Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]([O:3][C:4]([C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cccs2)CCC=CCC1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)C1(c2cccs2)CCCCCC1
Yield: 86.7 %

Procedure:
1-Thiophen-2-yl-cyclohept-4-enecarboxylic acid ethyl ester (Example 5b) (2.86 g) was dissolved in ethanol (30 mL) and tris(triphenylphosphine)rhodium(I) chloride (0.100 g) was added. The reaction mixture was stirred rapidly under 5 atmospheres of hydrogen overnight. Further tris(triphenylphosphine)rhodium(I) chloride (0.050 g) was added and the reaction mixture was stirred under 5 atmospheres of hydrogen for 3 days. A third addition of tris(triphenylphosphine)rhodium(I) chloride (0.050 g) was made and the reaction mixture was stirred under 3 atmospheres of hydrogen overnight. The contents were evaporated to dryness and purified on silica eluting with ethyl acetate/isohexane (5/ 95) to afford the sub-titled compound (2.500 g) as a clear almost colourless oil
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([OH:26])=O)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([NH:45][CH2:46][C@@H:47]2[NH:51][CH2:50][C@H:49]([OH:52])[CH2:48]2)[CH2:44][CH2:43]1>CN(C=O)C>[CH:42]1([NH:45][CH2:46][C@H:47]2[CH2:48][C@@H:49]([OH:52])[CH2:50][N:51]2[C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:26])[CH2:44][CH2:43]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: O[C@H]1CN[C@@H](CNC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@H](O)C[C@@H]2CNC2CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.28 mmol), EDC (64 mg, 1.2 eq.), HOBt (45 mg, 1.2 eq.) in DMF (3 mL) was added TEA (0.098 mL) and (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol. The mixture was stirred at rt for overnight. After the usual work up, 65 mg of the titled compound was obtained as a yellow solid.
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:49])[C:11]2[CH2:17][CH:16]([CH2:18][N:19]([CH2:26][C:27]3[CH:48]=[CH:47][C:30]([C:31]([NH:33][C@H:34]([C:42]([O:44]CC)=[O:43])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:32])=[CH:29][CH:28]=3)C(=O)C(F)(F)F)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.C>[OH-].[Na+]>[NH2:7][C:8]1[N:9]=[C:10]([OH:49])[C:11]2[CH2:17][CH:16]([CH2:18][NH:19][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([NH:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:32])=[CH:47][CH:48]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)C(=O)C(F)(F)F)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CNCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C2
Reaction time: 4 h
Yield: 76 %

Procedure:
A solution of 0.48 g, of diethyl N-[N-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-ylmethyl)-N-trifluoroacetyl-4-aminomethylbenzoyl]-glutamate in 10 mL of 1N sodium hydroxide was stirred at 25° C. for 72 hours. To the reaction mixture was added charcoal and the suspension filtered through Celite. The filtrate was rendered acidic with acetic acid and stored at 0° C. for 4 hours. The solid which formed was collected, and washed sequentially with water, ethanol, and ether to give 0.241 g (76% yield) of N-[N-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamic acid; mp 263° C. (dec); 1H NMR (Me2SO d6) delta 1.8-2.25 (m, 4H), 2.27 (t, 2H, J=6.95 Hz), 2.73-3.00 (m, 2H), 3.28-3.31 (m, 1H), 4.05 (s, 2H), 4.14 (s, 2H), 4.21 (s, 2H), 4.36-4.41 (m, 1H), 7.41-7.7.45 (m, 2H, AA'BB'), 7.80-7.82 (m, 2H, AA'BB'), 8.61 (s, 1H). Anal. Calcd for C21H26N6O6.H2O: C, 53.95; H, 5.82; N, 17.97. Found: C, 54.07; H, 5.48; N, 17.76.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][C:11]([CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)([CH3:13])[CH3:12])(=[O:9])[CH3:8].Cl>CO>[C:7]([NH:10][C:11]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)([CH3:13])[CH3:12])(=[O:9])[CH3:8]
Reactant: COC(=O)C1CCC(C(C)(C)NC(C)=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](C(C)(C)NC(C)=O)CC1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (30.0 g) was added to a solution (150 ml) of a cis- and trans- mixture of methyl 4-(1-acetamido-1-methylethyl)cyclohexanecarboxylate (30.8 g) in methanol and the mixture was refluxed under heating for 40 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was poured into ice water, neutralized with conc. hydrochloric acid and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The resultant crystals were recrystallized from methanol to give 24.5 g of methyl trans-4-(1-acetamido-1-methylethyl)cyclohexanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2([CH3:22])[CH2:21][O:20]2)=[O:18])=[CH:12][C:11]=1[CH3:23]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:18])[C:19]([OH:20])([CH3:21])[CH2:22][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][C:11]=1[CH3:23]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1F
Reactant: Oc1ccc(F)cc1
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(F)cc2)ccc1F

Procedure:
N-(4-Fluoro-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1c starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.4% methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[O:13]1[CH2:15][C@H:14]1[CH2:16]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:16][C@@H:14]2[CH2:15][O:13]2)[CH:3]=1
Reactant: CC(=O)Nc1ccc(F)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(F)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of N-(4-fluoro-2-hydroxyphenyl)acetamide (1.69 g, 10.0 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.59 g, 10.0 mmol) and Cs2CO3 (4.87 g, 15.0 mmol) in DMF (15 mL) was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethylacetate and H2O. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was purified by silica gel flash chromatography to give the subtitled compound (1.35 g).
Reaction SMILES: [O:1]=[C:2]1[NH:20][C@@H:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][C@@H:4]2[O:3]1.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[C@@H:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:8][CH2:9][C@@H:4]2[O:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@@H]2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (3aR,7aS)-benzyl 2-oxohexahydrooxazolo[4,5-c]pyridine-5(6H)-carboxylate (1.0 equiv.) in dichloromethane (0.09 M) was added BOC2O (1.1 equiv.), triethylamine (1.1 equiv.), and a catalytic amount of DMAP. The reaction was stirred at room temperature for one hour at which point it was concentrated under vacuo and filtered through a plug of silica gel eluting with ethylacetate. The product was dried under vacuo to yield (3aR,7aS)-5-benzyl 3-tert-butyl 2-oxotetrahydrooxazolo[4,5-c]pyridine-3,5(2H,6H)-dicarboxylate as a white solid in 75% yield. LCMS (m/z): 277.2 (MH+), Rt=3.43 min.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[OH:18])#[N:7].[H-].[Na+].[C:22]([O:25][CH2:26][CH2:27][CH2:28]Br)(=[O:24])[CH3:23]>O>[C:6]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:28][CH2:27][CH2:26][O:25][C:22](=[O:24])[CH3:23])#[N:7]
Reactant: CC(=O)OCCCBr
Reactant: N#Cc1cc2cccc(O)c2oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCOc1cccc2cc(C#N)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25 %

Procedure:
In 150 ml. of dry dimethylformamide was dissolved 9.35 g. of 3-cyano-8-hydroxycoumarin. To the resulting solution was added 2.5 g. of about 60% sodium hydride with agitation and ice-cooling, and after raising to room temperature, the solution was agitated for 20 minutes. After adding dropwise 9.05 g. of 3-acetoxypropyl bromide at a temperature of 80° to 90° C. with agitation, the reaction was carried out for 5 hours with agitation. After the completion of the reaction, the reaction mixture was poured into 200 ml. of water added with ice, and extracted with three 200 ml. portions of methylene chloride. The obtained extract was dried with magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue was purified by a silica-gel column chromatography (silica-gel: 350 g., eluent: methylene chloride) to give 3-cyano-8-(3-acetoxypropoxy)coumarin (yield: 25%). The product was further recrystallized from ethyl acetate to give light yellow needles having a melting point of 132° to 135° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(NC(C)C)(C)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]=[C:20]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:3]=1)[CH3:22]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc2c(Br)nn(-c3ccsc3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1nn(-c2ccsc2)c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Yield: 86.9 %

Procedure:
Methyl 3-bromo-1-(thiophen-3-yl)-1H-indazole-6-carboxylate (1.414 g, 4.19 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.58 ml, 8.41 mmol), diisopropylamine (1.18 ml, 8.40 mmol), triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt hydrate (275.8 mg, 0.431 mmol), and palladium(II) acetate (48.3 mg, 0.215 mmol) were dissolved in N,N-dimethylformamide (15 ml)/water (5 mL), placed in a sealed tube and heated to 100° C. for 4 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (20 mL), and the mixture extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 330 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-15%). The title compound (1.0847 g, 3.64 mmol, 87% yield) was recovered as a white solid. LC-MS: [M+1]=299.2.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=4)[N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.O.CN(C=O)C>[C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26]([N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[O:27])[CH:20]=4)[N:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3cc(-c4csc(CS(=O)(=O)c5ccccc5)n4)c(=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(2-benzenesulfonylmethyl-thiazol-4-yl)-1H-quinolin-2-one-7-carboxylic acid (step (h), 0.1 g, 0.2 mmol), EDC (0.08 g, 0.4 mmol), HOBt (0.08 g, 0.6 mmol), DMAP (4 mg), and 4 mL of DMF were stirred for 15 min, and then 1-methyl piperazine (0.13 mL, 1.2 mmol) was added. The reaction was stirred at RT for 24 h. The reaction was diluted with 50 mL of H2O and extracted with EtOAc (4×). The combined EtOAc layers were washed with 0.5N HCl, saturated NaHCO3, and brine. The acidic aqueous layer was neutralized with 1N NaOH and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting solid was suspended in a minimum of EtOAc and filtered to give a solid. MS m/z: 509.4 (M+1). Anal. Calc'd for C25H24N4O4S2: C, 59.04; H, 4.76; N, 11.02. Found: C, 58.75; H, 4.87; N, 10.90.
Reaction SMILES: [C:1]([NH:5][S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:15][CH2:14]C1.C([Li])CCC.CN(C)C=O>CCOC(C)=O>[C:1]([NH:5][S:6]([C:9]1([CH:14]=[O:15])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)NS(=O)(=O)C1CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)C1(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round-bottom flask equipped with a stir bar was added N-(tert-butyl)cyclopropanesulfonamide (10.0 g, 56.4 mmol) and THF (220 mL). The flask was placed under a nitrogen atmosphere and the solution was then cooled to −78° C. To the stirred solution was added dropwise over 10 minutes n-butyllithium (46.3 mL, 2.5M in hexanes). The resulting solution was stirred at −78° C. for 30 mins and then the cold bath was removed and the solution was allowed to warm to room temperature temperature with stirring for 30 mins. The solution was cooled to −78° C. To the solution was added N,N-dimethylformamide (13.1 mL, 169 mmol). The solution was allowed to slowly warm to room temperature with stirring for 17 h. The mixture was concentrated and the resulting yellow residue was dissolved in EtOAc (100 mL). The solution was transferred to a separatory funnel and was washed with aq. 1N HCl (150 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organics were washed with sat. aq. NaCl (50 mL); dried over Na2SO4; and filtered. The filtrate concentrated in vacuo to afford a yellow viscous oil which solidified upon standing at room tempearture. This material was dissolved in EtOAc (10 mL); diluted with hexanes (50 mL); and the resulting solution was then stored at −78° C. for 2 h upon which crystals formed. The crystals were collected via filtration; were washed with cold hexanes; and residual solvent was removed in vacuo to afford N-(tert-butyl)-1-formylcyclopropane-1-sulfonamide as a colorless, crystalline solid (8.89 g, 77%). 1H NMR (500 MHz, CDCl3) δ 9.52 (s, 1H), 4.72 (br. s., 1H), 1.90-1.85 (m, 2H), 1.66-1.62 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][CH2:12][CH:13]([OH:36])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([OH:36])[CH2:12][NH:11][C:7]34[N:6]=[CH:5][N:4]=[C:3]3[CH:2]=[N:10][CH:9]=[N:8]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(CNC12N=CN=CC1=NC=N2)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 6-chloropurine (0.728 g, 4.7 mmol), 1-amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol (1.73 g, 4.77 mmol) and triethylamine (1.36 mL, 9.5 mmol) in MeOH (20 mL) was heated to reflux for 7 days and the solvent was removed in vacuo. The residue was dissolved in CHCl3 and the extracted with aqueous sodium bicarbonate (2×100 mL); the organic phase was dried over sodium sulfate and evaporated to give a solid which was purified by flash chromatography on silica gel with 5% MeOH in CHCl3. The product was a colorless solid which was triturated with ether, 1.5 g (70%), mp 140°-170° C.; IR (KBr) 3000 cm-1 ; 300 MHz 1H NMR (CDCl3); δ: 8.17 (s, 1H), 8.11 (s, 1H), 7.5-7.0 (m, 8H), 4.90 (br s, 1H), 4.34 (s, 1H), 3.87 (br s, 1H), 3.7-2.0 (m, 12H); MS 480 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]3([OH:36])[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([C:16]3([OH:36])[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:18][CH2:17]3)[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCOC1
Product: OC1CCN(CC(c2ccccc2)c2ccccc2)CC1C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.5 Parts by volume of 1.5 M solution of lithium perhydro-9b-boraphenallyhydride in tetrahydrofuran is added to a stirred, cold (-78° C.) solution of 0.65 part of 1-(2,2-diphenylethyl)-3-[1-(2,2-diphenylethyl)-4-hydroxypiperidin-4-yl]-4-piperidinone in 25 parts by volume of tetrahydrofuran under nitrogen atmosphere. The reaction is allowed to run for about 30 minutes and then it is quenched with the addition of 25 parts by volume of 10% ammonium chloride solution. Ethyl ether is added to the reaction mixture and it is allowed to warm to room temperature. After 2 hours the organic layer is separated and then extracted twice with 10% hydrochloric acid. The combined acid extracts are made alkaline with 50% sodium hydroxide and then extracted twice with ethyl ether. The organic fractions are combined, dried, and concentrated to yield yellow gum which crystallizes when triturated with ethyl ether to afford 1-(2,2-diphenylethyl)-3-[1-(2,2-diphenylethyl)-4-hydroxypiperidin-4-yl]-4 -piperidinol. This compound melts at about 174°-175° C. after recrystallization from absolute ethanol, and is represented by the following structural formula ##STR39##
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:26][CH:27](Br)[C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[Br:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[S:10]1(=[O:18])=[O:19]
Reactant: Cc1ccccc1C(Br)Br
Reactant: O=S1(=O)Nc2ccccc2N1c1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(Cc2ccccc2CBr)c2ccccc2N1c1cccc(F)c1F

Procedure:
In an analogous manner to general procedure IV, 1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 75 mg, 0.27 mmol) was treated with cesium carbonate (132 mg, 0.4 mmol) and α,α-dibromo-ortho-xylene (346 mg, 1.32 mmol) to give 68 mg of 1-[2-(bromomethyl)benzyl]-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH:16]=[C:17]([CH3:22])[CH2:18][N+:19]([O-:21])=[O:20]>O1CCCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][CH:16]=[C:17]([CH3:22])[CH2:18][N+:19]([O-:21])=[O:20])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=CCBr)C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=C(C)C[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.1 Mol of diethyl malonate and 0.25 Mol of sodium hydride in tetrahydrofuran was added a solution of 0.1 Mol 1-bromo-3-methyl-4-nitro-2-butene in tetrahydrofuran and stirred for 3 hours at room temperature. The reaction mixture was worked up via an acid extraction with ether. The excess of diethyl malonate was cautiously removed via distillation and the product purified by column chromatography over silica gel using ether/hexane 1:1 as eluent. A yellow oil was obtained.
Reaction SMILES: C.Cl[C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[CH:4]=1.C(O)=O>C(N(CC)CC)C.O.[Pd]>[CH3:21][O:20][CH2:19][CH2:18][NH:17][C:5]1[CH:4]=[CH:3][CH:8]=[C:7]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: COCCNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: O
Product: COCCNc1cccc(NCCOC)c1[N+](=O)[O-]

Procedure:
0.4 g of palladium at a concentration of 10% on active charcoal is added to 0.084 mole (25.5 g) of 4-chloro-2-(β-methoxyethyl)amino-6-(β-methoxyethyl)aminonitrobenzene in 33.4 ml of triethylamine, after which 7 ml of formic acid are added dropwise. At the end of the additions, the reaction mixture is heated for 1 hour 30 minutes, under reflux. The reaction mixture is diluted with 100 ml of 96° alcohol and 100 ml of water. The expected product precipitates. After filtration, the expected product containing the catalyst is dissolved in 90 ml of isopropyl alcohol. The catalyst is removed by hot filtration. The expected product crystallizes.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:17]=1)[CH:2]=[CH2:3].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C:18]1[N:17]=[C:16]([N:5]2[C:6]3=[N:7][C:8]([NH:41][C:40]4[CH:39]=[CH:38][C:37]([N:34]5[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:36][CH2:35]5)=[CH:43][CH:42]=4)=[N:9][CH:10]=[C:11]3[C:12](=[O:13])[N:4]2[CH2:1][C:2]#[CH:3])[CH:21]=[CH:20][CH:19]=1
Reactant: COCCN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(CC(C)(C)O)n1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CCOC)CC4)cc3)nc2n1-c1cccc(CC(C)(C)O)n1

Procedure:
31 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 81-2 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-[4-(2-methoxyethyl)piperazin-1-yl]aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.