Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][C:20]=1[S:31](=[O:34])(=[O:33])[NH2:32]>O1CCCC1>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](=[O:24])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:21][C:20]=1[S:31]([NH2:32])(=[O:34])=[O:33]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC(C)COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
1-Bromo-4-isobutoxy-benzene (625 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (250 mg, 0.91 mmol) in tetrahydrofuran (2 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 120 mg (37% yield) of the title compound. 1H NMR (DMSO) δ 1.00 (d, 6H, J=6.56 Hz), 2.01-2.10 (m, 1H), 3.88 (d, 2H, J=6.57 Hz), 7.11 (d, 2H, J=8.85 Hz), 7.76 (d, 2H, J=8.85 Hz), 7.81-7.84 (m, 3H), 7.89 (dd, 1H, J=2.02, 8.08), 8.24 (d, 1H, J=2.02). MS (m/z): 366 (M−1). CHN Calc C, 55.51; H, 4.93; N, 3.81. Found C, 55.38; H, 4.74; N, 3.77.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23].CCN(CC)CC>C(Cl)Cl>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([NH:3][S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])[CH2:5][CH2:6]2)=[O:11])[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 32.6 mg (0.1 mmol) trans-(4-amino-cyclohexyl)-(4-isopropyl-piperazin-1-yl)-methanone, dihydrochloride, 28 mg (0.2 mmol) propane-1-sulfonyl chloride and 101 mg (1 mmol) NEt3 in 2 ml DCM was stirred for 16 h at 40° C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 13.9 mg (39%) of the title compound. MS (m/e): 360.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1>[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:14][CH:13]=[C:12]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Brc1cncnc1
Reactant: Cc1csc(NC(=O)c2nc(C(C)(C)O[SiH2]C(C)(C)C)ccc2N)n1
Agent: [Pd]
Product: Cc1csc(NC(=O)c2nc(C(C)(C)O[SiH2]C(C)(C)C)ccc2Nc2cncnc2)n1

Procedure:
Palladium catalysed arylation of 3-Amino-6-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide with 5-Bromopyrimidine according to the general procedure described in example 4 step 4 yielded the title product as a light yellow solid, MS (ISP): m/e=457.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15].[CH3:21]I.[OH-].[Na+]>CC(C)=O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:21])[C:3]=1[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15]
Reactant: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 25 °C
Yield: 90.2 %

Procedure:
2-Methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (31.0 g., 0.1035 mole) was combined with 230 ml. of acetone and cooled to 10° C. Methyl iodide (21.9 g., 0.155 mole) was added, followed by the dropwise addition, over 10 minutes, of sodium hydroxide (103.5 ml. of 1 N). The cooling bath was removed and the reaction mixture allowed to slowly warm to room temperature (about 45 minutes), then heated at 35° C. for 2 hours and finally at 39°-40° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with 200 ml. of acetone, treated with activated carbon, filtered and concentrated in vacuo at 0°-5° C. to about 50 ml. The resulting slurry was filtered, and solids washed with ice-water and then dried in vacuo to yield 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide [29.26 g., 90%; m.p. 106°-107.5° C.; m/e 313; ir(KBr) 3345, 2941, 1684, 1351, 1053 cm-1 ].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: O=Cc1cccnc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2ccc(Br)cc2c1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 5-bromo-2-methyl-1H-indole (J. Chem. Soc., 1428 (1965)) (2.0 g) and 3-pyridinecarboxaldehyde (1.02 g) in dry dichloromethane (20 ml) was added dropwise over 10 minutes to a stirred solution of triethylsilane(3.30 g) in trifluoroacetic acid (20 ml) at 0° C. The solution was stirred at 0° C. for 30 minutes and then evaporated under vacuum, keeping the temperature below 35° C. The residue was dissolved in dichloromethane, and the solution was washed with 2N sodium hydroxide, water and dried (MgSO4). The solution was evaporated and the residue was chromatographed on silica gel, using dichloromethane/methanol (50:1) as eluent. The product fractions were combined and evaporated, and the residue was crystallised from ether to give the title compound (2.15 g), m.p. 188°-190° C. Found: C,59.62; H,4.43; N,9.26. C15 H13BrN2 requires: C,59.82; H,4.35; N,9.30%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10]1([CH3:33])[CH:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]2[C:19](=[O:32])[CH:20]([NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]2[S:11]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:9][C:10]2([CH3:33])[CH:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]3[C:19](=[O:32])[CH:20]([NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:12]3[S:11]2)=[N:4][N:3]=1
Reactant: Cc1nnc(S)s1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CSc1nnc(C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.4 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.4 g) was dissolved in a mixture of pH 7.3 phosphate buffer (20 ml) and acetone (20 ml). To this solution was added a solution of methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.80 g) in acetone (10 ml) and the mixture was stirred for 4 hours at room temperature. After the reaction was completed, acetone was distilled off from the reaction mixture and the residue was extracted with ethyl acetate. The extract was washed with sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (60 g) and eluted with chloroform. The eluate was separated into fractions of each about 30 ml to give methyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.28 g) from the fourth to seventh fractions.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[N:6][CH:5]=[N:4]1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.[Cl-].[Na+]>O1CCCC1>[O:19]1[CH2:18][CH:17]1[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: BrCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ncn(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
The intermediate 2,3-epoxypropoxy-4-(1,2,4-triazol-1-yl)-benzene is prepared in the following manner: 2.9 g (0.067 mole) of sodium hydride, as a 55% strength suspension in liquid paraffin, are introduced into 70 ml of anhydrous tetrahydrofuran, and a solution of 10.8 g (0.067 mole) of 4-(1,2,4-triazol-1-yl)-phenol in 50 ml of tetrahydrofuran is added dropwise. 9.2 g (0.067 mole) of epibromohydrin are then added dropwise. The reaction mixture is stirred for from 5 to 10 hours at room temperature and then poured onto 500 ml of aqueous sodium chloride solution, and the precipitate which separates out is filtered off under suction and washed thoroughly with water. The crude product is recrystallized from toluene/petroleum ether. 11.2 g (77%) of product of melting point 104°-105° C. are isolated.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH2:4].[CH2:21]([O:23][C:24]1[C:27](=O)[C:26](=[O:29])[C:25]=1[O:30]CC)[CH3:22]>C(O)C>[OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH:4][C:27]1[C:26](=[O:29])[C:25](=[O:30])[C:24]=1[O:23][CH2:21][CH3:22]
Reactant: NCC(O)COCc1cccc(CN2CCCCC2)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(NCC(O)COCc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Reaction time: 5 h

Procedure:
2.78 g (0.01 mol) of 2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propylamine in 10 ml of ethanol are slowly added dropwise to 1.70 g (0.01 mol) of 1,2-diethoxycyclobutene-3,4-dione and the mixture is stirred for 5 hours. The title compound, which is obtained after the reaction solution has been concentrated by evaporation, is subsequently reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)(=O)C.CCO>[Cl:12][C:13]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1Cl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 2-chloro-3-(trifluoromethyl)benzaldehyde (0.42 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.64 g, in 93% yield, mp: 261.5° C. 1H NMR (CD3OD) δ 8.89 (s, 1H), 8.51 (d, 1H), 7.85 (m, 3H), 7.56 (t, 1H), 6.89 (d, 2H). 13C NMR (CDCl3) δ 166.9, 163.1, 144.3, 135.7, 132.8, 132.5, 131.0, 130.3, 130.1, 128.5, 125.4, 124.3, 123.2, 116.4. Anal. Calcd for C15H10ClF3N2O2. ½H2O: C, 51.22; H, 2.86; N, 7.96; CI, 10.08; F, 16.20. Found: C, 51.17; H, 3.04; N, 7.53; CI, 10.25; F, 15.93.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[O:7][CH2:8][CH:9]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)[N:12]=3)[CH:5]2[O:4][CH2:3]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:17][C:16]1[C:11]([NH:10][CH:9]2[CH:5]3[O:4][CH2:3][CH:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]3[O:7][CH2:8]2)=[N:12][C:13]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[N:14][CH:15]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(N)COC34)n2)cn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(NS(C)(=O)=O)COC34)n2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of N4-(6-aminohexahydrofuro[3,2-b]furan-3-yl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (57.0 mg, 0.16 mmol) in dichloromethane (5 mL) were added TEA (26.2 mg, 0.26 mmol) and N,N-dimethylpyridin-4-amine (4.1 mg, 0.03 mmol). The mixture was cooled to 0° C., and methanesulfonyl chloride (28.3 mg, 0.25 mmol) was added to. The mixture was stirred at 0° C. for 30 min, and stirred at room temperature overnight. The solution was concentrated in vacuo, and the residue was purified with a silica gel column chromatography (MeOH/DCM (v/v)=1/30) to afford the target product as an off-white solid (28.0 mg, 40.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:5][C:6]1[C:7](=[O:23])[N:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[CH3:12].[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:27][C:25]1[CH:26]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:7](=[O:23])[N:8]([CH2:13][C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][N:15]=3)[CH:9]=[CH:10][C:11]=2[CH3:12])[CH:24]=1)[C:28]#[N:29]
Reactant: CN(C)C=O
Reactant: Cc1ccn(Cc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccn(Cc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 90 °C

Procedure:
To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-methyl-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)pyridin-2(1H)-one (11-6; 100 mg, 0.224 mmol) and zinc cyanide (29 mg, 0.247 mmol) in DMF (1 mL) was added palladium tetrakis triphenylphosphine (51.9 mg, 0.045 mmol) and the mixture was degassed and heated to 90° C. for 20 minutes. After this time, additional zinc cyanide (29 mg, 0.247 mmol) and palladium tetrakis triphenylphosphine (51.9 mg, 0.045 mmol) were added and the mixture heated to 90° C. for 20 hours. The reaction mixture was then filtered through Gelman Acrodisc and purified on Gilson LC using a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA). Fractions containing desired compound were combine and the solvent concentrated in vacuo on a rotary evaporator. The residue was further purified using RediSep (4 g) and eluting with a 0-65% EtOAc/CH2Cl2 gradient. The desired fractions were combined and the solvent removed on the rotary evaporator to provide the title compound. 1H NMR (CDCl3): δ 11.48 (br s, 1H), 8.55 (d, 1H), 8.26 (d, 1H), 7.40 (d, 1H), 7.27 (dd, 1H), 7.14 (dd, 1H), 7.09 (dd, 1H), 6.96 (dd, 1H), 6.09 (dd, 1H), 5.48 (s, 2H) and 2.08 (s, 3H) ppm. LRMS (M+1)=392.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:24][CH2:23][CH2:22][Cl:21])(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C

Procedure:
A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g, 40 mmol). K2CO3 (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford 6.5 g or an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol water to yield 2.2 g (51%) of a solid, m.p.=124°-126° C. ANALYSIS: Calculated for C13H18ClNO3: 57.89%C 5.98%H 5.19%N Found: 57.08%C 5.85%H 5.13%N
Reaction SMILES: [C:1]([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[CH:15]([OH:19])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:9][C@H:10]([C@@H:13]1[CH2:17][C@@H:16]([CH3:18])[CH:15]([O:19][C:20](=[O:22])[CH3:21])[O:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC[C@H](OC(=O)c1ccccc1)[C@@H]1C[C@@H](C)C(OC(C)=O)O1
Yield: 72.5 %

Procedure:
To a solution of [(1S)-1-[(2S,4R)-5-hydroxy-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28i, crude, 1.2 g, 4.5 mmol) in pyridine (60 mL) was added acetic acid anhydride (0.918 g, 9 mmol) and DMAP (200 mg) with stirring. After being stirred 25° C. for 2 hours, the mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (40 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:5 EtOAc in petroleum ether) to afford 1.0 g of [(1S)-1-[(2S,4R)-5-acetoxy-4-methyl-tetrahydrofuran-2-yl]propyl] benzoate (compound 28j) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]=[C:15]1[C:20](=[O:21])[CH:19]2[CH2:22][CH2:23][N:16]1[CH2:17][CH2:18]2.Cl>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH:9]([CH2:14][CH:15]2[C:20](=[O:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)[C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: C=C1C(=O)C2CCN1CC2
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)C(CC1C(=O)C2CCN1CC2)C(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 93.10 g (0.47 mole) 1-(4-chlorophenyl)-1,3-butanedione in 500 ml acetone add 60.0 g (0.39 mole) 2-methylene-3-quinuclidinone. Stir the solution at reflux for about 24 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (EtOAc:MeOH, 9:1). At the completion of the reaction, chill the solution in an ice/water bath. Acidify dropwise with 35 ml concentrated hydrochloric acid to precipitate the product. Collect the precipitate by filtration to obtain the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(N=C=NC2CCCCC2)CCCC[CH2:28]1>CCO.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C/C(=C\c1ccc(C(=O)O)s1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1

Procedure:
A suspension of 0.161 g (0.437 mmol) of 5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylic acid, (Compound 3, 0.03 g, 0.655 mmol) in EtOH, 0.099 g (0.48 mmol) of 1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate washed with water and brine. The organic layers were combined and dried (MgSO4), The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)C.[CH2:18](N)[CH2:19][NH2:20]>C(O)C>[NH:20]1[CH2:19][CH2:18][N:5]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1
Reactant: NCCN
Reactant: CCON=Cc1ccc(C(=O)OCC)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
The resulting ethyl 4-[1-(ethoxy)iminomethyl]benzoate hydrochloride (2.00 g) was dissolved in ethanol (30 ml). Under ice cooling, ethylenediamine (0.52 ml) was added to the resulting solution, followed by heating to room temperature. The reaction mixture was stirred overnight. To the residue obtained by distilling off the solvent under reduced pressure, dilute hydrochloric acid was added to make it acidic, followed by concentration again. The residue was purified by chromatography through a synthetic adsorbent (“Diaion HP-20”, trade name; water˜50% acetonitrile-water). Solution of hydochloride in ethanol was added to the resulting fraction and the mixture was concentrated. Colorless crystalline powder precipitated by the addition of tetrahydrofuran was collected by filtration and dried, whereby the title compound (1.63 g, 19%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:22])[C:13]2[CH:18]=[N:17][N:16]([CH2:19][CH2:20][CH3:21])[C:14]=2[N:15]=1)[CH3:2].[Cl:23][S:24](O)(=[O:26])=[O:25]>C(OCC)C>[Cl:23][S:24]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[CH:18]=[N:17][N:16]([CH2:19][CH2:20][CH3:21])[C:14]=3[N:15]=2)[CH:6]=1)(=[O:26])=[O:25]
Reactant: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Reactant: O=S(=O)(O)Cl
Solvent: CCOCC
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
6-(2-Ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1; 0.5 g, 0.0017 mol) was added portionwise to stirred chlorosulphonic acid (3 ml) at 0° C. and the resulting solution stirred at room temperature for 14 hours. The reaction mixture was then added dropwise to ice/water (20 g) and the aqueous solution thus obtained was extracted with dichloromethane (4×30 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated under vacuum to give a white solid; trituration was diethyl ether (50 ml) gave the title compound (0.67 g, 100%), m.p. 177-180° C., which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[CH2:16][C:17]([NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[O:18]>>[CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH2:16][C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])=[O:18])[CH2:3]1
Reactant: Cc1ccc(N2CCNCC2C)cc1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Product: Cc1ccc(N2CCN(CC(=O)Nc3c(C)cccc3C)CC2C)cc1

Procedure:
The title compound was prepared from (±)-3-methyl-4-(4-methylphenyl)piperazine (0.1 g) and 2-chloro-N-(2,6-dimethylphenyl)acetamide (0.1 g) by the method of Example 1 step (iii) as a white solid. Yield 0.056 g.