Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16](=[O:27])[C:17]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=5[S:20][C:18]=4[N:19]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:28]([N:30]([CH2:38][CH3:39])[C:31]1[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1)[CH3:29].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-:50].[NH4+]>C1COCC1>[ClH:50].[ClH:50].[CH2:38]([N:30]([CH2:28][CH3:29])[C:31]1[N:36]=[CH:35][C:34]([NH:37][C:16]([C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[NH:19][C:14](=[O:15])[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:9]=2)=[O:27])=[CH:33][N:32]=1)[CH3:39]
Reactant: O=c1oc(-c2cccc(CN3CCOCC3)c2)nc2sc3c(c12)CCCC3
Reactant: [Cl-]
Reactant: CCN(CC)c1ncc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)c1ncc(NC(=O)c2c(NC(=O)c3cccc(CN4CCOCC4)c3)sc3c2CCCC3)cn1
Product: Cl
Reaction time: 1 h

Procedure:
To a mixture of 350 mg of 2-[3-(morpholin-4-ylmethyl)phenyl]-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one, 150 mg of 2-N,2-N-diethylpyrimidine-2,5-diamine and 5.0 mL of THF was added dropwise 1.0 mL of lithium hexamethyldisilazide (1.0 M in THF) under ice cooling, followed by stirring for 1 hour at the same temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform). Ethyl acetate and 0.5 mL of 4.0 M hydrogen chloride/ethyl acetate solution were sequentially added to the residue, followed by stirring for 30 minutes at room temperature. The insoluble material was collected by filtration, thereby obtaining 174 mg of N-[2-(diethylamino)pyrimidin-5-yl]-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide dihydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:20])[CH2:18][NH2:19].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:18][CH:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH3:20])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccccc1C(C)CN
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(C)CNc1cc(Cl)ncn1
Reaction time: 18 h
Yield: 77 %

Procedure:
As shown in step 4-v of Scheme 4, a mixture of 4,6-dichloropyrimidine (817 mg, 5.49 mmol), 2-(2-methoxyphenyl)-1-propanamine (0.997 g, 6.03 mmol), and DIEA (2.13 g, 2.87 mL, 16.5 mmol) in isopropanol (5.0 mL) was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by medium pressure chromatography on silica gel (25% EtOAc in hexanes) to give 6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine as a colorless solid (Compound 2012, 1.18 g, 77% yield): 1H NMR (CDCl3) δ 8.31 (s, 1H), 7.23 (dd, J=12.0, 4.5 Hz, 2H), 7.03-6.87 (m, 2H), 6.41 (s, 1H), 5.42 (s, 1H), 3.89 (s, 3H), 3.67-3.18 (m, 3H), 1.35 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN([CH2:18][CH3:19])CC.F[C:21]([C:24](Br)([C:31]([F:34])([F:33])[F:32])[C:25]1[CH:30]=[CH:29]C=CC=1)(F)F>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:30]1[CH:29]=[C:18]([CH2:19][N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12]2)[CH:21]=[C:24]([C:31]([F:32])([F:33])[F:34])[CH:25]=1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: FC(F)(F)C(Br)(c1ccccc1)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1cc(CN2CCNC(c3ccccc3)C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 145.4 %

Procedure:
To a solution of 2-phenylpiperazine (4.0 g, 24.65 mmol) in dry CH2Cl2 (200 mL) at -78° C. under nitrogen was added Et3N (5.15 mL, 36.97 mmol) followed by the dropwise addition of a CH2Cl2 solution(46.60 mL) of bis(trifluoromethyl)benzyl bromide (4.66 mL, 24.65 mmol). The flask was kept at -78° C. then it was gradually warmed to room temperature overnight. After TLC showed that the reaction was complete, the material was washed with brine (150 mL, 2×), dried over MgSO4, filtered, and evaporated under vacuum to yield a tan solid. The crude product was purified by flash silica get chromatography (150 g), eluting with 2.5% MeOH/CH2Cl2 to give (+,-) 1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-3-phenylpiperazine (6.96 g, 17.92 mmol, 72.7%) as an oil. A portion of this oil (0.5 g, 1.287 mmol)) was converted to its hydrochloride salt by dissolving the oil in CH2Cl2 (20 mL) and treating with 2.3M HCl-EtOH (1.3 mL 2.99 mmol). After stirring at room temperature for 10 minutes, all solvents were removed under high vacuum and the residue was dried overnight, m.p. 229°-233° C.; FAB MS [M+1]+ 389;
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[F:17])(=O)=O.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>O1CCCC1>[F:13][C:12]1[CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]([F:17])[C:7]=1[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: C1CSCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Temperature: 70 °C
Reaction time: 56 h
Yield: 63.6 %

Procedure:
2,6-Difluoro-4-nitrophenyl trifluoromethanesulfonate (992 mg, 3.23 mmol) is dissolved in dry tetrahydrofuran (15 mL) and then treated dropwise with thiomorpholine (0.487 mL, 4.85 mmol). The reaction is then heated to reflux (70° C.) under nitrogen for 16 hours. The reaction is then allowed to cool to room temperature, stirring over the weekend (56 hours) under nitrogen. At this time, the reaction is found to be complete by thin layer chromatography. The reaction mixture is concentrated under reduced pressure to yield a yellow solid and then absorbed onto silica gel (25 g). The material is then chromatographed on more silica gel (75 g, packed with hexane), eluting with 5% ethyl acetate/hexane to give 535 mg (64%) of the title compound as a solid, mp: 104-105° C.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>Cl>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(=O)OC(CCc2ccc(C(=O)O)c(F)c2)(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Methyl 4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorobenzoate (example B(5)) (300 mg) was treated with 4N NaOH (10 ml) and stirred for 4 hrs at room temperature. The mixture was then acidified with 1N HCl (20 ml) and the product was extracted with ethyl acetate (2×20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to a solid. The solid was recrystallised from diethyl ether to afford the title compound as a white solid (120 mg). 1H NMR (300 MHz, MeOD): δ 1.38–2.30 (m, 11 H), 2.80–3.12 (m, 6 H), 6.91 (d, J=7.19 Hz, 1 H), 7.17 (m, 1 H), 7.86 (d, J=719 Hz, 1 H)
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O.O1CCCC1>[CH3:14][N:13]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[N:2]([CH3:1])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CNc1cccc2cccc(NC)c12
Reactant: CCCCCCCCCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC1N(C)c2cccc3cccc(c23)N1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N,N'-dimethyl-1,8-naphthalene diamine (prepared in Example 1) (0.50 g, 2.7 mmol, 186), tridecanal (0.56 g, 2.85 mmol. 197), p-toluenesulfonic acid (5 mg), and tetrahydrofuran (5 ml) was prepared and stirred at room temperature for 15 minutes. The mixture was basified with 25% sodium hydroxide (1.0 ml), diluted with water (20 ml) and extracted with ether (100 ml). The extract was dried over potassium carbonate, concentrated to give 2,3-dihydro-1,3-dimethyl-2-dodecyl perimidine as a solid: mp 30°-32° C.; NMR (CDCl3) 7.13(m, 4H), 6.32(d, 2H), 4.27(t, 1H), 3.02(s, 6H), 1.7-1.1(m, 22H), 0.85(t, 3H); IR (neat) 1595 cm-1.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[N:5][C:4]=1[CH3:12])=O.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:35]CCl>CN(C)C=O>[ClH:35].[ClH:35].[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][CH2:1][C:3]2[S:7][C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[N:5][C:4]=2[CH3:12])[CH:19]=1
Reactant: ClCCl
Reactant: Cc1ccnc(N)c1
Reactant: Cc1nc(NC(=N)N)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc(NCc2sc(NC(=N)N)nc2C)c1
Product: Cl
Reaction time: 140 h

Procedure:
To a suspension of 5-formyl-2-guanidino-4-methylthiazole (1.0 g) and 2-amino-4-picoline (587 mg) in N,N-dimethylformamide (10 ml) and dichloromethane (60 ml) was added sodium triacetoxyborohydride (1.82 g), and the mixture was stirred for 140 hours. The mixture was evaporated under reduced pressure, and to the residue was added hydrochloric acid (1N, 12 ml). The pH was adjusted to 12 with 4N aqueous sodium hydroxide. The mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 5% methanol in dichloromethane), and the fractions containing objective compound were combined and evaporated. The residue was dissolved in ethanol, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 2 ml). The precipitate was collected by filtration, washed with ethyl acetate-ethanol (1:1, 3 ml) and dried to give N-(5-(4-methylpyridin-2-ylaminomethyl)-4-methylthiazol-2-yl)-guanidine dihydrochloride (513 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)OCC(Cl)(Cl)Cl
Yield: 54.9 %

Procedure:
To a solution of 2-aminobenzothiazole (1.00 g, 6.66 mmol) and pyridine (0.633 ml, 7.99 mmol) in tetrahydrofuran (22 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.11 ml, 7.99 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and 1.19 g (54.7%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].CCN(CC)CC>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)[C:10]([O:12][CH2:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionic acid (380 mg) was dissolved in ethyl acetate (5.0 mL). A commercially available reagent of 2-bromoacetophenone (164 mg) and Et3N (115.7 μL) were added and the mixture was stirred at room temperature for 2 days. To the reaction solution was added ethyl acetate and the mixture was washed with water and a saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The product was purified by recrystallization in 15% ethyl acetate/n-hexane to obtain 2-oxo-2-phenyl-ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate (277 mg, yield 89% over 2 steps) as colorless crystal (LCMS m/z 452 (M+1) Rt 232 min.).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[CH3:6].CCN(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([CH3:7])[CH3:6]
Reactant: CCCNC(C)(C)Cc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNC(C)(C)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of compound D-3-6 (195.0 g, 799 mmol) in THF (1.0 L) and H2O (1.0 L) is added Et3N (242.0 g, 2.4 mol) and Boc2O (174.0 g, 799 mmol). The resulting mixture is stirred at room temperature overnight, then extracted with EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (using 10:1 petroleum ether:EtOAc) to provide compound D-3-7 (100.0 g, 56% yield over 4 steps).
Reaction SMILES: [C:1]1(C)C=[CH:5][C:4](S(Cl)(=O)=O)=[CH:3][CH:2]=1.[OH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22](=[CH:23][CH2:24][CH2:25][CH2:26]1)[CH2:21][CH2:20]3.C([O:34]CC)C>>[O:34]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22](=[CH:23][CH2:24][CH2:25][CH2:26]1)[CH2:21][CH2:20]3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOCC
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1

Procedure:
To 30 ml. of dihdropyran containing 450 mg. of p-toluenesulfonyl chloride was added 6.0 g. of the product of Step B and the solution was stirred at room temperature for 1 hr. The solution was then diluted with ethyl ether and washed with a 20% pyridine water mixture twice, and then water, then brine, and dried and evaporated to yield a pale yellow oil which crystallized (8.5 g.), and had a m.p. of 92°-96° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2sc3ccccc3c2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.75 (s, 2H); 7.20-7.45 (m, 6H); 7.56 (ddd, J1=8 Hz, J2=1 Hz, 1H); 7.93 (d, J=9 Hz, 1H); 8.15 (d, J=8 Hz, 1H); 11.06 (br s, 1H); retention time=2.57 min., m/z=325.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[CH:3]=1.[CH3:35][O-:36].[Na+]>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:4]3[CH:3]=[C:2]([O:36][CH3:35])[N:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: C[O-]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4cc(Cl)ncn4)CC3)nc3ccccc32)cc1
Agent: [Na+]
Solvent: CO
Product: COc1cc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ncn1

Procedure:
A mixture of 6 parts of N-[1-[2-[(6-chloro-4-pyrimidinyl)amino]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 2.5 parts of a sodium methoxide solution 30% and 40 parts of methanol was stirred and refluxed overnight. The reaction mixture was evaporated and water was added to the residue. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.4 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(6-methoxy-4-pyrimidinyl)amino]-ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 145.8° C. (compound 98).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Product: CCc1ccc(-c2ccc3cc[nH]c3c2)cc1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 4-ethylphenylboronic acid: ESMS m/e: 221.9 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:40])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl>[CH3:40][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH:22][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCCc1nc2cc(N)ccc2n1CCCN(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(NC(=O)c3ccccc3)ccc2n1CCCN(C)C
Temperature: 25 °C

Procedure:
Triethylamine is added to a solution containing Compound 27 in chloroform, and then benzoyl chloride is added thereto while being cooled with ice. The mixture is stirred at room temperature to give the entitled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(CC(=O)C)C(C)=O.C(OCC)(=O)C.CCCCCC>C(O)(=O)C.C(OCC)(=O)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:14]2[CH3:13])[N:3]=1
Reactant: Cc1ccccc1
Reactant: Nc1cccc(Br)n1
Agent: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1cccc(Br)n1
Yield: 47 %

Procedure:
To a 1 L round-bottomed flask equipped with Dean-Stark trap, condenser, and nitrogen inlet were added 21.3 g (123 mmol) 2-amino-6-bromopyridine, 400 mL toluene, 14.1 g (123 mmol) acetonylacetone, and 20 drops acetic acid. The reaction was refluxed 5 days (tlc in 1/1:ethyl acetate/hexane, Rf=0.8(product), 0.5 (starting material)), cooled, poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using 5% methanol in methylene chloride to afford 14.4 g(47%) of the product as a low-melting yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][C:4]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 1-(2-hydroxyethyl)cyclohexanol (11.2 g) and pyridine (17 ml) in dichloromethane (100 ml) was added p-toluenesulphonyl chloride (19.5 g). The mixture was then stirred at room temperature under an atomosphere of nitrogen for 3 hours before being partitioned between ether (300 ml) and water. The organic layer was washed consecutively with 4N hydrochloric acid, water, 5% sodium hydrogen carbonate solution, and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (500 g silica gel; 20% ethyl acetate in petroleum ether as eluant) to give 1-(2-p-toluenesulphonyloxyethyl)cyclohexanol [E; n=1, R1 +R2 =--(CH2)5 --] as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Reaction time: 3.25 h

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 9.9 parts of lead tetraacetate was refluxed in 30 parts of glacial acetic acid for 6.5 hours. A further 9.9 parts of lead tetraacetate were added and the reflux was continued for another 3.25 hours. After cooling, the reaction mixture was extracted with ether. The ether extract was washed with sodium bicarbonate solution and water and was dried. Evaporation of the ether gave an oil which was chromatographed on silica gel using a 9:1 mixture of toluene and ethanol for elution. This yielded 0.23 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5°C (after crystallisation from light petroleum (b.p. 40°-60°C). This product was shown by spectral means to be the same as that of Example 13.