Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.00026 mol, 1 eq.) and potassium carbonate (0.072 g, 0.000526 mol, 2 eq.) in anhydrous N,N-dimethylformamide (8 mL) was added tert-butyl 2-bromoacetate (0.0768 g, 0.00039 mol, 1.5 eq.) at room temperature. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and washed with water (3 mL). The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) as mobile phase to yield tert-butyl 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}acetate (0.10 g, 0.0002 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.8 min. MS: MH+ 501.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[NH2:32])[O:17][N:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]([NH:32][C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[NH:21][CH2:20][C:18]1[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[CH:19]=1)=[N:30][CH:29]=[CH:28][CH:27]=2)=[O:6])[CH3:2]
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.6 g, 13 mmol) was added over a period of ten minutes to a cooled (6° C.) solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (4.1 g, 12 mmol) and anhydrous triethylamine (2.6 mL, 18 mmol) in anhydrous dichloromethane (150 mL). After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (1.1 g) was added. The reaction was stirred for an additional 30 minutes and then was diluted with dichloromethane and washed with saturated aqueous potassium carbonate. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-ethoxy-N-[4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)[1,5]naphthyridin-3-yl]acetamide as a black oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][OH:17])=[N:13][N:14]=2)[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)=[N:13][N:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nnc(CCO)s2)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[5-(2-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.86 g), dihydropyrane (0.95 mL) and p-toluenesulfonic acid hydrate (0.13 g) in AcOEt (25 mL) was stirred at 20° C. for 1 h. The solution was diluted with AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated in vacuum. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:2) as eluent to give 3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (1.60 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH2:17]CCO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(CCl)CC(=O)OCCCc1ccccc1
Reaction time: 18 h
Yield: 103.1 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (134 g, 815 mmol) and 3-phenyl-1-propanol (111 mL, 821 mmol) was heated in toluene, with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (214 g). Electrospray MS m/z 219 [M−Cl+H]+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C1C=CC(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.Cl.CCOCC>[N:24]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1])=[N+:25]=[N-:26]
Reactant: OCc1ccccc1I
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To a solution of 2-iodobenzyl alcohol (6.0 g, 25.4 mmol) and DPPA (6.8 mL, 30.5 mmol) in toluene (65 mL) was added DBU (5.0 mL, 33.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with 3M HCl (60 mL) and ether (150 mL). The organic phase was separated and the aqueous phase was extracted with ether (×3). The combined organic extracts were washed with water (×2) and and then with brine. The solution was dried over anhydrous Na2SO4 and concentrated in vacuo. Silica gel column chromatography using 95:5 hexanes:EtOAc afforded 6.1 g (93%) of 1-azidomethyl-2-iodo-benzene.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:64]2[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]2)=[O:28])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cc(O)cc3c2[C@]2(C)CC[C@H]4C(C)(C)CCC[C@]4(C)[C@H]2CS3(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.5 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methylmorpholine (0.10 mL, 1.5 mmol) and 1-methyl piperazine (0.15 mL, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulted solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1). The resulting material was further purified by preparative HPLC (NH4OAc/CH3CN) to give (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-3-[(4-methylpiperazin-1-yl)carbonyl]-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (94) (0.085 g, 34%) as a white solid. 1H NMR (CDCl3): δ 7.29 (d, 1H), 6.77 (d, 1H), 3.62-3.20 (m, 5H), 2.70-2.00 (m, 10H), 1.78-1.24 (m, 10H), 1.20-1.00 (m, 2H), 0.99-0.92 (m, 4H), 0.88 (s, 3H), 0.82 (s, 3H). MS m/z 489 (C27H40N2O4S+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([NH2:30])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[N:32]1[C:38](=O)[O:37]C(=O)[C:34]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:33]12.N1C=CC=C[CH:45]=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:26]=[C:27]([N:30]([C:38]([NH:32][C:33]3[CH:34]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:37])[CH3:45])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: c1ccncc1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CCCCc1nc2ccc(N(C)C(=O)Nc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 0.8 g (2.00 mMol) of 4'-[[2-n-butyl-6-aminobenzimidazol-1-yl]-methyl]biphenyl-2-carboxylic acid and 0.9 g of N-methyl-isatoic acid anhydride in 3 ml of pyridine is refluxed for 48 hours, then evaporated to dryness, the residue is suspended in about 5 ml of methylene chloride, suction filtered, washed with a further 5 ml of methylene chloride and dried.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:24]([O:28][C:29]([N:13]1[CH2:14][CH2:15][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:12]1)=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOC(=O)Cl
Reactant: O=C(NC1CCNC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 3.20 g pyrrolidin-3-yl-carbamic acid benzyl ester hydrotrifluoracetate in 50 ml dichloromethane were added dropwise 3.7 ml triethylamine and 1.3 ml butylchloro-formate at 0° C. After stirring for 12 h the reaction mixture was diluted with dichloromethane, washed with 0.1 M HCl, saturated NaHCO3 and brine. The crude product thus obtained was purified by flash chromatography on silica using ethyl acetate/heptane 1:2 as eluent.
Reaction SMILES: F[B-](F)(F)F.[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:30]1(=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36].C(O)(=O)C.C(N(CC)CC)C>CO>[CH2:17]([C:16]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:32]2[CH2:33][CH2:34][CH2:35][C:30](=[O:37])[C:31]=2[O:36]1)[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: O=C1CCCCC1=O
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCC2=C1OC(CC(=O)c1ccccc1)(c1ccccc1)C=C2c1ccccc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A suspension of 13.51 g of 2,4,6-triphenylpyryliumtetrafluoroborate (34.1 mmol) and 4.78 g of cyclohexane-1,2-dione (42.6 mmol) is heated to boiling point in methanol, then a solution of 4.56 g of acetic acid (75.9 mmol) and 7.68 g of triethylamine (75.9 mmol) in a little methanol is added dropwise. After heating at reflux for 7 h, the solution is allowed to cool to room temperature. A light yellow precipitate is extracted by suction, washed in portions with 100 ml of ice-cold methanol and dried to constant weight. 11.37 g of a light yellow powder (79.3%) with a melting point of 178-179° C. (lit.: 182-184° C.) is obtained.
Reaction SMILES: [F-].C([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])CCCC)CCC.O1CC[CH2:21][CH2:20]1.[OH2:24].C(NCC)C>CCCCCC.C(O)(C)C>[N:6]1[CH:11]=[CH:12][CH:13]=[C:14]2[CH2:20][CH2:21][CH2:18][CH2:17][CH:16]([OH:24])[C:15]=12
Reactant: O
Reactant: C1CCOC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCNCC
Solvent: CC(C)O
Solvent: CCCCCC
Product: OC1CCCCc2cccnc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1 mL of 1 M tetrabutylammonium fluoride-tetrahydrofuran solution was added to the compound obtained in the above 1, and stirred at 50° C. for 4 hours. Then, the reaction liquid was cooled to room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through basic silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain 19 mg of a racemate of the entitled compounds. The racemate was optically resolved in an optically-active column (Daicel's CHRALPAC AD column, 2 cm×25 cm; 0.1% diethylamine, hexane/isopropyl alcohol=9/1; flow rate, 20 mL/min). From the former fraction (retention time; 8.1 min), 6.4 mg of (7S,9R)-7-(spiro[8-aza-bicyclo[3.2.1]octa-3,1′(3′H)-isobenzofuran]-8-ylmethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol was obtained; and from the latter fraction (retention time; 9.8 min), 6.4 mg of the (7R,9S) form was obtained, both as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[C:22]([C:19](=[O:21])[CH3:20])[CH:23]=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CC(=O)c1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-acetyl-phenylboronic acid to give 1-{3-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 343(MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([O:25][CH3:26])=[O:24].O>C(Cl)Cl>[C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH2:14][CH:15]([C:23]([O:25][CH3:26])=[O:24])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1Cc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1Cc2ccc(C(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 250 cm3 reaction vessel fitted with a stirrer, a cooler, a dropping funnel and a thermometer, is placed 23.2 g (0.173 mole) of anhydrous aluminum chloride in suspension in 40 ml of methylene chloride. 35.3 g (0.252 mole) of benzoyl chloride dissolved in 40 cm3 of methylene chloride is then slowly added at ambient temperature. The aluminum chloride tends to pass into solution while the temperature gradually rises several degrees. The mixture is cooled to hold the temperature close to 20° C. and a solution of 11.1 g (0.063 mole) of methyl indane-2-carboxylate dissolved in 50 cm3 of methylene chloride is added. The temperature gradually rises during the course of the addition and the mixture turns a light brown color. The mixture is stirred for one hour at ambient temperature and is then heated to reflux for 3 hours. After cooling, the mixture is poured into acidified iced water and the resulting mixture is extracted with chloroform. The chloroform extract is then washed with water containing caustic soda, then with slightly acidified water and finally with water. It is dried over anhydrous sodium sulphate. The product is then filtered and the filtrate concentrated to an oily residue which is distilled and a fraction is collected boiling at 178°-184° C. at 0.6 to 0.8 torr.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]([C:25]4[N:26]([C:34]5[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=5[Cl:41])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=4)=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(CC(O)=O)(F)F>ClCCl>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=1[N:26]1[CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[N:29]=[C:25]1[C:22]1[S:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(-c4nc(C(F)(F)F)cn4-c4cc(Cl)ccc4Cl)s3)cn2)CC1
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cn(-c2cc(Cl)ccc2Cl)c(-c2ccc(-c3ccc(N4CCNCC4)nc3)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
4-(5-{5-[1-(2,5-Dichloro-phenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-thiophen-2-yl}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.17 mmol) was mixed with 4 mL 50% trifluoromethylacetic acid in dichloromethane, and stirred at room temperature for 2 hrs. All solvent was removed; the residue was redissolved in dichloromethane and neutralized to pH 7 by saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was precipitated from dichloromethane/Hexane mixture, then filtered and washed several times with dichloromethane to give yellow solid (50 mg, 57% yield). 1H-NMR. (400 MHz, CDCl3): δ 3.30-2.97 (m, 4H), 3.57-3.54 (m, 4H), 6.63 (d, J=8.7, 1H), 6.78 (d, J=4.0, 1H), 6.96 (d, J=4.0, 1H), 7.31 (s, 1H), 7.60-7.50 (m, 4H), 8.37 (m, 1H). MS (ES): 524.3, 526.5, [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:41][C:40]([F:57])=[CH:39][C:38]=1Br)(=[O:34])[CH3:33]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:41][C:40]([F:57])=[CH:39][C:38]=1[C:6]1[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:20][N:19]=2)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=1)(=[O:34])[CH3:33]
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 29.9 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 197f (244 mg, 0.58 mmol), 197d (200 mg, 0.46 mmol), Pd(PPh3)4 (33 mg, 0.030 mmol) in 2 N Na2CO3 (1 mL) and DME (2 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 30% (90 mg) of 197g as a solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(CO)CO
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC(CO)CO)nc3N(C3CCCC3)C2=O)c1F
Yield: 71.4 %

Procedure:
1-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.50 g (1.11 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.30 g (3.32 mmol) of serinol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.38 g (72%) of the title compound: mp 172° C.–174° C. MS (APCI) (m+1)/z 480.1.
Reaction SMILES: [CH2:1]([S:8][CH:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[N:21][C:22](=[O:25])[NH:23][CH:24]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([S:8][CH:9]([N:23]1[CH:24]=[C:19]([Cl:18])[CH:20]=[N:21][C:22]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(SCc1ccccc1)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1C(SCc1ccccc1)c1ccccc1

Procedure:
α-Chlorobenzyl benzyl sulphide (see R. H. Mitchell, Tetrahedron Letters 44, 4395 (1973) (4 mmol) in CH2Cl2 (10 ml) was added dropwise over a period of 5 minutes at 0° C. to a mixture of 5-chloropyrimidin-2-one hydrochloride (4 mmol) and triethylamine (8 mmol) in CH2Cl2 (30 ml). The mixture was stirred for 3 hours at room temperature and 1/2 hour at 40° C. before chloroform (20 ml) was added and the solution washed with water (3 times). The dried (MgSO4) solution was evaporated, ether added to the crude product and the insoluble product collected. Yield 0.35 g (26%), m.p. 118° C. 1H-NMR (CDCl3): δ(CH2) 7.12 (--CH--), 7.27 (Ph), 7.33 (Ph), 8.12 (H-4, d, J 3 Hz)), 8.30 (H-6, d, J 3 Hz).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.O>[C:13]([O:1][CH:2]1[O:10][C@H:9]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([O:8][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:5]([O:6][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:3]1[O:4][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC[C@H]1OC(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
100 g of D-glucose (555 mmol; 1 eq) are dissolved in 2 l of pyridine and the reaction medium is heated under reflux for 1 hour before 387 ml (3,330 mmol; 6 eq) of benzoyl chloride are added thereto in the hot. After addition, the medium is diluted with water, the product precipitates and is filtered off and rinsed with water to neutrality. After drying, it is purified by recrystallisation from ethyl acetate.