Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1.O[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)C(C)C)(C)C.[O:33]1CCCC1>>[N:7]1[O:8][N:9]=[C:5]2[CH:4]=[C:3]([CH2:2][O:33][C:19]3[CH:20]=[CH:21][CH:22]=[C:15]4[C:14]([NH:13][C:17](=[O:18])[C:16]=34)=[O:23])[CH:11]=[CH:10][C:6]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)c2c(OCc3ccc4nonc4c3)cccc21
Temperature: 25 °C
Yield: 94 %

Procedure:
5-(Bromomethyl)benzo[c][1,2,5]oxadiazole (0.441 g, 2.07 mmol) was added to a solution of N-hydroxyphthalimide (0.336 g, 2.06 mmol) in dry tetrahydrofuran (15 ml). N,N-Diisopropylethylamine (0.519 g, 4.02 mmol) was added and the solution was stirred at reflux under nitrogen for 23 h and cooled to room temperature. The suspension was concentrated in vacuo to a pale beige solid. This was diluted with water and filtered. The residue was washed with plenty of water and dried under vacuum to give (benzo[c][1,2,5]oxadiazol-5-yl)methoxyphthalimide (0.571 g, 94%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[C:15]2[C:11](=[CH:12][S:13][CH:14]=2)[NH:10][C:9](=[O:16])[C:8]=1[C:17]#[N:18].[O:19]1C=CC=[C:20]1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[O:16]=[C:9]1[C:8]([C:17]#[N:18])=[C:7]([N:27]2[CH2:28][CH2:29][N:24]([C:20]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:19])[CH2:25][CH2:26]2)[C:15]2[C:11](=[CH:12][S:13][CH:14]=2)[NH:10]1
Reactant: c1ccoc1
Reactant: c1coc(N2CCNCC2)c1
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cscc2[nH]c1=O

Procedure:
To yield compounds of structure (II) wherein R2 is carbonitrile, R3 is furan, and R1 is as defined above, intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was reacted with 1-(2-furyl)-piperazine to yield 5-oxo-7-[4-(furan-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (35). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield the target compounds of structure (II) with R2 as carbonitrile, R3 as furan, and R1 as defined above, as shown in Scheme 17.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O.O1CCCC1>[NH2:13][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([Cl:12])[C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)c(N)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of methyl 4-amino-5-chloro-3-nitrobenzoate (4.29 g, 18.6 mmol) in ethanol (115 mL), water (250 mL) and tetrahydrofuran (200 mL) was added sodium hydrosulfite (80 g, 391 mmol). The reaction was stirred at ambient temperature for two hours. To the reaction was added water (55 mL). After stirring for an additional hour saturated aqueous sodium bicarbonate (140 mL) was added to the reaction. The reaction mixture was filtered and the filtrate was extracted twice with ethyl acetate (200 mL each). The organic extracts were combined and washed with saturated aqueous sodium bicarbonate (100 mL) followed by saturated aqueous sodium chloride (100 mL). The organic layer was concentrated in vacuo to a final volume of 100 mL and then allowed to sit at ambient temperature overnight to give a precipitate. The mixture was filtered and dried under a stream of nitrogen to give methyl 3,4-diamino-5-chlorobenzoate (973 mg, 26%). The filtrate was concentrated in vacuo to give methyl 3,4-diamino-5-chlorobenzoate (2.45 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (d, J=1.95 Hz, 1H) 7.08 (d, J=1.95 Hz, 1H) 5.44 (s, 2H) 5.08 (s, 2H) 3.70 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Nc1ccc(Oc2ccc(CCN)cc2)cc1
Solvent: CO
Product: CC(=O)Nc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
Combine N-{4-[4-(2-amino-ethyl)-phenoxy]-phenyl}-acetamide (100 mg, 0.37 mmol), benzaldehyde (47 mg, 0.44 mmol), 3 Å molecular sieves (300 mg), and methanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (28 mg) to the reaction and stirred at room temperature for 2 hours. Concentrate on a rotary evaporator and purified by radial chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield N-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-acetamide, (61 mg): 1H NMR (CDCl3, 300.00 MHz): 7.51-6.88 (m, 13H), 3.84 (s, 2H), 2.97-2.78 (m, 4H), 2.21 (s, 3H), 1.55 (s, 1H); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: O[C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[O-:33]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:30]1[C@H:5]2[CH2:6][C@@H:7]3[C@@H:16]([C@@:17]4([CH3:20])[CH2:18][CH2:19][CH2:2][CH2:3][C@:4]124)[CH2:15][CH2:14][C@@:12]1([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]1=[O:21].[O:33]1[C@@H:5]2[CH2:6][C@@H:7]3[C@@H:16]([C@@:17]4([CH3:20])[CH2:18][CH2:19][CH2:2][CH2:3][C@@:4]124)[CH2:15][CH2:14][C@@:12]1([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]1=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45CCCC[C@]35C)[C@@H]1CCC2=O
Product: C[C@]12CC[C@H]3[C@@H](C[C@H]4O[C@]45CCCC[C@]35C)[C@@H]1CCC2=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3β-hydroxyandrost-5-en-17-one (0.81 g) in CH2Cl2 (7.4 mL) cooled at 0° C., a solution of mCPBA (0.77 mg) in CH2Cl2 (14 mL) was added dropwise. After 0.5 h at 0° C. and 0.5 h at room temperature, a 10% Na2SO3 aqueous solution was added. The mixture was neutralized by addition of 5% aqueous NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness to give 5α,6α-epoxyandrostan-17-one and 5β,6β-epoxyandrostan-17-one as a white foam (1/1 mixture; 1.24 g, 97%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): 3β-hydroxy-5α,6α-epoxyandrostan-17-one δ 3.26 (1H, d), 2.96 (1H, d), 2.70-1.12 (18H, m), 1.36 (3H, s), 0.83 (3H, s); 3β-hydroxy-5α,6β-epoxyandrostan-17-one: δ 2.98 (1H, d), 2.93 (1H, d), 2.71-1.13 (18H, m), 1.06 (3H, s), 0.84 (3H, s).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=O.[CH3:20][CH:21]([CH3:25])[C:22](=O)C.CCOC(C)=O>O1CCOCC1>[CH3:19][O:18][CH2:17][O:16][C:14]1[CH:15]=[C:8]2[C:9]([CH:10]=[C:20]([CH:1]=[O:4])[C:21]([CH3:25])([CH3:22])[O:7]2)=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C(C)C
Reactant: COCOc1ccc(C=O)c(O)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCOc1ccc2c(c1)OC(C)(C)C(C=O)=C2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
K2CO3 (835 mg) was suspended in dioxane (40 mL), and 2-hydroxy-4-(methoxymethoxy)benzaldehyde (1 g) and 3-methyl 2-butanal (0.787 mL) were added thereto, followed by stirring at 110° C. overnight. EtOAc was added thereto, the insoluble materials were removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 70:30) to obtain 7-(methoxymethoxy)-2,2-dimethyl-2H-chromene-3-carbaldehyde (320 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.CO.COC1CCSCC=1.OC1C(O)=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>CC1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:33][O:32][C:29]1[C:1]2[O:2][C:3]3([O:9][C:10]=2[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1)[CH2:8][CH2:7][S:6][CH2:5][CH2:4]3
Reactant: COc1ccc(C(=O)O)c(O)c1O
Reactant: COC1(OC)CCSCC1
Agent: COC1=CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)O)c2c1OC1(CCSCC1)O2
Temperature: 145 °C
Yield: 60.4 %

Procedure:
P-Toluenesulfonic acid (97 mg, 0.51 mmol) was added to 4,4-dimethoxytetrahydro-(4H)-thiopyran (20.7 g, 128 mmol) and the mixture was heated to 145° C. and kept at that temperature until approximately one equivalent of methanol (5.17 mL, 128 mmol) was distilled off. The mixture was then cooled to 130° C. and distillation under reduced pressure afforded 10.1 g of a 5:3 mixture of 5,6-dihydro-4-methoxy-(2H)-thiopyran [1H NMR (DMSO) δ 4.87 (m, 1H), 3.44 (s, 3H), 3.15 (dt, 2H), 2.72 (t, 2H), 2.22 (m, 2H)] and 4,4-dimethoxytetrahydro-(4H)-thiopyran. Without further purification the mixture was added to 2,3-dihydroxy-4-methoxybenzoic acid (2.00 g, 10.9 mmol) and the suspension was exposed to microwave heating (180° C., one hour) in a sealed reaction vessel. Ethyl acetate (100 mL) was added and the organic phase was first washed with 0.5 M HCl (40 mL) and then extracted with saturated aqueous NaHCO3 (2×30 mL). The aqueous phase was washed with Et2O (2×40 mL), acidified to pH=1 with concentrated HCl and extracted with dichloromethane (2×30 mL). The organic phase was dried over MgSO4. Evaporation under reduced pressure afforded 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (1.86 g, 61%). 13C NMR (DMSO) δ 164.9, 148.2, 146.6, 134.5, 123.8, 118.0, 107.2, 106.9, 56.1, 35.9, 25.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:35])([F:37])[F:36]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) in pyridine (3 mL) was added 1-isocyanato-2-(trifluoromethyl)benzene (53 μL, 0.348 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (15 mL)/tetrahydrofuran (5 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→90/10), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (10 mL) to give the title compound (95 mg, 61%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[CH3:22][NH2:23]>CO>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)/[C:3]([NH:23][CH3:22])=[O:2]
Reactant: CN
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Solvent: CO
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Yield: 100 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (1.00 g, 0.0035 mole) was dissolved in methanol (7 ml) and 40% methylamine solution in methanol (0.54 g, 0,007 mole) was added to the mixture, which was refluxed for 70 minutes. A 40% methylamine solution in methanol (1.36 g, 0.0175 mole) was further added to the mixture, which was refluxed for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give E-2-hydroxyimino-N-methyl-2-[2-(4methylphenoxy)phenyl]acetamide (1.00 g, yield: 100.0 %) as an amorphous.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[C:25]([CH2:33][C:34](=O)[CH3:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[C:25]([C:33]1[C:34]([CH3:35])=[N:2][C:3]2[C:4]([C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=[CH:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)c3ccccc3)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 69.8 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxy-benzophenone hydrochloride (2.0 g), benzoylacetone (0.917 g) and ethanol (35 ml) was stirred under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (10:1, v/v) gave 3-benzoyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline (1.75 g, 70%). This compound was recrystallized from ethanol to give colorless prisms, mp. 151°-152° C.
Reaction SMILES: N1C=CC=[CH:3][CH:2]=1.Br[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.C([NH:25][C:26](=[S:28])[S-:27])C>C(O)C>[CH2:2]([S:27][C:26]1[S:28][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:25]=1)[CH3:3]
Reactant: CCNC(=S)[S-]
Reactant: c1ccncc1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Solvent: CCO
Product: CCSc1nc(-c2ccccc2)c(-c2ccccc2)s1

Procedure:
1.106 g of pyridine and 3.68 g of 2-bromo-1,2-bis-phenylethanone are added while stirring to a solution, cooled to 5°, of 1.694 g of ethyldithiocarbamate in 25 ml of ethanol. The mixture is then stirred for 30 minutes at 5° and for 90 minutes at room temperature, concentrated to dryness by evaporation under reduced pressure, and the residue is partitioned between methylene chloride and water. The aqueous phase is acidified with N hydrochloric acid and extracted by shaking again twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. The remaining oil is purified by chromatography over 100 g of silica gel with toluene/hexane (1:1) as eluant. Concentration by evaporation yields 2-ethylthio-4,5-bis-phenylthiazole in the form of an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[F:40]C1C=CC=CC=1N1CCNCC1.[ClH:53]>O1CCCC1>[OH2:7].[ClH:53].[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:40])[CH2:10][CH2:9]1)=[O:7]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccccc2F)CC1
Product: O

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 1.5 g (0.009 mole) of 1,1'-carbonyldiimidazole, 0.8 g (0.009 mole) of unsym-dimethylethylenediamine and 1.7 g (0.009 mole) of 1-(2-fluorophenyl)piperazine in a total volume of 200 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give the title compound as a white crystalline solid, m.p. 146°-150° C.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4](CS([O-])(=O)=O)=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=S(=O)([O-])Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(=O)c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Temperature: 110 °C
Yield: 96.7 %

Procedure:
Following general procedure A, a mixture of 4-biphenylmethanesulfonate (124 mg, 0.5 mmol), 4′-aminoacetophenone (81 mg, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 15-50% EtOAc/hexanes) to provide the title compound as a white solid (139 mg, 97%), mp 136-139° C. 1H NMR (300 MHz, CDCl3) δ: 7.90 (d, J=9.0 Hz, 2H), 7.59 (m 4H), 7.45 (t, J=7.0 Hz, 2H), 7.35 (t, J=7.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.35 (s 1H), 2.55 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 196.8, 148.4, 140.7, 140.2, 136.2, 130.9, 129.3, 129.1, 128.4, 127.3, 127.0, 120.9, 114.9, 26.5 ppm. IR (neat, cm−1): 3324, 1656, 1586, 1524, 1487, 1339, 1278, 1178, 827, 763.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[CH:28]=[CH:27][NH:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[C:28]([I:29])=[CH:27][NH:26][N:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(-c2cc[nH]n2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Clc1cc(-c2n[nH]cc2I)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1H-pyrazole (4.06 g 10.05 mmol) in DCM (50 ml) was added N-iodosuccinimide (2.35 g, 10.45 mmol) in bulk. The mixture was stirred at room temperature for two hours and then partitioned between water and DCM. The organics were washed with saturated sodium thiosulphate solution then water and dried in vacuo to give a yellow crystalline mass, which was triturated from ethyl acetate by the gradual addition, whilst stirring, of hexanes to give 3-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-iodo-1H-pyrazole (5.21 g, 97%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C:5]([CH3:7])([NH:8][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([F:10])([F:22])[F:23])(=[O:20])=[O:19])[CH3:6]
Reactant: COC(=O)C(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
Methyl-2-amino-2-methylpropanoate hydrochloride (1 g, 6.53 mmol) was dissolved in CH2Cl2 (20 ml), and added with 2-(trifluoromethyl)benzene-1-sulfonylchloride (1.76 g, 7.18 mmol) and triethylamine (3.6 ml, 26.1 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(2-(trifluoromethyl)phenylsulfonamido)propanoate (1.98 g, 6.08 mmol, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:22]([N:24](CC)[CH2:25][CH3:26])[CH3:23].Cl.N1CCCC1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:24]2[CH2:25][CH2:26][CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 4-bromophenethyl alcohol (2.54 mmol) and p-toluenesulfonyl chloride (2.74 mmol) in anhydrous dichloromethane (5 mL) under nitrogen was added triethylamine (2.74 mmol) dropwise by syringe at room temperature. The reaction was stirred for 16 hours at room temperature. A white precipitate formed. 1N HCl solution (5 mL) was added to the suspension and the reaction became clear. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (5 mL), dried over magnesium sulfate and concentrated in vacuo to give a white solid. To this crude product was added pyrrolidine (1 mL) under nitrogen and the reaction was stirred at 50° C. for 90 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (20 mL) and washed successively with water (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (20-100% ethyl acetate/hexanes) afforded the title compound as a white solid (80%). ESMS [M+H]+: 254.2.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1.[Cl-].[Na+].O>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl indane-2-carboxylate (Schaaf et al., J. Med. Chem. 1983, 26, 328-334) (2.00 g, 10.5 mmol) in THF at −78° C. was added sodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF, 15.8 mmol) dropwise, over 10 min. The mixture was stirred for 15 min, then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added dropwise, over 30 min. The resulting mixture was stirred for 30 min at −78° C., then poured into brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2 SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=368 (M+Na+CH3 CN).