Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=[CH:6]2.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cccc2cc(OC)ccc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of 9.1 g of 6-methoxynaphthoic acid and 7.2 g of anhydrous potassium carbonate in 45 ml of acetone was heated to 50°-55° C. for 15 minutes, and 4.5 ml of dimethyl sulfate were then slowly dripped in over a period of 15 minutes. The mixture was then heated at reflux for one hour and cooled to room temperature, after which all the acetone was stripped under vacuum. After workup, it was determined that the process resulted in the formation of 8.85 g of methyl 6-methoxynaphthoate having an HPLC purity of 83.3%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)[N:3]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:28][CH2:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([CH3:20])[CH:16]=1)[O:12][C:4]1[C:5]([CH:9]([CH3:10])[CH3:11])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of 2,4-dichloro-6-(3,5-dimethyl-phenoxy)-5-isopropyl-pyrimidine (9.72 g, 31 mmol), NBS (5.56 g, 31 mmol), and benzoyl peroxide (0.756 g, 3.1 mmol) in carbon tetrachloride (60 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the reaction mixture was filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:19)) to afford 8 g (62%) of a white solid. m.p. 98-101° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.38 (3H, s), 3.59 (1H, m), 4.47 (2H, s), 6.86 (1H, s), 6.97 (1H, s), 7.13 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)=[C:11]3[NH:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3cccnc23)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2NCCC3)ccn1
Yield: 25.1 %

Procedure:
To a mixture of N-{4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}acetamide (120 mg, 0.34 mmol, 1 eq) in 2 mL of ethanol is added sodium borohydride (29 mg, 0.76 mmol, 2.2 eq). The mixture is refluxed for 1 h. The mixture is then poured into water, extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 0:1) as eluent and 30 mg (25%) of N-{4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}acetamide are obtained as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:4]=1[CH2:5][N:6]([C:12]1[S:13][C:14]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)=[C:15]([CH2:22][N:23]([CH2:25][CH2:26][O:27][CH3:28])[CH3:24])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(OCC)C.C(O)C.[C].[Pd]>[F:2][C:3]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:4]=1[CH2:5][N:6]([C:12]1[S:13][C:14]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=2)=[C:15]([CH2:22][N:23]([CH2:25][CH2:26][O:27][CH3:28])[CH3:24])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(N(Cc2c(F)cccc2F)C(=O)OCC)sc(-c2ccc([N+](=O)[O-])cc2)c1CN(C)CCOC
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(N(Cc2c(F)cccc2F)C(=O)OCC)sc(-c2ccc(N)cc2)c1CN(C)CCOC
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 2N hydrochloride in diethyl ether (21 ml) and 10% palladium-carbon (50% wet, 3.73 g) were added to a solution of ethyl 2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-4-[N-(2-methoxyethyl)-N-methylaminomethyl]-5-(4-nitrophenyl)thiophene-3-carboxylate (12.43 g) (JP-A-2001-278884, WO 00/56739) in ethanol (315 ml). The mixture was stirred vigorously under hydrogen atmosphere for 1 hour. The catalyst was removed, and the filtrate was neutralized with sodium hydrogen carbonate solution. The solvent was distilled off, and the residue was distributed between ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to an NH-silica gel (Fuji Silysia Chemical) chromatography to give the title compound (11.44 g) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[CH:18]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CN(C=O)C>[CH:18]1([CH2:24][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CCCCC1

Procedure:
In 175 ml of DMF containing 138 g of anhydrous potassium carbonate (1.0 m) was added 100 g of 3-hydroxy-4-methoxybenzaldehyde and 127 g of cyclohexylmethybromide. The mixture was heated at reflux temperature overnight and then poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated in vacuo to render the desired subtitled intermediate, b.p. 130°-135 ° C.
Reaction SMILES: [O-2].[La+3:2].[O-2].[O-2].[La+3].[N+]([O-])(O)=O.[C:10]([OH:15])(=[O:14])[C:11]([OH:13])=[O:12]>O>[C:10]([O-:15])(=[O:14])[C:11]([O-:13])=[O:12].[La+3:2].[C:10]([O-:15])(=[O:14])[C:11]([O-:13])=[O:12].[C:10]([O-:15])(=[O:14])[C:11]([O-:13])=[O:12].[La+3:2]
Reactant: O=C(O)C(=O)O
Agent: [La+3]
Agent: [O-2]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Yield: 193.3 %

Procedure:
50 g (0.15 mol) of untreated lanthanum oxide (Fluka) were converted to the nitrates by adding 68.39 ml of concentrated nitric acid and 1.5 1 of demineralized water. During this, the solution was stirred and gently heated in order to speed up the dissolution process. After cooling the solution to room temperature, 84.27 g (0.67 mol, 1.5 equiv.) of oxalic acid, dissolved in 500 ml of demineralized water, were added with stirring and lanthanum oxalate was precipitated out. Decantation and filtration through a Buchner funnel were then carried out. The resulting white solid was dried overnight in a drying cabinet at 110° C. 78.43 g (0.145 mol, 94.3% of theory) of lanthanum oxalate were obtained. 2 g of the lanthanum oxalate were then calcined in air in a tubular furnace at 650° C. for 18 hours. After cooling to 50° C. in the stream of nitrogen, the prepared, white lanthanum oxide was transferred to a Schlenk tube filled with argon. A further 6 g of lanthanum oxalate were calcined to lanthanum oxide for 18 hours in the muffle furnace at 700° C., cooled in the desiccator and likewise stored in a Schlenk tube under argon.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[N:3]=1.[CH3:18][O-:19].[Na+].C(Cl)(Cl)Cl.O>CO>[Cl:12][C:11]1[C:2]([O:19][CH3:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:6]([CH3:17])[CH:5]=2
Reactant: COC(=O)c1cc2nc(Cl)c(Cl)nc2cc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2nc(Cl)c(OC)nc2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under cooling in an ice-acetone bath, to a mixed liquid of 10.0 g of methyl 2,3-dichloro-7-methylquinoxaline-6-carboxylate in methanol was added dropwise a mixed liquid of 8.54 g of a 28% sodium methoxide solution in methanol and 80.0 mL of methanol over 6 hours. After stirring at the same temperature for 1 hour, the mixture was warmed to room temperature, followed by stirring for 1 hour. To the reaction mixture were added chloroform and water, followed by extraction with chloroform, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 10.1 g of methyl 3-chloro-2-methoxy-7-methylquinoxaline-6-carboxylate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccc(Cl)cc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(Cl)cc3)c2O1

Procedure:
The title compound was prepared (0.056 g, 71%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:25]=[CH:24][C:18]([O:19]C2CNC2)=[CH:17][CH:16]=1>O1CCCC1.O.C1C=CC=CC=1>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH:11]2[CH2:9][N:8]([C:1]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[O:2])[CH2:12]2)=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CC(Oc2ccc(C(F)(F)F)cc2)C1)n1ccnc1
Reaction time: 6 h
Yield: 45 %

Procedure:
A mixture of 1.7 g (0.01 mole) 1,1'-carbonyldiimidazole in 50 ml of tetrahydrofuran and 3 g (0.015 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine was stirred for 6 hr. The reaction mixture was diluted with water and extracted with 3×50 ml of methylene chloride. The extracts upon concentrating in vacuo gave an amber residue which was dissolved in 20 ml of benzene and washed with dilute hydrochloric acid, then washed with water. The benzene portion was concentrated to give a semi-solid residue which when triturated with isopropyl ether gave 1.4 g of gray material. Recrystallization from acetonitrile gave 1.3 g (41.8%) of fine gray crystals, m.p. 139°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[O:30][CH3:31].B(F)(F)F.CCOCC.[CH2:41]([Mg]Cl)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][S@@:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:4][C:3]=1[O:30][CH3:31]
Reactant: COc1cc(C(=N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: Cl[Mg]Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C(Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 0.17 h

Procedure:
To a solution of (R)-N-((4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (4.4 g, 9.42 mmol) in CH2Cl2 (190 mL, 0.05 M) at −71° C. was added BF3.Et2O (2.37 mL, 18.8 mmol). The reaction mixture was stirred for 10 min and BnMgCl (25 mL, 1N in Et2O, 26 mmol) was added. The reaction mixture was stirred at −75° C. for an additional 5 min, and quenched by the addition of saturated NH4Cl. The organic portion was separated, washed by H2O, dried over Na2SO4 and filtered. The solvent was then removed under reduced pressure and the residue was purified by ISCO chromatography using hexanes/EtOAc (0-80%) to give (R)-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a mixture of two diastereomers. The mixture (1 to 4 ratio) was then separated by chiral AD column using 20% IPA/hep/0.15 DEA as mobile phase to afford (R)-N-((S)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.79 g, 15% yield). LCMS: RT=2.09 min, [M+H] 560.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C=O)C.[CH2:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=2)[CH2:21][CH2:20]1)[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:43])=O>>[ClH:43].[CH2:15]([N:17]([CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=2)[CH2:23][CH2:24]1)[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1
Reactant: CCNCC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCN(c2ccnc(C(F)(F)F)n2)CC1)C(=O)c1cccnc1
Product: Cl
Reaction time: 18 h
Yield: 67 %

Procedure:
Nicotinic acid (6.16 g, 50 mmole) was refluxed in thionyl chloride (40 ml) for 3 hr. The excess thionyl chloride was removed in vacuo to give a white powder. DMF (90 ml) was added, followed by N-Ethyl-N-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]amine (9.75 g, 33.8 mmole) and sodium carbonate (10.6 g, 100 mmole). The mixture was stirred for 18 hr and then was filtered and concentrated in vacuo. The residue was chromatographed on silica gel using 5% methanol/ethyl acetate to give formula I product (8.9 g, 67%). The free base was converted to the hydrochloride salt using excess ethanolic HCl to give a light brown powder (mp: 79°-110°).
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:10][CH:11]([OH:13])[CH3:12])=O)(C)(C)C.O1CCOCC1.C(Cl)[Cl:32]>>[ClH:32].[NH2:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:10][CH:11]([OH:13])[CH3:12]
Reactant: CCOc1cc(C(CC(C)O)NC(=O)OC(C)(C)C)ccc1OC
Reactant: ClCCl
Solvent: C1COCCO1
Product: CCOc1cc(C(N)CC(C)O)ccc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of (tert-butoxy)-N-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]carboxamide (0.98 g, 2.89 mmol) and 4Nhydrochloric acid/dioxane (3 mL) in methylene chloride (10 mL) was stirred at room temperature for 16 hours. The resulting slurry was filtered and washed with ethyl acetate to give 4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol hydrochloride as a white solid (0.68 g, 85%); 1H NMR (D2O) δ 7.12 (m, 3H), 4.47 (t, J=7.0 Hz, 1H), 4.20 (q, J=7.4 Hz, 2H), 3.90 (s, 3H), 3.83-3.76 (m, 1H), 2.21-2.15 (m, 2H), 1.43 (t, J=6.9 Hz, 3H), 1.24 (d, J=6.1 Hz, 3H); 13C NMR (D2O) δ 151.75, 150.48, 131.92, 123.09, 115.05, 114.54, 67.86, 66.98, 58.53, 55.35, 44.41, 24.49, 16.68.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 30 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 12.8 mg (0.067 mMol) 4-methylbenzenesulfonyl chloride, 5.3 mg (31%) of the title compound were recovered as a light beige solid.
Reaction SMILES: [C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]Cl.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: O=S(=O)(c1cccc2ccccc12)n1ccc2c(N3CCNCC3)cccc21
Reaction time: 4 h

Procedure:
A mixture of 461 mg (1.43 mmole) 1-(naphthalene-1-sulfonyl)-1H-indol-4-ylamine, 255 mg (1.43 mmole) bis(2-chloroethyl)amine hydrochloride, and 0.5 mL diisopropylethylamine in 5 mL chlorobenzene was heated under reflux. After 4 hours, 0.25 mL diisopropylethylamine was added and heating under reflux was continued for 15 hours. The mixture was partitioned between 25 mL ethyl acetate and 10 mL 5% sodium hydroxide. The organic phase was washed with 5 mL saturated sodium chloride solution, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 8% methanol in chloroform. 1-(Naphthalene-1-sulfonyl)-4-piperazin-1-yl-1H-indole (1) was isolated as the hydrochloride salt from ethyl acetate/ether, 54 mg, M+H=392.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:41])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37]Cl)=[C:30]([O:39][CH3:40])[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].[K]>CN(C)C=O>[CH2:23]([O:25][C:26](=[O:41])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[C:30]([O:39][CH3:40])[CH:29]=1)[CH3:24]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1

Procedure:
A mixture of 9.1 g (0.03 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 8.6 g (0.03 mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.5 g of potassium iode in 150 ml of dimethylformamide was heated on a steambath for 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an off-white solid which was recrystallized from isopropyl ether/2-propanol. The yield of the title compound was 12.7 g (77%), mp 110°-112° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:17])[C@H:4]1[C@H:8]([CH2:9][O:10][CH3:11])[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>>[CH3:11][O:10][CH2:9][C@@H:8]1[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5][C@H:4]1[C:3]([Cl:17])=[N:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Solvent: CCN(CC)CC
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
(2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135.0 mmol) was dissolved in Et2OH (600 mL) and cooled in an ice bath. Methanesulfonyl chloride (10.49 ml, 135.0 mmol) was added, followed by dropwise addition of triethylamine (18.82 ml, 135.0 mmol). The reaction was stirred for 30 minutes and then filtered and concentrated. The residue was purified on 1 Kg SiO2 (1 to 5% EtOAc in CH2Cl2) to afford (2R,3S)-3-(methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (22.6 g, 66.12 mmol, 48.98% yield).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[N:31]1[CH:36]=[CH:35][C:34]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccncc1
Yield: 56 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and pyridin-4-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (56% yield); 1H-NMR (d6-DMSO) 1.11 (9H, s), 3.67 (2H, t), 4.13 (1H, t), 6.74 (1H, s), 7.18 (2H, m), 8.43 (2H, m); 13C-NMR (d6-DMSO) 27.7, 41.3, 66.9, 119.3, 134.7, 149.5; MS ES(+) 263.0 (M++1); HRMS m/z calcd for C14H18N2O3+H+ 263.1296 [M+H+]. Found 263.1402. IR λmax=1695 cm−1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=C(C#N)[N:2]=1.[CH3:13][Mg]Br.CC[O:18][CH2:19][CH3:20]>O1CCCC1>[C:19]([C:20]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:18])[CH3:13]
Reactant: C[Mg]Br
Reactant: N#Cc1cc2ccccc2cn1
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccccc2cn1
Temperature: 0 °C
Yield: 87 %

Procedure:
Isoquinoline-3-carbonitrile (1.76 g, 11.4 mmole) is dissolved in 10 ml tetrahydrofuran in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution is cooled to 0° C., is diluted with 5 ml diethyl ether, and is treated with methyl magnesium bromide in ether (5.7 ml, 17.1 mmole). The reaction is warmed to reflux for one hour, is cooled to 0° C., and is quenched with 15 ml 6 M hydrochloric acid. The reaction mixture is warmed to 50° C. for one hour, is cooled, and is poured into 75 ml 2N sodium hydroxide. The mixture is extracted with 3×50 ml ethyl acetate and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to a crude orange solid. The crude material is chromatographed over 60 g silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 22 ml fractions. Fractions 7-11 are combined and concentrated to provide 1.7 g (87%) of 3-acetyl-isoquinoline.