Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1.[CH3:18][NH:19][NH2:20]>>[CH3:18][N:19]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:20]
Reactant: C=CCCC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: CNN
Product: C=CCCC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
12.3 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl)pyrido[4,3-c]pyridazine and 50 cc of methylhydrazine are stirred at a bath temperature of 90° for 30 minutes. The crude title compound is obtained in crystalline form upon cooling the mixture with ice. The title compound has a M.P. of 128°-130° (decomp., from isopropanol).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16])C.O.[Li+].[OH-].Cl>CO>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[C:7]([CH3:16])[CH:8]=1)=[O:11]
Reactant: CCOC(=O)Cc1ccc(C(=O)OC)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CC(=O)O)c(C)c1
Yield: 91.5 %

Procedure:
Methyl 4-(2-ethoxy-2-oxoethyl)-3-methylbenzoate (366 mg) was suspended in MeOH (10 ml) and H2O (2 ml) and treated with LiOH (48 mg) over 3 days. After the reaction mixture was acidified with 1N HCl, the product was extracted with EtOAc. Evaporation and drying in vacuum afforded the desired product (295 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([Cl:16])[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-:18].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.[Na]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([OH:18])([CH3:15])[C:11]([Cl:16])=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1c(Cl)[nH]n(-c2cc(Cl)cc(Cl)c2)c1=O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC1(O)C(=O)N(c2cc(Cl)cc(Cl)c2)N=C1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
1 g of 1-(3,5-dichlorophenyl)-3-chloro-4-methyl-5-pyrazolone, 30 ml of ethyl acetate and 1 g of potassium carbonate were cooled to 0° C. and 0.9 g of 75% m-chloroperbenzoic acid were added. The mixture was stirred for 1 hour at 0° C. and the reaction mixture was poured into ice to which sodium hydrogenosulfite had been added. The mixture was extracted with ethyl acetate and the organic phases were washed with a saturated aqueous solution of sodium bicarbonate, then with a solution of ammonium sulfate, and finally with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure. The residue was dissolved in hot isopropyl ether and pentane was added. Cooling was carried out to obtain 0.97 g of 1-(3,5-dichlorophenyl)-3-chloro-4-hydroxy-4-methyl-5-pyrazolone.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:12]=1)(=O)=O.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33](=[O:38])[CH2:32]3)O1.[Li+].[Cl-].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([N:10]2[CH2:11][CH:12]=[C:7]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][C:33](=[O:38])[CH2:32]4)[CH2:8][CH2:9]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(OC1=CCN(c2ccccc2)CC1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2cc(C3=CCN(c4ccccc4)CC3)ccc2N1
Temperature: 120 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 1-phenyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (104 mg, 0.339 mmol) in 1,4-Dioxane (3 ml) and H2O (1 ml) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (97.6 mg, 0.377 mmol), Pd(PPh3)4 (38.8 mg, 0.00336 mmol), LiCl (47.1 mg, 1.11 mmol) and K2CO3 (140 mg, 1.01 mmol). After stirring at 120° C. in microwave reactor for 1 h, the reaction mixture was quenched by sat. NaHCO3 aq. The resulting mixture was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)indolin-2-one (75.8 mg) as mixture of triphenylphosphine oxide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:42])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:42][CH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(C)nc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CBr)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a refluxing solution of ethyl 2-methylquinoline-4-carboxylate (1.6 g, 7.60 mmol) in CCl4 (150 mL), benzoyl peroxide (186 mg, 0.767 mmol) was added followed by NBS (750 g, 4.23 mmol). After 1 h, a second batch of NBS (750 g, 4.23 mmol) was added and the refluxing was continued overnight. The reaction mixture was allowed to cool to rt and washed with satd. Na2CO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:100-2:3 EtOAc/heptanes) to obtain ethyl 2-(bromomethyl)quinoline-4-carboxylate. Mass Spectrum (LCMS, ESI pos.) Calcd. For C13H12BrNO2: 294.0 (M+H). Found 294.1.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH3:18])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1)(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29](=[O:31])[NH:28][N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C=O)C>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[O:30][C:29](=[O:31])[N:28]([CH2:6][C:7]3([CH3:18])[O:11][C:10]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]4[CH2:8]3)[N:27]=2)=[CH:24][CH:25]=1
Reactant: CC1(COS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(Cn2nc(-c3ccc(Br)cc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 100 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
A mixture of 2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl methanesulfonate prepared in Example 41 (1.02 g, 3.67 mmol), 5-(4-bromophenyl)-3H-[1,3,4]oxadiazol-2-one (680 mg, 2.82 mmol), potassium carbonate (580 mg, 4.2 mmol), sodium iodide (890 mg, 5.94 mmol) and DMF (15 ml) was stirred at 100° C. for 3 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford 5-(4-bromophenyl)-3-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-3H-[1,3,4]oxadiazol-2-one (17.4 mg, yield 2%) as a light yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:12]=[C:13]([C:22]2[NH:23][C:24](=[O:46])[C:25]3[C:26](=[C:28]([CH2:44][CH3:45])[N:29]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[N:30]=3)[N:27]=2)[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:15][CH:16]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([C:11]1[CH:12]=[C:13]([C:22]2[NH:23][C:24](=[O:46])[C:25]3[C:26](=[C:28]([CH2:44][CH3:45])[N:29]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:30]=3)[N:27]=2)[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCN(C(=O)OC(C)(C)C)CC3)nc2c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCNCC3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (7 ml, 40%vol) was added to a solution of the title compound of example 129 in dry Methylene chloride (10 ml), and the mixture was stirred at room temperature under nitrogen for 45 mins. The mixture was concentrated in vacuo and the residue partitioned between NaHCO3 (sat. aq., 50 ml) and Methylene chloride (100 ml). The organic layer was separated (emulsion) and washed with water (50 ml). Organic layer was removed, and the aqueous extracted with Methylene chloride (2×50 ml). The combined organics were dried (MgSO4), and concentrated in vacuo. The crude product was purified by column chromatography (95:5:0.5 methylene chloride:methanol:0.88 NH3 as eluent) to yield the title compound (containing trace impurity; carried through crude to next step).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.[CH2:19]=O>>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH3:19])[CH2:9][C:7]=2[N:8]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Reactant: C=O
Agent: Cl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2

Procedure:
Method as intermediate 8 using (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) and formaldehyde as starting materials.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:25][CH2:24][Si:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]3)=[C:15]([F:28])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:21][CH2:22][Si:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]3)=[C:15]([F:28])[CH:14]=2)[CH2:8]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si]1(C)CCN(c2c(F)cc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si]1(C)CCN(c2c(F)cc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the Mesyl compound 18a (320 mg, 0.74 mmol) in DMF, NaN3 (63 mg, 0.97 mmol) is added and stirred at 60° C. for 2 h. Water (5 mL) is added and extracted with DCM (2×5 mL), dried and concentrated. The crude (300 mg) is used for further steps without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]([CH2:17][OH:18])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.I[CH3:27]>C1(C)C=CC=CC=1.[Ag-]=O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]([CH2:17][O:18][CH3:27])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C1(CO)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CI
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: COCC1(C(=O)OC)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-3-carboxylate (89 mg) in toluene (2.0 mL) were added silver(I)oxide (135 mg) and iodomethane (0.217 mL). The mixture was stirred at 70° C. for 2 d. After cooling, the residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (65.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:26](OC(OCC)OCC)C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[N:12]1([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:26]1
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2cnc3ccccc3c21
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was filtered and concentrated to give 5.25 g of tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light yellow syrup.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1cc(Nc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 85 °C
Yield: 69.5 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol) and 2-(4-aminophenyl)ethanol (0.134 g, 0.89 mmol) and 4M HCl in dioxane (0.222 mL, 0.89 mmol) in EtOH was heated for 2.5 h at 85° C. After this time, the mixture was neutralized with NaHCO3 at 0° C. and purified by silica gel chromatography eluting with methylene chloride and methanol to afford the title compound (0.145 g, 70%) as a yellow solid. MW=353.85. 1H NMR (DMSO-d6, 500 MHz) δ 9.53 (s, 1H), 8.33-8.28 (m, 2H), 7.62-7.55 (m, 4H), 7.22 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 4.62 (t, J=5.2 Hz, 1H), 3.63-3.59 (m, 2H), 2.72-2.64 (m, 4H), 1.26 (t, J=7.6 Hz, 3H); ESI MS m/z 354 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C[N+]1([O-])CC[O:21]CC1>C(#N)C>[CH:2]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])=[O:21]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 30 %

Procedure:
Ethyl 4-bromomethyl-3-nitrobenzoate (46.11 g) was dissolved in 500 ml of acetonitrile, then 20 g of 4-methylmorpholine-N-oxide was added and the mixture was stirred at room temperature for 80 minutes. The reaction solution was concentrated in vacuo, water was added and the mixture was extracted with chloroform. The organic layer was washed with a saturate aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluting solvent to give 10.723 g of ethyl 4-formyl-3-nitrobenzoate.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH:24]=1.O>CN(C)C=O>[N:13]1([CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[O:23][CH:24]=3)=[CH:5][CH:6]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
Sodium hydride (90 mg) was added to a solution of 1-[3-(4-hydroxyphenyl)propyl]imidazole (405 mg) in N,N-dimethyl formamide at room temperature and stirred for 1.5 hours. 4-Chloromethyl-2-(2-thienyl)oxazole (480 mg) was added, and the resultant was stirred at 90° C. for further 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel chromatography. From the fraction eluted with ethyl acetate-methanol (50:1, v/v), 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole (650 mg, 89%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C1(C(N)C2CCCCC2)CCCCC1.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:9]=2)[CH:5]=[C:4]([CH2:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1
Reactant: CCOC(=O)C=CCc1cc(C)c2[nH]ncc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C=CCc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To the clear solution of ethyl 4-(7-methyl-1H-indazol-5-yl)but-2-enoate (760 mg, 3.11 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) was added dicyclohexylmethyl amine (2.6 mL, 6.2 mL, 2.0 equiv) followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.66 mL, 3.73 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between 0.5 N sodium hydroxide and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual colorless oil was purified by flash column chromatography (20% ethyl acetate in hexanes) to afford the desired product as a colorless oil (1.08 g, 93%). MS (ESI) [M+H]+=375.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([N+:13]([O-])=O)[CH2:11][N:10]([CH3:16])[CH2:9]2)=[CH:4][C:3]=1[F:17].C(O)(=O)C>CO.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH3:16])[CH2:11][C@H:12]2[NH2:13])=[CH:4][C:3]=1[F:17]
Reactant: CN1C[C@@H]([N+](=O)[O-])[C@H](c2ccc(Cl)c(F)c2)C1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C[C@@H](N)[C@H](c2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
Zinc dust (5.76 g, 88 mmol) was added into a mixture of (+/−)-(3R,4S)-3-(4-chloro-3-fluorophenyl)-1-methyl-4-nitropyrrolidine (2.28 g, 8.81 mmol) in MeOH (29.4 mL) and acetic acid (30 mL, 524 mmol). The reaction mixture was stirred at room temperature for 5 h and filtered. Solvent was removed under vacuum. The residue was neutralized to pH 9, then extracted by IPA:CHCl3 (3:7). The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/Methanol/NH3 90:9:1) to obtain (+/−)-(3S,4R)-4-(4-chloro-3-fluorophenyl)-1-methylpyrrolidin-3-amine in 40% yield. LCMS (m/z): 229.2 (MH+), 0.25 min.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9][CH2:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][N:12]=3)=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=[O:25].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9]([CH2:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][N:12]=3)=[O:25])=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(SCc3cc(OCC4CC4)ccn3)nc2c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=S(Cc1cc(OCC2CC2)ccn1)c1nc2cc(F)ccc2[nH]1
Reaction time: 0.25 h

Procedure:
5- Fluoro-2-[[(4-cyclopropylmethoxy-2-pyridinyl)methyl]thio]-1H-benz-imidazole (1.25 g, 0.0036 mol) was dissolved in CH2Cl2 (40 ml). NaHCO3 (0.6 g, 0.0072 mol) dissolved in H2O (20 ml) was added and the mixture was cooled to +2° C. m-Chloroperbenzoic acid, 84% (0.73 g, 0.0036 mol) dissolved in CH2Cl2 (5 ml) was added under stirring. Stirring was continued at room temperature for 15 min. The two phases were separated and NaOH (0.29 g, 0.0072 mol) dissolved in H2O (25 ml) was added to the organic phase. The mixture was stirred, the phases were separated and the H2O phase was treated with Norite and filtered. Methylformiate (0.45 ml, 0.0073 mol) dissolved in H2O (5 ml) was added dropwise under stirring. After extraction with CH2Cl2 and drying with Na2SO4 the solvent was evaporated. In this way the title compound was obtained [0.93 g, 69%). NMR data for the final product is given below. NMR data for the intermediates are given below.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[S:16]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])(=[O:19])(=[O:18])[NH2:17]>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:21]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cccc(S(N)(=O)=O)c2)C(=O)OC1=O

Procedure:
To a hot solution of 2.12 g. (0.01 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 40 ml. of methanol is added 1.72 g. (0.01 mol) of m-sulfamylaniline and the mixture is refluxed for one hour. The solid is filtered from the reaction mixture to obtain 5-acetyl-4-hydroxy-3-[1-(3-sulfamylphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 237° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]5[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=5[N:23]4[CH3:26])=[CH:19][CH:18]=3)[C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: COc1ccc(-c2cc[nH]c(=O)c2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)cc1
Temperature: 135 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A suspension of 4-(4-methoxyphenyl)pyridin-2(1H)-one (103 mg, 0.510 mmol), tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (223 mg, 0.612 mmol), CuI (116 mg, 0.612 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and Cs2CO3 (183 mg, 0.561 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (98 mg, 40%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 7.64-7.53 (m, 3H), 7.46 (d, J=7.2 Hz, 1H), 7.36 (br s, 1H), 7.08 (dd, J=8.1, 1.5 Hz, 1H), 7.01 (d, J=8.7 Hz, 2H), 6.87 (d, J=1.8 Hz, 1H), 6.51 (dd, J=7.2, 1.8 Hz, 1H), 4.68-4.60 (m, 2H), 3.88 (s, 3H), 3.82-3.73 (m, 2H), 3.65 (s, 3H), 2.85-2.78 (m, 2H), 1.52 (s, 9H).