Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][NH:28][C:27]=1[C:33]([OH:35])=O.[NH2:36][CH2:37][C:38]1[C:39]([F:55])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:49]#[N:50])[C:41]([Cl:44])=[CH:42][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][NH:28][C:27]=1[C:33]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([C:49]#[N:50])[CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:39]=1[F:55])=[O:35]
Reactant: O=Cc1c[nH]c(C(=O)O)c1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cc(C=O)c3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-4-formyl-1H-pyrrole-2-carboxylic acid (0.028 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). The solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc, followed by washing the organic layer with a 15% Na2CO3 solution and drying over MgSO4. The solid was filtered off, and the solvent was evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to give an orange film which was triturated in acetone to afford the title compound (0.014 g, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br. s., 1H), 9.75 (s, 1H), 8.27 (t, 1H), 7.77-7.82 (m, 1H), 7.73 (s, 1H), 7.46-7.51 (m, 2H), 7.44 (t, 1H), 7.36 (t, 1H), 4.54 (d, 2H). LCMS: m/z=464.3 (M−1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10].CCN(CC)CC.N1CCCC1=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:13]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC[C@@H]1CCC(=O)N1)(c1ccccc1)c1ccccc1
Yield: 73.8 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (10 g, 87 mmol) in CH2Cl2 (50 mL) was added tert-butylchlorodiphenylsilane (25.6 g, 93 mmol), Et3N (12.1 mL, 87 mmol) and DMAP (1.06 g, 8.7 mmol). The mixture was stirred at room temperature until the starting pyrrolidinone was completely consumed and then diluted with CH2Cl2 (50 mL) and washed with water (50 mL). The organic layer was dried (Na2SO4), filtered, evaporated in vacuo and the crude material was submitted to flash chromatography (silica gel; 30 to 100% of EtOAc/hexanes) to afford (S)-5-((tert-butyldiphenylsilyloxy)methyl)pyrrolidin-2-one (22.7 g, 74% yield) as a colorless oil. LC-MS (M+H)+=354.58. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (br s, 1H), 7.64-7.61 (m, 4H), 7.50-7.42 (m, 6H), 3.67-3.62 (m, 1H), 3.58-3.51 (m, 2H), 2.24-2.04 (m, 3H), 1.87-1.81 (m, 1H), 1.00 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C@@H:26]([OH:28])[CH3:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C@@H:26]([O:28][CH3:32])[CH3:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CI
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)oc4c([C@H](C)O)cccc34)c(C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)oc4c([C@H](C)OC)cccc34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of (S)-1-{3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-benzofuran-7-yl}-ethanol (0.19 g, 0.50 mmol) in THF (5 mL) is cooled to 0° C., treated with 60% NaH (23 mg, 0.56 mmol). The mixture is stirred at 0° C. for 30 min. CH3I (47 uL, 0.76 mmol) is added and the resulting mixture is stirred at 0° C. for 1 h and gradually warmed to rt. and stirred at rt overnight. The excess reagent is removed in vacuo. The residue is taked up with H2O (20 mL) and EtOAc (50 mL). It is washed with sat. NH4Cl (2×30 mL). The organic lay is dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (0.17 g, 0.41 mmol, 82%). 1H NMR (CDCl3): δ. 0.90 (t, J=7.5 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H), 1.63 (d, J=4.0 Hz, 1.5H), 1.64 (d, J=4.0 Hz, 1.5H), 1.78-1.92 (m, 4H), 2.44 (s, 3H), 2.46 (s, 3H), 2.48 (s, 3H), 3.34-3.42 (m, 1H), 4.90-4.98 (m, 1H), 6.68 (s, 1H), 7.17-7.19 (m, 1H), 7.26-7.29 (m, 2H) ppm. ES-MS (m/z): calcd for C25H31N3O2 (M+H)+: 406.5. found: 406.2.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:51])[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)[C:27]([CH2:46][CH2:47][CH3:48])=[N:26][C:25]=3[CH2:49][CH3:50])[C:16]=2[O:15]1>C(OCC)(=O)C>[CH3:51][C:14]1([CH3:13])[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)[C:27]([CH2:46][CH2:47][CH3:48])=[N:26][C:25]=3[CH2:49][CH3:50])[C:16]=2[O:15]1
Reactant: CCCc1nc(CC)c(Oc2cccc3c2OC(C)(C)C3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc3c2OC(C)(C)C3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogen carbonate (0.34 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.21 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.09 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.11 g, 49%).
Reaction SMILES: S(=O)(=O)(O)O.[C-:6]#[N:7].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1[CH3:20].[OH-:21].[Na+]>C(O)(=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:7][CH:6]=[O:21])([CH3:18])[CH3:19])=[CH:12][C:11]=1[CH3:20]
Reactant: CC(C)=Cc1ccc(F)c(C)c1
Reactant: [C-]#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(CC(C)(C)NC=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.9 mL concentrated sulfuric acid are added dropwise at 5° C.-15° C. to 1.5 g (31 mmol) sodium cyanide in 5 mL glacial acetic acid. Then the mixture is combined with 3.9 g (24 mmol) of 1-fluoro-2-methyl-4-(2-methylpropenyl)benzene, dissolved in 10 mL glacial acetic acid, and stirred for 1 hour at 50° C.-60° C. The reaction mixture is diluted with ice water, made alkaline with concentrated sodium hydroxide solution, and extracted with dichloromethane. The organic phase is dried with sodium sulfate and freed from solvents in vacuo. The slightly yellow oil thus obtained is further reacted directly. Yield: 4.3 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15].C(N)CCC.[I:21]I.[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([I:21])[C:5]2=[O:15]
Reactant: COc1cc2[nH]c(C)cc(=O)c2cc1Cl
Reactant: II
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCN
Product: COc1cc2[nH]c(C)c(I)c(=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirred solution of 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (6.43 g, 28.7 mmol) and n-butylamine (28 ml, 287 mmol) in dimethylformamide (57 ml) cooled by a room temperature water bath was added iodine (7.30 g, 28.7 mmol) in a saturated solution of aqueous potassium iodide (29 ml). The reaction mixture was stirred 12 hours at room temperature. Residual iodine was quenched with 0.1 M aqueous sodium thiosulfate, and the resulting solution was concentrated in vacuo. The residue was resuspended in water and filtered to give 8.93 g (89% yield) of 6-chloro-3-iodo-7-methoxy-2-methylquinolin-4(1H)-one as a light brown powder. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (bs, 1H), 7.59 (s, 1H), 6.41 (s, 1H), 3.91 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: CC1(C)CCN(C2C=CC(SC(F)(F)F)=CC=2)C(=O)N1CC1C2C(=NC=CC=2)NC=1.[CH3:31][C:32]1([CH3:49])[CH2:36][N:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=2)[C:34](=[O:48])[NH:33]1.Cl[CH2:51][C:52]1[CH:53]=[C:54]([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH:55]=[CH:56][CH:57]=1>>[CH3:31][C:32]1([CH3:49])[CH2:36][N:35]([C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44]([F:47])([F:45])[F:46])=[CH:41][CH:42]=2)[C:34](=[O:48])[N:33]1[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH:53]=1
Reactant: CC1(C)CN(c2ccc(OC(F)(F)F)cc2)C(=O)N1
Reactant: ClCc1cccc(-c2nccs2)c1
Agent: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Product: CC1(C)CN(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
4,4-dimethyl-3-[3-(1,3-thiazol-2-yl)benzyl]-1-[4-(trifluoromethoxy)phenyl]imidazolidin-2-one was prepared similar to procedure for compound 5, using the following reagents: 4,4-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazolidin-2-one and 2-[3-(chloromethyl)phenyl]-1,3-thiazole. 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1 H); 7.87-7.78 (m, 2 H); 7.58 (d, J=8.6 Hz, 2 H); 7.45 (d, J=7.7 Hz, 1 H); 7.38 (t, J=7.6 Hz, 1H); 7.32 (d, J=3.2 Hz, 1 H); 4.50 (s, 2 H); 3.56 (s, 2 H); 1.28 (s, 6 H). LCMS [M+H]+=448.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@H:22]1[CH2:31][O:32][CH2:33][CH2:34][OH:35])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@H:22]1[CH2:31][O:32][CH2:33][CH:34]=[O:35])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Under nitrogen atmosphere at -70° C., to a solution of oxalyl chloride (4.31 ml) in dichloromethane (200 ml) were added dropwise dimethyl sulfoxide (7.01 ml), a solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (17.57 g) in dichloromethane (50 ml) and triethylamine (37.8 ml). The reaction mixture was stirred at the same temperature for 2 hours and then allowed to warm to ambient temperature. Precipitate was filtered off and to the filtrate was added a mixture of ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate and active carbon was added thereto. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (9:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-(2-oxoethyl)oxymethyl-4-methanesulfonyloxypyrrolidine (15.7 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=3)[C:10]([CH2:24][CH3:25])=[C:9]([CH3:26])[N:8]=2)=[CH:4][CH:3]=1.C[N:28]([C:30](ON1N=NC2C=CC=NC1=2)=[N+:31](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:31][C:30]#[N:28])=[O:22])=[CH:16][CH:15]=3)[C:10]([CH2:24][CH3:25])=[C:9]([CH3:26])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetic acid (30 mg, 0.077 mmol, 1 eq.), cyamide (30 mg, 0.71 mmol, 9 eq.), HATU (44 mg, 0.16 mmol, 1.5 eq.), diisopropylethylamine (35 mg, 0.27 mmol, 3.5 eq.) and DMF (0.5 ml). The resulting mixture was stirred at rt overnight until the starting acid was consumed. The mixture was added to NaHCO3 aq. (5 ml) and extracted with ethyl acetate (5 ml×3). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using 0.5˜3% of MeOH in DCM as eluent to give the title compound as a white solid (16 mg, 50% yield). MW=411.91. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (brs, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.55 (d, J=4.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.15 (d, J=4.0 Hz, 1H), 5.77 (s, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.20 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1)CCC>CN(C)C=O.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[Pd]Cl>[C:28]1([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)c2cc(C3=CCCCC3)nc(N3CCCC3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 371 mg (1 mmole) tributyl-cyclohex-1-enyl stannane, and 70 mg bis(triphenylphosphine)-palladium(II)-chloride in 20 ml dimethylformamide is stirred for 3 hours at 80° C. The solvent is removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with saturated aqueous potassium fluoride, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography of the residue (silicagel, hexane/AcOEt 3/1) yields 191 mg (50%) pure 4-(2-cyclohex-1-enyl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine as a white solid. mp 237-238° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CS(O[C@H:28]1[CH2:33][CH2:32][C@@H:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]2)[CH2:30][CH2:29]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@H:28]4[CH2:29][CH2:30][C@H:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]5)[CH2:32][CH2:33]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)CC1=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1

Procedure:
Prepared by reacting 4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline with (cis)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane in N-methyl-2-pyrrolidinone at 125° C. in the presence of potassium carbonate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: NCc1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccncc1)c1cccc2c1OCCO2
Temperature: 60 °C
Yield: 72.1 %

Procedure:
N,N′-Carbonyidiimidazole (1.62 g, 10 mmol) was added to a stirred solution of 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(1.64 g, 10 mmol) in tetrahydrofuran (25 mL) and the resulting solution was heated at 60° C. for 15 minutes. The solution was cooled to room temperature and -4-(aminomethyl)pyridine (1.08 g, 10 mmol) was added. The reaction mixture was heated at 60° C. for 2 hours, cooled, poured into water, and extracted 3 times with ethyl acetate. The combined ethyl acetate extract was dried (Na2SO4) and evaporated in vacuo to a crystalline residue which was triturated with water, filtered, and dried in vacuo to give 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (pyridin-4-ylmethyl)amide as a white solid (1.95 g, 72%); m.p. 120-121° C.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:14]2=[O:42])[CH2:9][CH2:8]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([N:15]2[CH2:16][C:17]3[C:18](=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:21][CH:22]=3)[N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]3)[C:14]2=[O:42])=[CH:35][CH:36]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (90 mg, 0.24 mmol) (from Example 19b supra) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL) (Aldrich) at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to give crude product which was recrystallized from ethyl acetate-hexanes to give 3-(4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 41 mg, 59%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.C([N:23]([CH2:26]C)CC)C.CS(C)=[O:30]>O1CCCC1.Cl.OS(O)(=O)=O>[NH2:23][C:26](=[O:30])[CH:2]([OH:1])[CH:3]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CS(C)=O
Reactant: O=C(NC(CO)Cc1cccs1)OCc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: NC(=O)C(O)C(Cc1cccs1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40.2 g of pyridine-SO3 complex were added in portions to a mixture of 36.8 g of phenylmethyl [2-hydroxy-1-(2-thienylmethyl)ethyl]carbamate (126.3 mmol) and 51.2 g of triethylamine in 220 ml of dimethyl sulfoxide at about 16° C., and the mixture was stirred at room temperature for 3 hours. It was then poured into ice-water (1.5 l) and extracted with ethyl acetate, and the organic phase was washed with 1N HCl and sat. NaCl solution, dried and evaporated. The resulting oil (38 g) was dissolved in 150 ml of tetrahydrofuran, and a solution of 44.4 g of NaCN in 225 ml of saturated NaHCO3 solution was added dropwise. After 2 hours, the phases were separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with H2O and saturated NaCl solution, dried and concentrated. The residue obtained in this way was again dissolved in 400 ml of tetrahydrofuran and, over the course of 30 minutes, 65 ml of conc. HCl and 150 ml of conc. H2SO4 were added dropwise in parallel while cooling in ice, and the mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was poured into ice-water and extracted with ethyl acetate, and the organic phase was washed with 1N NaOH and sat. NaCl solution, dried and concentrated. The remaining oily residue was stirred with diethyl ether, and the resulting solid was filtered off with suction and dried, resulting in 16.3 g of the title compound as a whitish gray amorphous solid.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:10](Cl)[CH:11]=[C:12]([CH3:14])[CH3:13]>>[CH2:10]([C:3]1[C:4]([OH:5])=[CH:6][C:7]([OH:8])=[CH:9][C:1]=1[OH:2])[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCCl
Reactant: Oc1cc(O)cc(O)c1
Product: CC(C)=CCc1c(O)cc(O)cc1O

Procedure:
Phloroglucinol was treated with prenylchloride using the same procedure as described in Example 2 to yield prenylphloroglucinol. Prenylphloroglucinol was treated with butyrylchloride, according to the same procedure as described for the preparation of 2,4-dibutyrylphoroglucinol in Example 34 (Method 2) to yield 5,7-dihydroxy-6,8-dibutyryl-2,2-dimethylchroman (36 after chromatography with silica gel (petroleum ether, ethyl acetate, 4:1).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=3)([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:20][C:15]1[CH:14]=[C:13]([C:7]2([OH:12])[C:6]3[CH:5]=[N:4][CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)[C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(C2(O)CCCc3c(Br)cncc32)cc1C
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2(O)CCCc3c(-c4ccc(C#N)cc4)cncc32)cc1C
Yield: 79 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-4-bromo-8-(3,4-dimethylphenyl)-5,6,7,8-tetrahydroisoquinolin-8-ol (intermediate A-3) was reacted with 4-cyanophenylboronic acid to give the title compound as white powder in 79% yield. MS: 355.2 (M+H+).