Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C@H:8]1[CH2:21][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]=O)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][O:31][NH2:32]>C(O)C>[CH3:30][O:31][N:32]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH2:21][C@H:8]([NH:7][C:6](=[O:22])[C:10]([CH3:18])([CH3:11])[CH3:9])[CH2:9][C:10]=3[C:18]=2[CH:17]=1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2[nH]c3ccc(C=O)cc3c2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=Cc1ccc2[nH]c3c(c2c1)C[C@@H](NC(=O)C(C)(C)C)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom flask add [(R)-7-formyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid tert-butyl ester (1.00 g; 3.33 mmol), ethanol (10 ml), potassium carbonate (552 mg, 4 mmol), and O-methylhydroxylamine hydrochloride (334 mg; 4.0 mmol). Stir the mixture at room temperature for 1 h. Remove the solvent in vacuo and add water (15 mL). Stir the mixture 30 min and filter to give 790 mg (72%). MS (m/z): 330 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:18]=1.[CH3:25][O-:26].[Na+].O.C1[CH2:33][O:32]CC1>>[CH3:25][O:26][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([O:32][CH3:33])[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:18]=1
Reactant: C[O-]
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: COc1nc(N2CCCCC2)c2nc(OC)nc(N3CCCCC3)c2n1
Yield: 46 %

Procedure:
2,6-Di chloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) was dissolved in dry THF (15 ml), then added to freshly prepared sodium methoxide (4.1 ml, 1.22M, 5 mmol) in dry THF (5 ml) under a N2 atmosphere, and the mixture heated under reflux for 20 hours. After cooling to room temperature water (20 ml) was added and the product extracted into ethyl acetate (4×20 ml). The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo. Recrystallisation from methanol/water yielded the title compound as a yellow crystalline solid (0.083 g, 46%), m.p. 130-131° C. Found: C, 59.41; H, 7.27; N, 22.17. C18H26N6O2 requires C, 60.32; H, 7.31; N, 23.44%.
Reaction SMILES: [CH3:1][C:2]([CH2:5][C@H:6]1[NH:10][C@@H:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:12])[C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@:7]21[C:37](=[O:38])[NH:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]2=1)([CH3:4])[CH3:3]>CO.O>[CH3:4][C:2]([CH2:5][C@@H:6]1[NH:10][C@@H:9]([C:11]([NH:13][CH:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)=[O:12])[C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@@:7]21[C:37](=[O:38])[NH:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]2=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C[C@H]1N[C@@H](C(=O)NC2CCC(O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]12C(=O)Nc1cc(Cl)ccc12
Solvent: CO
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCC(O)CC2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reaction time: 72 h
Yield: 26 %

Procedure:
In an alternative procedure, MI-773 (77 mg) was dissolved in 15 mL MeOH/H2O (v/v=1:1). After 3 days, the needle crystals that had formed were collected, washed with cold MeOH/H2O (v/v=1:1) and dried in vacuum to give MI-77301 as the free amine (20 mg; >95% purity as determined by HPLC). 1H NMR (300 MHz, MeOH-d4): 7.49-7.55 (m, 1H), 7.25-7.31 (m, 1H), 7.10-7.16 (m, 1H), 6.82 (d, J=1.8 Hz, 1H), 6.50-6.71 (m, 1H), 6.49 (d, J=8.4 Hz, 1H), 4.32 (d, J=9.0 Hz, 1H), 4.09 (d, J=8.7 Hz, 1H), 3.57-3.69 (m, 1H), 3.49 (d, J=9.2 Hz, 1H), 3.46-3.57 (m, 1H), 1.83-2.07 (m, 3H), 1.68-1.80 (m, 1H), 1.54 (dd, J=9.0, 14.3 Hz, 1H), 1.12-1.45 (m, 5H), 0.80 (s, 9H). The absolute stereochemical configuration of MI-77301 was determined by X-ray analysis.
Reaction SMILES: COCC[S](F)(F)([F:10])CCOC.O[C:14]([CH3:44])([CH3:43])[CH2:15][N:16]1[CH2:21][CH2:20][C:19]2([CH2:24][C:23]3([O:42][C:27]4=[CH:28][N:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=5)[CH:31]=[C:26]4[CH2:25]3)[CH2:22]2)[CH2:18][CH2:17]1.O>ClCCl.CO>[F:10][C:14]([CH3:44])([CH3:43])[CH2:15][N:16]1[CH2:21][CH2:20][C:19]2([CH2:24][C:23]3([O:42][C:27]4=[CH:28][N:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=5)[CH:31]=[C:26]4[CH2:25]3)[CH2:22]2)[CH2:18][CH2:17]1
Reactant: CC(C)(O)CN1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Reactant: COCC[S](F)(F)(F)CCOC
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(F)CN1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Reaction time: 3 h

Procedure:
Bis(2-methoxyethyl)sulfur trifluoride (50% in toluene; 40 μL) is added to a solution of 1″-(2-hydroxy-2-methyl-propyl)-5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (20 mg) in dichloromethane (5 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 2 h before another portion of bis(2-methoxyethyl)sulfur trifluoride (50% in toluene; 20 μL) is added. After stirring for 3 h, a few drops of methanol and water are added. The resulting solution is concentrated and the residue is purified by HPLC on reversed phase (acetonitrile/water/trifluoroacetic acid) to give the title compound as bis(trifluoroacetic acid) salt. LC (method 1): tR=0.76 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [CH3:1][I:2].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5][C:4]1=[S:13]>C(O)C>[IH:2].[CH3:1][S:13][C:4]1[NH:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1
Reactant: S=C1NCc2ccccc2N1
Reactant: CI
Solvent: CCO
Product: CSC1=Nc2ccccc2CN1
Product: I
Yield: 68.2 %

Procedure:
Methyl iodide (11.5 ml, 184 mmol) was added to a solution of 3,4-dihydro-1H-quinazoline-2-thione (7.55 g, 46 mmol) in ethanol (150 ml), and the mixture was heated to reflux (3.5 h). The majority of the solvent was then evaporated under reduced pressure, and the precipitate was collected by filtration and washed with a small amount of cold ethanol. The thus obtained title compound (9.60 g, 68%) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[N:19]([CH:29]1[CH2:32][N:31]([S:33]([OH:36])(=[O:35])=[O:34])[C:30]1=[O:37])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K].C([N+](CCCC)(CCCC)CCCC)CCC.O=C1C(N(Cl)C([O:64][CH2:65][C:66]2C=CC=[CH:68][CH:67]=2)=O)CN1S([O-])(=O)=O>>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH2:65]([O:64][C:29]1([NH:19][C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:32][N:31]([S:33]([OH:36])(=[O:35])=[O:34])[C:30]1=[O:37])[CH2:66][CH2:67][CH3:68]
Reactant: O=C(OCc1ccccc1)N(Cl)C1CN(S(=O)(=O)[O-])C1=O
Reactant: O=C(Cc1ccccc1)N(Cl)C1CN(S(=O)(=O)O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K]
Product: CCCCOC1(NC(=O)Cc2ccccc2)CN(S(=O)(=O)O)C1=O

Procedure:
Following the procedure of Example 80, but substituting N-chloro-N-(2-oxo-1-sulfo-3-azetidinyl)-2-phenylacetamide, tetrabutylammonium salt (see Example 47A for preparation of the corresponding potassium salt) for 2-oxo-3-[N-chloro-N-[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt, yields the title compound as an oil: nmr (CDCl3) 3.62 (s,2H,C6H5CH2), 4.03 (ABq,2H,ν=7 cps, C-4 CH2), 6.98 (s,1H,NH) and 7.30 ppm (S,5H,C6H5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([CH3:11])[CH:3]=1.[CH3:12]I.[H-].[Na+].O.C[N:18]([CH:20]=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:9])[C:20]#[N:18])=[C:4]([CH3:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CI
Reactant: Cc1cc(Br)ccc1CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1C(C)(C)C#N
Temperature: 0 °C
Yield: 66 %

Procedure:
To a stirred solution of 2-(4-bromo-2-methylphenyl)acetonitrile (3.93 g, 18.8 mmol) in anhydrous DMF (35 mL) is added methyl iodide (2.45 mL, 39.4 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 1.47 g, 61.1 mmol) is added in 3 equal portions over 20 min. The reaction mixture is then left stirring and slowly warmed up to room temperature for 18 h. The solution turned to a thick brown-orange paste. At 0° C., water (50 mL) is then slowly added and the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL). The organic layer is washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The crude is purified by flash-chromatography, eluting with hexane/EtOAc (9:1) to provide the expected product 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 66%) as a clear yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.30 (2H, m), 7.16 (2H, d, J=8.5 Hz), 2.63 (3H, s), 1.77 (6H, s).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].B>C1COCC1.CO>[CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(CO)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a stirring solution of 4-(ethylsulfonyl)benzoic acid (500 mg, 2.33 mmol) in THF (5 mL) at 0° C. under argon was added 1 M borane in THF solution (3.5 mL, 3.5 mmol). The reaction mixture was stirred at 70° C. for 20 min. The reaction mixture was then cooled to room temperature, and the THF was removed under reduced pressure. The residue thus obtained was diluted with methanol (5 mL) and stirred for 5 min. Methanol was then removed under reduced pressure. This process was repeated two more times to ensure complete methanolysis of any borane complex. After residual solvent removal under vacuum, 420 mg of the title compound was obtained as a colorless gum. HPLC/MS: retention time=1.373 min, [M+H]+=201.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O[Li].O.P(=O)(O)(O)[OH:35].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:35])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LiOH.H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH:5]([CH2:7]CS([O-])(=O)=O)[CH2:4][O:3]1.[NH2:14][CH2:15][CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:13][C:2]1([CH3:1])[CH2:6][CH:5]([CH2:7][NH:14][CH2:15][CH2:16][NH2:17])[CH2:4][O:3]1
Reactant: CC1(C)CC(CCS(=O)(=O)[O-])CO1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(CNCCN)CO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
A suspension of 4.00 g of [(2,2-dimethyl-4-tetrahydrofuryl) methyl]methanesulfonate, 10.4 g of 1,2-diaminoethane and 2.87 g of potassium carbonate in 40 ml of acetonitrile was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and water was then added thereto, followed by extraction with dichloromethane, The organic layer was dried over magnesium sulfate, anhydrous, and then concentrated under a reduced pressure to obtain 1.38 g of N-[(2,2-dimethyl-4-tetrahydrofuryl) methyl]-1,2-diaminoethane as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.C([O:18]O)(C)(C)C>ClCCl.CCCCCCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[O:18][CH:8]3[CH2:9][C:10]=2[CH:11]=1
Reactant: CC(C)(C)OO
Reactant: FC(F)(F)c1ccc2c(c1)CC=C2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCCCCCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(c1)CC1OC21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(trifluoromethyl)-1H-indene (1.1 g, 6 mmol) in anhydrous dichloromethane (80 mL) at −78° C. was added a 5.5 M solution of tert-butyl hydroperoxide in n-decane (1.3 mL) followed by titanium tetrachloride (0.79 mL, 7.2 mmol). After being stirred at −78° C. for 1 h, the resulting brown solution was quenched with a mixture of Et2O/saturated Na2SO3 solution. The mixture was stirred at ambient temperature for 1 h to give a colorless solution. The organic layer was separated and washed with brine, dried over MgSO4 and concentrated to give the crude product (1.2 g) as a solid. LC/MS calculated for C10H2F3O: (M+H)+201; found 201.0.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.Br[CH2:17][CH2:18][C:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[N:12]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Reactant: O=c1cc(I)c(F)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Cesium carbonate (2.01 g, 6.16 mmol) was added to a solution of the 5-fluoro-4-iodopyridin-2(1H)-one (491 mg, 2.06 mmol) and ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (767 mg, 2.67 mmol in THF (30 mL). The resulting suspension was heated to reflux and stirred at this temperature overnight. The reaction was filtered through celite (−1 inch), and the filter pad was washed with ethyl acetate (2×30 ml). The combined filtrates were concentrated and the crude was purified via flash chromatography on an Analogix SF15-12g column and an eluant of ethyl acetate in heptane (30-100%) to afford the title compound as a white gum (319 mg, 34.9%). LC-MS m/z 446.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.12 Hz, 3 H) 1.75 (s, 3 H) 2.40-2.58 (m, 2 H) 3.10 (s, 3 H) 3.87-3.99 (m, 1 H) 4.16-4.25 (m, 1H) 4.29 (q, J=7.22 Hz, 2 H) 7.15 (d, J=5.85 Hz, 1 H) 7.20 (d, J=3.32 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH3:16]>CN(C=O)C>[CH3:16][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH2:1])=[CH:3]2
Reactant: Nc1ccc2c(O)cccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cc(N)ccc12
Reaction time: 1 h

Procedure:
To a solution of 6-aminonaphth-1-ol (1.0 g) in DMF (50 mL), NaH (60% in mineral oil, 0.17 g) was added, and the reaction was stirred for 1 hour. Iodomethane (0.39 mL) was added, and the reaction was stirred for another 1 hour. The reaction was then partitioned between NaHCO3 (aq., 150 mL) and EtOAc (100 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated. The crude reaction was purified over silica gel (gradient of EtOAc in heptane) to provide the title compound (0.8 g) as an orange oil:: 1H NMR (DMSO-d6) δ 7.81 (d, 1H); 7.16 (dd, 1H), 7.04 (d, 1H), 6.85 (dd, 1H), 6.75 (d, 1H), 6.53 (dd, 1H), 5.32 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[C:8]([C:10]#N)[O:9][C:5]=2[CH:4]=1.[O:14]1CCCC1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>O1CCCC1>[CH:19]1([C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]=3[CH:7]=2)=[O:14])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccc2cc(C#N)oc2c1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2cc(C(=O)C3CCCCC3)oc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution (20 mL) of 6-methoxy-1-benzofuran-2-carbonitrile (1.00 g) synthesized above in tetrahydrofuran was added 1.0M cyclohexylmagnesium bromide tetrahydrofuran solution (11.5 mL), and the mixture was stirred at 50° C. overnight, and stirred with heating under reflux for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (584 mg, 39%) as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1.Br[C:25]1[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=1>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][N:17]([C:25]3[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=3)[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: CC(=O)NCc1ccc(Br)cc1C
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
Sodium tert-butoxide (0.3 g), Tris(dibenzylidene acetone)dipalladium(0) (chloroform adduct)(0.04 g) and xantphos (0.07 g) was added to the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.59 g) and N-(4-bromo-2-methylbenzyl)acetamide (0.5 g) in toluene under argon atmosphere, and the mixture was heated with stirring at 80° C. for 5 hours. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methylbenzyl}acetamide (0.6 g).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>O1CCCC1>[CH3:21][S:22]([O:4][CH2:3][C:2]([CH3:1])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)[CH3:5])(=[O:24])=[O:23]
Reactant: CC(C)(CO)n1cc([N+](=O)[O-])cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(COS(C)(=O)=O)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (13 g) obtained in Step G of Example 103 in tetrahydrofuran (100 mL) were added successively dropwise triethylamine (12 mL) and methanesulfonyl chloride (6.3 mL) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (18 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.44 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 109° C., (yield 0.645 gm, 89.3%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7]1([C:13](=O)[CH2:14][CH2:15][CH2:16]Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C)C>[CH3:1][N:2]1[C:3](=[S:6])[NH:4][N:5]2[CH2:16][CH2:15][CH2:14][C:13]12[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CNC(=S)NN
Solvent: CC(C)O
Product: CN1C(=S)NN2CCCC21c1ccccc1

Procedure:
4.2 g of 4-methyl-thiosemicarbazide and 8.0 g of 1-phenyl-4-chlorobutan-1-one in 200 ml of isopropanol is refluxed for 48 hours. The solvent is then evaporated and the residue is dissolved in methylene chloride. The resulting solution is washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride and then dried over sodium sulfate. Evaporation of the solvent leaves a brownish oil which crystallizes partially. This is treated with ether to give a light yellow powder which is purified by flash chromatography, using 10% ethyl acetate/methylene chloride as the eluent to give 5,6,7,7a-tetrahydro-1-methyl-7a-phenyl-1H-pyrrolo[1,2-b][1,2,4]triazole-2(3H)-thione as colorless crystals melting at about 148°-151° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: CCS(=O)(=O)NCCOc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and ethanesulfonyl chloride.