, sequentially, anhydrous sodium carbonate (110 mg, 1.04 mmol), 2-pyridylmethyl chloride hydrochloride (85 mg, 0.52 mmol) and sodium iodide (10 mg). The resulting mixture was heated at 100° C. for 18 hours, then allowed to cool to room temperature. It was then partitioned between ethyl acetate and water, and the organic phase separated, washed with water (3×), dried (Na2SO4), and evaporated under reduced pressure to give an oil. Purification by column chromatography on silica gel, eluting with an ethanol in dichloromethane gradient (0 to 5% ethanol), afforded the title compound as a gum (62 mg). [α]D25 +22° (c=0.1, CH3OH). Found: C,59.89; H,6.44; N,9.07. C23H29N3O2S; 0.75 CH2Cl2 requires C,60.02; H,6.47; N,8.84%. δCDCl3): 1.35(3H,t), 1.50-1.90(4H,m), 2.30-2.40(1H,m), 2.65-2.75(1H,m), 2.90(3H,q and m), 3.00-3.20(2H,m), 3.20-3.30(4H,m), 3.60(1H,d), 4.28(1H,d), 5.30(1.5H,s,CH2Cl2), 7.02(1H,d), 7.05(1H,s), 7.16-7.20(1H,dd), 7.30(1H,d), 7.40(1H,s), 7.50(1H,d), 7.70(1H,dd), 8.14(1H,br s), 8.58(1H,d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17].O>Cl.C(O)C>[CH3:12][C:13]1[NH:10][C:7]2[C:8]([C:14]=1[CH2:15][CH2:16][CH3:17])=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2
Reactant: CCCCC(C)=O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCc1c(C)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 200 ml 2-neck round bottom flask, equipped with a magnetic stirrer and a cold water condenser, 4-nitrophenylhydrazine was dissolved in 75 mL concentrated hydrochloric acid and stirred at room temperature for 15 minutes. A solution of 2-hexanone (5 mL) in ethanol (25 mL) was added slowly and the reaction flask was heated in an oil bath at 105° C. for 18 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc. The organic layer washed with saturated sodium bicarbonate solution, water, and brine solutions and evaporated to dryness. The oily residue was absorbed on silica gel and purified by silica gel chromatography with 20% EtOAc in Hexane solution to give 2-methyl-5-nitro-3-propyl-1H-indole. This indole product was dissolved in trifluoroacetic acid (10 mL) and 1 pellet sodium borohydride (0.7 g) was added and the reaction was stirred at room temperature for 18 h. Water (10 mL) was carefully added and the reaction mixture was extracted twice with EtOAc (15 mL). The organic layer washed with brine and dried over MgSO4, and purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexanes to give 280 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=[C:8]3[CH:7]=2)=[N:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=[C:8]3[CH:7]=2)=[N:2]1
Reactant: CCOC(=O)c1cnc2cc(-c3cc[nH]n3)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(-c3cc[nH]n3)ccn12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of ethyl 7-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxylate (62) (103 mg, 0.4 mmol) in THF:MeOH:H2O (3:2:1, 1.6 mL) was added 6N LiOH (0.035 mL). The reaction was stirred at room temperature for 20 minutes. The pH was adjusted between 4-5 with 3N HCl. The resulting mixture was concentrated to yield 7-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (63). MS (m/z) 229.2 (M+1)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>[Pd]>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOc3ccccc3)cc2)C(O)C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] with (E)-(4-bromo-but-2-enyloxy)-benzene there was obtained tert-butyl (E)-(3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate. Subsequent hydrogenation with palladium/charcoal analogously to Example 73 (c) yielded tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 1 (g) gave tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 582 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:14]C.[CH3:16][CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][C:19](=O)[CH2:18]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:14][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([O:8][C:19]1[CH2:18][CH:17]([CH3:16])[CH2:22][C:21](=[O:23])[CH:20]=1)=[O:7]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: CNc1c(Cl)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1CC(=O)C=C(OC(=O)c2ccc(Cl)c(N)c2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (1.1 mmol) of 4-chloro-3-(methylamino)-2-nitrobenzoic acid, 410.3 mg (3.3 mmol) of 5-methylcyclohexane-1,3-dione, 275.7 mg (1.4 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 13.5 mg (0.1 mmol) of 4-(dimethylamino)pyridine were dissolved in 6 ml of methylene dichloride and stirred at RT for 8 h. This was followed by washing with water and saturated NaHCO3 solution, after which the organic phase was dried over MgSO4 and then the whole was filtered through a small glass frit filled with 1 cm of silica gel, with suction, and the filter product was washed with heptane/ethyl acetate 1:2. The filtrate was concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl.Cl[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: ClCc1cccnc1
Agent: Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2cccnc2)c1=O
Yield: 38.5 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 3-(chloromethyl)pyridine hydrochloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 38.5%.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[S:6][CH2:5][CH2:4][N:3]3[CH:2]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:17]2[C:16](=[O:27])[NH:15][C:14](=[O:28])[C:13]=2[C:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[S:6](=[O:37])[CH2:5][CH2:4][N:3]4[CH:2]=2)=[CH:19]1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)SCC3)=C1c1c[nH]c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)S(=O)CC3)=C1c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(3,4-Dihydro-5-thia-2a-aza-acenaphthylen-1-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (0.50 g, 1.3 mmol) in dichloromethane was added meta-chloroperbenzoic acid (0.224 g, 1.3 mmol) at 0° C. The reaction mixture was stirred for 24 hours at room temperature and a saturated solution of sodium bisulfite and sodium bicarbonate (20 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL). The organic layer was subjected to silica gel chromatography, eluting with ethyl acetate/hexanes (1:1). Fractions containing product were combined and concentrated under reduced pressure to provide 0.168 g (32.3%).of the title compound.