Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH:16]([CH2:21][CH:22]=O)[C:17]2=O)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][CH2:15][C:16]3[CH:21]=[CH:22][N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:17]=3[C:18]=2[CH:19]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Reactant: CC(=O)NCCN
Solvent: ClCCl
Product: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)CC2
Yield: 80.8 %

Procedure:
N-Acetylethylenediamine (14.5 g) was dissolved in 250 ml of methylene chloride under argon, treated in succession with 250 g of molecular sieve 4 Å and a solution of 28.1 g of 1,2,3,4-tetrahydro-7-methoxy-1-oxo-2-naphthaleneacetaldehyde in 190 ml of methylene chloride and refluxed for 21 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 35.3 g of brown, amorphous material, was chromatographed on 600 g of silica gel with ethyl acetate as the eluent. There were obtained 29.6 g (81%) of N-[2-(4,5-dihydro-8-methoxy-1H-benzo[g]indol-1-yl)-ethyl]acetamide which was processed without further purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH:14]([N:13]([C@H:11]1[CH2:10][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:12]1)[CH3:17])([CH3:18])[CH3:15]
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 52A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.07 (d, J=8.42 Hz, 1H) 7.98 (d, J=1.87 Hz, 1H) 7.60 (dd, J=8.42, 1.87 Hz, 2H) 4.09 (s, 3H) 3.76-3.89 (m, 1H) 3.51-3.66 (m, 1H) 2.95-3.05 (m, 1H) 2.53-2.74 (m, 4H) 2.14 (s, 3H) 1.03 (d, J=6.55 Hz, 6H). MS: (M+H)+=369.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH2:35]O)=[CH:31][CH:30]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:35][CH2:34][O:33][C:32]2[CH:37]=[CH:38][C:29]([C:28]([F:27])([F:39])[F:40])=[CH:30][CH:31]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the tosylate of 2-(4-trifluoromethylphenoxy)ethanol (1.8 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1 ) and crystallized from diethyl ether-hexane to provide 1 g of alpha-oxo-4-[[2-(4-trifluoromethylphenoxy)ethyl]oxy] benzeneacetic acid methyl ester, mp 96°-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:23]=[C:24]([CH2:28][C:29](O)=O)C(O)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH:18]1([O:17][C:11]2[CH:10]=[C:9]([N:8]3[C:24](=[O:23])[C:28]([CH3:29])=[N:1][C:2]4[CH:7]=[CH:6][CH:5]=[N:4][C:3]3=4)[CH:14]=[CH:13][C:12]=2[O:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: COc1ccc(Nc2ncccc2N)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-n2c(=O)c(C)nc3cccnc32)cc1OC1CCCC1
Yield: 47.3 %

Procedure:
A mixture of 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (180 mg) and 2-oxosuccinic acid (90 mg) in ethanol (4 ml) was stirred under reflux for 1.5 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with ethanol to give 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg).
Reaction SMILES: [C:1]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:2][NH:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:1]([CH2:2][N:3]([CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22])=[O:11])[CH:14]=[CH2:15]
Reactant: O=C1CCC(=O)O1
Reactant: C=CCOC(=O)CNCC(=O)OCC=C
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)CN(CC(=O)OCC=C)C(=O)CCC(=O)O
Reaction time: 24 h
Yield: 51 %

Procedure:
Compound 9 (4.0 g, 10.39 mmol), succinic anhydride (1.04 g, 10.39 mmol), and 4-di(methylamino)pyridine (1.90 g, 15.59 mmol) were dissolved in CHCl3 (30 mL) and stirred for 24 h. The solvent was evaporated in vacuo and the crude material was purified by silica gel chromatography (40-80% EtOAc in hexanes) to give the compound 10 (1.66 g, 51%). 1H NMR (400 MHz, CDCl3) δ 2.64 (t, J=5.8, 2H), 2.70 (t, J=5.8, 2H), 4.21 (d, J=6.2, 4H), 4.61 (d, J=6.2, 2H), 4.65 (d, J=6.2, 2H), 5.22-5.35 (m, 4H), 5.89 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][NH:18][CH3:19])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].O>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][N:18]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH3:19])[CH2:13][CH2:14]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CNC[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a mixture solution of tert-butyl (S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate (112 g, 209 mmol) and Et3N (52.8 g, 522 mmol) in CH2Cl2 (1200 mL) was added dropwise a solution of benzyl chloroformate (39 g, 230 mmol) in CH2Cl2 (40 mL) at −20° C. After stirring for an additional 2 h, water (400 mL) was added and the mixture was extracted with CH2Cl2 (2×200 mL). The organic layers were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica chromatography to afford crude tert-butyl (S)-1-(4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (90 g) as an oil which was a mixture of two isomers. The isomers were separated by preparative HPLC. 1H NMR (CDCl3, 400 MHz): δ=0.08 (s, 6H), 0.89 (s, 9H), 1.28 (m, 4H), 1.40 (d, 9H), 1.59 (m, 4H), 2.96 (d, 3H), 3.05 (d, 1H), 3.15 (d, 1H), 3.45 (t, 3H), 3.90 (s, 1H), 5.12 (d, 2H), 7.33 (m, 5H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]([N:10]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:11]1[C:12]([CH3:25])=[C:13]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:9].[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:8]([N:10]([CH:26]1[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28][CH2:27]1)[C:11]1[C:12]([CH3:25])=[C:13]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:9]
Reactant: CC(C)=O
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(C)C)CC1
Temperature: 23 °C
Reaction time: 144 h
Yield: 16.9 %

Procedure:
To a stirred solution of methyl 3-[ethyl(piperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoate TFA salt (crude material, 1.30 g, 3.36 mmol) in CH2Cl2 (20 mL) and AcOH (5 mL) was added acetone (590 mg, 10.1 mmol) and sodium triacetoxyborohydride (1.80 g, 8.40 mmol). The reaction mixture was stirred at 23° C. for 6 days and then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2 heptane/ethylacetate=5/1) to give the titled compound as oil (220 mg, 17% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.79 (br. s., 1H), 7.44 (d, J=1.6 Hz, 1H), 3.91 (s, 3H), 3.10 (q, J=7.0 Hz, 2H), 2.86 (m, 2H), 2.61-2.75 (m, 2H), 2.53 (s, 3H), 2.06 (m, 2H), 1.70-1.80 (m, 2H), 1.58-1.69 (m, 2H), 1.00 (s×2, 6H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 387.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[O:20][C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.S(Cl)([Cl:32])(=O)=O>C(Cl)(Cl)Cl>[Cl:32][C:17]1([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:14]=[CH:13][C:12]=2[CH2:15][CH3:16])[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[O:20][C:19]([CH3:27])([CH3:26])[C:18]1=[O:28]
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1(Cl)C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.220 g, 0.525 mmol) in dry chloroform (4 ml) is added sulfuryl chloride (0.085 ml, 1.05 mmol), followed by stirring at room temperature for 4 hours. After dilution with diethyl ether (150 ml) the organic phase is washed with saturated sodium carbonate (150 ml) then dried over magnesium sulphate and the filtrate concentrated in vacuo to afford 4-chloro-4-(2′,4′-dichloro-4-ethylbiphen-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.229 g, 96%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([Cl:18])=[C:8]2[C:14]([CH3:15])=[N:13][N:12]([CH2:16][CH3:17])[C:9]2=[N:10][CH:11]=1)=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O>[Cl:18][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:16][CH3:17])[N:13]=[C:14]([CH3:15])[C:8]=12
Reactant: CCOC(=O)c1cnc2c(c(C)nn2CC)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(C)c2c(Cl)c(CO)cnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
63 g. of 4-Chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.235 mol.) are dissolved in 360 ml. of anhydrous tetrahydrofuran. Nitrogen is passed through the flask and while stirring and cooling with tap water, 5.2 g. of lithium aluminium hydride is added a bit at a time so that the reaction temperature does not exceed 25°. Stirring is continued for 2 hours at room temperature. Without further stirring the reaction mixture is allowed to stand over night. Then 300 ml. of 3N-hydrochloric acid is added while stirring and cooling with ice-water to keep the temperature between 15° and 20°. The clear solution is evaporated to dryness in vacuo, the residue is treated with 100 ml of water and precipitated starting material (5-6 g.) is filtered off. Then the filtrate is diluted with 300 ml. of water and refrigerated over night. 32- 39.3 g. (60-74%) of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-methanol which crystallizes is filtered and dried at 70°, m.p. 119°-21°. The compound is recrystallized from acetonitrile, m.p. 121°-122°. Acidification of the aqueous mother liquor with hydrochloric acid, evaporation in vacuo and extraction of the residue by means of boiling acetonitrile yielded up to 15 g. of the starting material in form of the hydrochloride.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.17 g of 5% palladium-carbon was added to a mixed solution of 8 mL of methanol and 8 mL of ethyl acetate containing 0.82 g of tert-butyl 2-nitro-4-phenoxybenzoate and stirred under hydrogen atmosphere at room temperature for 4 hours and 30 minutes. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane; ethyl acetate=10:1] to obtain 0.63 g of tert-butyl 2-amino-4-phenoxybenzoate as colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH:5]=O.[C:17]([S:21]([NH2:23])=[O:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.O.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1/[CH:5]=[N:23]/[S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
A mixture of 2,5-bis trifluoromethyl benzaldehyde (21.5 g, 88.8 mmol), tert butyl sulfinamide (16.1 g, 133 mmol) and anhydrous CuSO4 (16.5 g, 103 mmol) in DCM (94 ml) was stirred at room temperature for 16 hours and at reflux for 3 days. The fine suspension was diluted with water and extracted with DCM. The extracts were washed with water, dried (MgSO4) and evaporated in vacuo to an off white solid which was purified by chromatography (silica, 4-10% EtOAc/isohexane) to give the desired N-{(1E)-[2,5-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide as a white crystalline solid (14.8 g, 91%); 1H NMR δ (ppm)(CDCl3): 8.98 (1 H, d, J=1.8 Hz), 8.46 (1 H, s), 7.92-7.85 (2 H, m), 1.29 (9 H, s); m/z (ES+) 346 (MH+).
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(O)CNCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 80 °C
Yield: 48.2 %

Procedure:
Iminodiacetic acid (200 g, 1.50 mol) was dissolved in water (3 L) and sodium hydroxide (180 g, 4.5 mol) was added in small portions with stirring. After stirring for 15 minutes, p-toluenesulfonyl chloride (286.5 g, 1.5 mol) was added in small portions. The reaction mixture was heated to 80° C. for one hour, giving a clear solution. At the end of this time, the reaction solution was cooled in an ice bath to 10°--15° C., and concentrated HCl (110 ml) was added, precipitating the product as a white solid. This solid was filtered and washed with cold water, then dried in a vacuum oven at 55° C., giving 207.7 g (0.723 mol, 48.2% yield): mp 195°-196° C . (lit.* mp 191° C.); 1H NMR (DMSO-d6, 300 MHz) δ 2.38 (s, 3H), 3.66 (s, 4H), 7.39 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 20.90, 53.98, 126.55, 129.79, 136.70, 143.17, 171.77.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=1[OH:13])([CH3:10])([CH3:9])[CH3:8].Cl.O>O1CCCC1.C(N(CC)CC)C>[C:1]([O:18][C:16]1[CH:17]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]([OH:13])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl methacrylate was prepared by adding drop wise a solution of 5.8 grams of methacryloyl chloride in 25 milliliters of tetrahydrofuran to a solution of 11.1 gram of 2,6-di tert.butyl hydroquinone in 80 milliliters of tetrahydrofuran and 20.2 grams of triethylamine. The addition was completed in 15 minutes and the reaction mixture was stirred at room temperature for 5-1/2 hours. The reaction mixture was then poured into a mixture of 20 milliliters of concentrated hydrochloric acid and 400 milliliters of water, and the solid which precipitated was filtered off, dried, and recrystallized from hexane. There was obtained 10 grams of product which melted at 135° C. to 138° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([F:39])=[CH:25][C:26]([CH:36]2[CH2:38][CH2:37]2)=[C:27]([N:29]2[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]2)[CH:28]=1>C(O)(C(F)(F)F)=O.C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)=[N:7][C:2]([NH:22][C:23]2[C:24]([F:39])=[CH:25][C:26]([CH:36]3[CH2:38][CH2:37]3)=[C:27]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:28]=2)=[N:3][CH:4]=1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC2CCC(=O)N21
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CC5CCC(=O)N5C(C)(C)C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 100 °C

Procedure:
A mixture of 7-(2-chloro-5-fluoropyrimidin-4-ylamino)-hexahydro-5,5-dimethylindolizin-3(5H)-one isomer B (trans) (100 mg), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (100 mg) and TFA (5 drops) in isopropanol (1 ml) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed in vacuo and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give product as racemic mixture.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Cl)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(5-Chloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chlorosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.60-2.64 (m, 4H), 3.58-3.65 (m, 4H), 3.70 (s, 2H), 5.40 (s, 1H), 6.76-6.78 (m, 1H), 6.96-6.99 (m, 1H), 7.13-7.15 (m, 1H), 7.85 (s, 1H), 10.60 (br s, 1H), 12.65 (br s, 1H). Mass spectrum (ES) MH+=321.
Reaction SMILES: B#B.[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:16](O)=[O:17].CO>O1CCCC1>[OH:17][CH2:16][C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[C:4]=1[CH3:3]
Reactant: Cc1c(C(=O)O)oc2ccc([N+](=O)[O-])cc12
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)oc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h

Procedure:
1 Molar diborane in tetrahydrofuran (18.0 ml, 18.0 mmole) was added dropwise to a suspension of 3-methyl-5-nitrobenzofuran-2carboxylic acid (1.1 g, 5 mmole) in tetrahydrofuran at 0°. Stirring was continued at 0° for 30 minutes then at room temperature for 18 hours when a second portion of diborane (5.0 ml) was added and the reaction mixture was subjected to ultrasound for 2.5 hours. Methanol was then added cautiously to the reaction mixture and the solvent was removed by evaporation. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate, dried (MgSO4), the solvent removed by evaporation in vacuo and purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and evaporated to give the title compound, yield 0.96 g. A sample was recrystallised from ethyl acetate, m.p. 149°-150°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:42]=[CH:41][C:31]([O:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])(=[O:4])=[O:3].[ClH:43].B(Br)(Br)Br.CO>C(OCC)(=O)C.C(OCC)C>[ClH:43].[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[C:16]([O:27][C:28]3[CH:42]=[CH:41][C:31]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:30][CH:29]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])(=[O:3])=[O:4]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(S(C)(=O)=O)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1S(C)(=O)=O
Temperature: 0 °C
Yield: 45 %

Procedure:
Dissolve the product of Example 35 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the 6-(3,4-bis-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (O to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2 mm of Hg) at 65° C. for 48 hours to give 61 mg of the title compound (45%): mass spectrum (ion spray): m/z: 594.9 (M+H—HCl).