Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.4 %

Procedure:
To a solution of 4-aminophenol (4.27 g, 39.1 mmol) in DMF (50 ml) at 0° C. under an atmosphere of argon was added triethylamine (7.44 ml, 53.4 mmol, 1.5 eq). The reaction mixture was stirred for 10 minutes before slow addition of benzoyl chloride (5 g, 35.6 mmol, 1 eq) over a period of 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred over 18 hours. The DMF was removed under reduced pressure and the mixture was treated with ethyl acetate/water. Precipitation of a white solid resulted, which was filtered off and dried under reduced pressure. The title compound (8.0 g) was isolated in 96% yield.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.II.[I:14](O)(=O)(=O)=O.C(O)(=O)C.O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:6]=[C:5]([I:14])[S:4][C:3]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: Brc1ccsc1-c1nnc[nH]1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(I)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a mixture of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (1.12 g, 4.87 mmol), iodine (1.12 g, 4.41 mmol) and periodic acid (4.80 g, 24.8 mmol) in acetic acid (11.0 mL, 200 mmol) were added water (8.0 mL, 400 mmol) and sulfuric acid (2.0 mL, 40 mmol) and the reaction mixture was stirred at rt for two days. The resulting white precipitate was collected by filtration. The solid cake was washed with water and dried under high vacuum at 40° C. to yield product as a white solid (1.74 g, 100% yield, as a white solid). LCMS: (FA) ES+, 357.7. 1H NMR (400 MHz, d6-DMSO) δ: 8.63 (s, 1H), 7.43 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].[NH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Li+].[OH-].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([OH:20])=[O:19])=[O:9])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: COC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NC(C)(C)C(=O)O)cc1OCC
Reaction time: 48 h

Procedure:
210 mg of 3,4-diethoxybenzoic acid and 160 mg of methyl aminoisobutyrate were stirred in 3 ml of DMF at room temperature. It was treated with 440 mg of HATU and 0.4 ml of DIEA at the same temperature and the reaction was stirred for 2 days. The reaction was monitored by LC-MS, which indicated complete consumption of the starting materials. Product LC-MS (m/z 310.1). This crude reaction mixture was then diluted with 3 ml of water followed by an addition of 250 mg of LiOH. The reaction mixture was stirred at room temperature overnight and the LC-MS analysis indicated the reaction was completed. The reaction mixture was neutralized by 6N-HCl and the resulting creamy precipitates were collected by filtration and washed with water (50 ml). Drying the filter cake yielded the title compound. m/z 296.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH:38]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39]1.C(N(CC)CC)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:38]1([CH2:41][C:42]([NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)=[O:43])[CH2:40][CH2:39]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl (6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (11, 500 mg, 0.95 mmol), cyclopropylacetic acid (115 mg, 1.149 mmol) and triethylamine (400 μL, 2.86 mmol) in DMF (10 mL) under nitrogen were added HOBT hydrate (161 mg, 1.05 mmol) and EDC hydrochloride (457 mg, 2.38 mmol) reagents, and the reaction mixture was stirred at RT overnight. More cyclopropylacetic acid (115 mg, 1.149 mmol) and EDC hydrochloride (500 mg, 2.61 mmol) were added, and the reaction mixture was stirred at RT overnight. The reaction mixture was then quenched by addition of water and extracted with AcOEt. The organic layer was successively washed with water (×2), a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (SiliaFlash 40 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV and SiliaFlash 40 g; MeOH/DCM: 0/100 to 5/95 over 20 CV, then 5/95 to 10/90 over 10 CV), to afford the title compound 12 as pale yellow sticky solid. The material was used in the next step without any further purification. MS (m/z): 607.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:34]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:33]3[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:34]3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCN(C[C@H]2OCCN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMF (5 mL) were added potassium carbonate (170 mg), sodium iodide (190 mg) and methyl piperidine-4-carboxylate (88 mg), and the mixture was stirred at 100° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (110 mg).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(Cc2ccc(F)cc2)CC1

Procedure:
To 10 mmol of piperidin-4-one hydrochloride monohydrate and 20 mmol of triethylamine, dissolved in dichloromethane, there are slowly added 10 mmol of 4-fluorobenzyl chloride; the reaction mixture is then heated at reflux of the solvent for 48 hours, with vigorous stirring. After returning to ambient temperature, water is added and then, after separation of the phases, the organic phase is dried, filtered and concentrated in vacuo to yield the expected product in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:20]=2[N:19]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:18]2[NH:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:21]=3[N:22]=2)[C@H:10]([CH3:14])[CH2:9]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol from step (a) above (96 mg, 0.4 mmol) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (71 mg, 0.32 mmol, Example 1c) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1ccc([C@@H]2C[C@H]2NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and pyridine-2-carbaldehyde (0.17 mL, 1.80 mmol) in CH2Cl2 (12 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.48 g, 2.25 mmol) was slowly added and stirring continued for 2 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel [4% MeOH+1% NH3 (aq)/CH2Cl2] followed by preparative layer chromatography (5% MeOH/CH2Cl2) affording 0.08 g of N-[(trans)-2-phenylcyclopropyl]-N-(pyridin-2-ylmethyl)amine [Rf=0.3 (5% MeOH/CH2Cl2), colorless oil, 24% yield]. 1H-NMR (CDCl3, 250 MHz, δ): 8.60-8.54 (m, 1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H, ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m, 1H, CH2).
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:14].O1CCCC1.[H-].[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[C:22]([NH:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[CH3:13])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c(NC(=O)OCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-amino-3,5-dimethylbenzoate (2.0 g) was added to a tetrahydrofuran (THF) suspension of sodium hydride (0.82 g) in a nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. Subsequently, carbobenzoxychloride (4.4 ml) was added to the suspension and the mixture was stirred overnight. A small amount of water was added to the reaction solution and the mixture was poured into ice water, followed by extraction with ethyl acetate. Following washing and drying (with magnesium sulfate), the solvent was distilled off under vacuum. The resulting crystal was recovered by filtration in the presence of ethanol and dried under vacuum to yield the end product (3.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C>[CH2:11]([O:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)[CH3:12]
Reactant: CC[O-]
Reactant: CSc1nccc(Cl)n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(SC)n1
Temperature: 60 °C
Reaction time: 10 h
Yield: 94.4 %

Procedure:
4-Chloro-2-(methylthio)pyrimidine (3.0 g) was dissolved in ethanol (30 mL), sodium ethoxide (2.54 g) was added, and the mixture was stirred at 60° C. for 10 hr. The reaction mixture was cooled, and the solvent was concentrated under reduced pressure. Water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.0 g) as a slightly yellow oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH2:11]1[CH2:19][O:18][C:17]2[C:13](=[CH:14][NH:15][CH:16]=2)[O:12]1.[OH-].[Na+]>C(Cl)Cl>[CH:9]([C:14]1[NH:15][CH:16]=[C:17]2[O:18][CH2:19][CH2:11][O:12][C:13]=12)=[O:10]
Reactant: CN(C)C=O
Reactant: c1[nH]cc2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]cc2c1OCCO2
Reaction time: 12 h
Yield: 94.2 %

Procedure:
POCl3 (1.67 g, 10.92 mmol) was added to a solution of DMF (0.84 g, 11.44 mmol) in methylene chloride (5.0 mL) at 0° C. and the reaction mixture allowed to come to room temperature. The reaction mixture was then slowly added to a solution of 3,4-ethylenedioxypyrrole (1.3 g, 10.40 mmol) in methylene chloride (5.0 mL) at 0° C. and allowed to come to room temperature. After stirring for 12 h, an excess of 3.0 M NaOH solution was added and stirred for 2 h in a hot water bath. The reaction mixture was extracted with methylene chloride (40 mL×3) and the combined organic layers were dried over MgSO4. Purification of the residue was accomplished by chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to afford the product as a white solid (1.5 g, 65%): mp 147° C.; 1H NMR (300 MHz, CDCl3) δ9.43 (s, 1H), 9.02 (br, 1H), 6.62 (d, J=3.8 Hz, 1H), 4.24 (m, 4H); Anal. Calcd for C7H7NO3: C, 54.90; H, 4.61; N, 9.15. Found: C, 55.03; H, 4.48; N, 9.14.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].CS(O[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]=[O:22])(=O)=O>CN(C)C=O>[CH2:7]([N:6]([CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]=[O:22])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reactant: CCCCCNCCCCC
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)Cc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of dipentylamine (258 mg) and diiosopropylethylamine (212 mg) in dimethylformamide (2 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (350 mg). After stirring at room temperature for 2 weeks, the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash column chromatography using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give 3-[(dipentylamino)methyl]-4-phenylmethoxybenzaldehyde (356 mg) as a gum. 1H NMR (CDCl3) δ9.90 (s, 1H, CHO); 5.15 (s, 2H); 3.70 (s, 2H); 2.50 (m, 4H); 1.55 (m, 4H); 1.30(m, 8H); 0.90 (t, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[N:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(O)CO>[N:4]1[C:3]([CH2:2][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH2:24])=[O:23])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Yield: 63.5 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 2-(chloromethyl)imidazo[1,2-a]pyridine (Example 2, Step 1; 0.245 g), 4-(piperazin-1-yl)benzamide (0.302 g), diisopropylethylamine (Aldrich; 0.256 mL), and ethylene glycol (2 mL) gives 0.313 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 8/92, as eluent) and crystallization from methanol/dichloromethane; mp 249-250° C.; IR (mineral oil) 1608, 1398, 1253, 1739, 3133, 756 cm-1. 1H NMR (CDCl3) δ2.74, 3.36, 3.78, 5.7, 6.78, 6.88, 7.16, 7.55, 7.58, 7.71, 8.09.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:22]#[C:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[O:15]=[C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[C:22]#[C:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.4 g (36 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride, 6.9 g (29.7 mmol) of methyl 4-trimethylsilylethynylbenzoate and 100 ml of dichloromethane are introduced into a round-bottomed flask. 16.8 g (125 mmol) of AlCl3 are added portionwise at 0° C. and the mixture is stirred at room temperature for 8 hours. The reaction medium is poured into ice and extracted with dichloromethane, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (50/50% by volume). 6.8 g (61%) of the expected product are collected, with a melting point of 113-4° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]=[N:7]2.P(Cl)(Cl)([Cl:19])=O>[OH-].[NH4+]>[Cl:19][C:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])[N:7]=[CH:6][CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(C)c2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flask is placed 5,8-dimethyl-6-nitro-4-quinolone (3.01 g, 13.8 mmol) with phosphorus oxychloride (41.3 g, 268 mmol). The mixture is refluxed under argon with stirring for 3 hours. After cooling to room temperature the mixture is poured on crushed ice, and concentrated ammonium hydroxide (100mL) is added. Extraction with chloroform (2×200 mL), drying over potassium carbonate, filtration and solvent removal by rotary evaporation gives 4-chloro-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNc2ccnc(Nc3cccc(Cl)c3)n2)C1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (500 mg, 2.08 mmol) and tert-butyl (3S)-3-(aminomethyl)pyrrolidine-1-carboxylate (625 mg, 3.12 mmol) in THF (10 mL) is added diisopropylethylamine (0.73 mL, 4.16 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 356 mg (42% yield) of the desired compound: MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@H:24]([OH:26])[CH2:25][C@@H:20]4[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]>C(OCC)C.[Os](=O)(=O)(=O)=O>[CH3:8][CH:6]([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:28])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:27])[CH:20]([CH2:25][C:24](=[O:26])[CH2:23][CH2:22]2)[CH2:19][CH2:18]3)[CH2:11][CH2:10]1)[CH3:1])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Os](=O)(=O)=O
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 30 h
Yield: 90 %

Procedure:
2.5 Millimole of 3β-cholestanol was dissolved in 50 ml of diethyl ether, and MCOsOx containing osmium tetroxide in an amount equivalent to 2.5 mmol was added thereto, followed by stirring at 25° C. for 30 hours to cause a reaction to take place. MCOsOx was removed from the reaction solution, and a crude keto compound was recovered from the filtrate and purified by silica gel column chromatography (eluent:benzene) to give 3-cholestanon at a yield of 90%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[Cl:11].C([O-])([O-])=O.[K+].[K+].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C(=O)C.O>[Cl:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:7]=[O:8]
Reactant: O=Cc1ccc(CBr)c(Cl)c1
Reactant: Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(CNc2ccccn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,N-dimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J=3.9 Hz, 1H), 6.38 (d, J=6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[C:19]([CH3:20])=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH3:20][C:19]1[C:11]([CH2:10][CH2:9][OH:8])=[CH:12][C:13]2[O:17][CH2:16][O:15][C:14]=2[CH:18]=1
Reactant: Cc1cc2c(cc1CCOCc1ccccc1)OCO2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1CCO)OCO2
Reaction time: 1 h
Yield: 79 %

Procedure:
1.9 g of 5-(2-benzyloxyethyl)-6-methyl-1,3-benzodioxole was dissolved in 80 ml of ethanol. 0.2 g of 10% palladium/carbon (containing 50% water) and 4 ml of acetic acid were added thereto and the catalytic reduction was conducted under 3 atm/cm2 for 1 h. After removing palladium/carbon, ethanol was distilled off and the product was purified according to silica gel column chromatography (ethyl acetate/hexane=2:3) to obtain 1.0 g of the intended compound in the form of a faint yellow oil.