Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C([O-])(=O)C.[Na+].Cl.[CH3:31][O:32][NH2:33]>C(O)C>[CH3:1][C:2]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:33][O:32][CH3:31]
Reactant: CON
Reactant: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C1CCCCC1(C)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[[4-[(1-methyl-2-oxocyclohexyl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (3 g), sodium acetate (0.78 g) and O-methylhydroxylamine hydrochloride (0.66 g) were suspended in ethanol (200 mL) and refluxed overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and dried over MgSO4. Filtration and concentration left 3.25 g of yellow oil which was purified by high pressure liquid chromatography. The product, 2.21 g of yellow oil, was dissolved in ethanol (100 mL) and stirred overnight at room temperature with KOH (0.35 g). The solvent was removed using a rotary evaporator, ethyl acetate was added, and the product was dried over Na2SO4. After filtration and concentration, the product was dried overnight under vacuum at room temperature to give 1.79 g of thepotassium salt of the title compound as a white solid, which fuses at 135°-138° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[C:27]=[O:28]>C1COCC1>[CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:27]([NH:26][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=3)=[O:28])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 120 mg) in THF (2.4 ml) was added 1-isocyanato-3-(trifluoromethyl)benzene (101 mg) and the mixture was stirred overnight at RT. The mixture was concentrated, purified by column chromatography (EtOAc:Pet ether, 2:8) and crystallized in CHCl3/pet ether to give the title compound. Yield: 156 mg (83%); 1HNMR (DMSO-d6, 300 MHz): δ 9.12 (s, 1H), 9.08 (s, 1H), 8.36 (s, 1H), 8.03 (d, 1H), 7.74 (d, 2H), 7.61 (d, 2H), 7.55 (dd, 1H), 7.5 (m, 1H), 7.32 (dd, 1H), 4.33 (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.92 (d, 6H); MS (ES+): m/z 521 (M+1).
Reaction SMILES: C(N(C(OC(C)(C)C)=O)[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3[Cl:23])C=C1)(OC(C)(C)C)=O.COC1C=CC(C(N[C:50]2[N:58]=[C:57]([Cl:59])[N:56]=[C:55]3[C:51]=2[N:52]=[CH:53][N:54]3[C@@H:60]2[CH2:64][C@H:63]([N:65]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@@H:62]([OH:80])[C@H:61]2[OH:81])C2C=CC(OC)=CC=2)=CC=1>>[C:73]([N:65]([C:66]([O:68][C:69]([CH3:71])([CH3:72])[CH3:70])=[O:67])[C@H:63]1[CH2:64][C@@H:60]([N:54]2[CH:53]=[N:52][C:51]3[C:55]2=[N:56][C:57]([Cl:59])=[N:58][C:50]=3[Cl:23])[C@H:61]([OH:81])[C@@H:62]1[OH:80])([O:75][C:76]([CH3:78])([CH3:79])[CH3:77])=[O:74]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared from di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine using a procedure analogous to that use to prepare (1R,2S,3R,5S)-3-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol (Intermediate in the preparation of Intermediate ZA). 1H nmr (CDCl3, 400 MHz); 8.35 (s, 1H), 4.80 (m, 1H), 4.70 (m, 1H), 4.50 (m, 1H), 3.85 (m, 1H), 3.75 (m, 1H), 3.10 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H), 1.55 (s, 18H), MS (ES+) m/e 504 (MH+).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][CH2:15][CH:16](N)[CH2:17][OH:18]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:15]([CH:16]1[CH2:17][O:18][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1)[CH3:14]
Reactant: CCCCCCCCCCCC#N
Reactant: CCC(N)CO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCC1=NC(CC)CO1
Yield: 89.6 %

Procedure:
25 g (137.9 mmoles) of undecyl cyanide was treated with 15.2 ml (165 mmoles) of DL-2-amino-1-butanol in presence of 919 mg (3.54 mmoles) of cadmium acetate dihydrate in 1-butanol as outlined under Example 1. 31.31 g (89.6%) of product was obtained on distillation at 124°-125° C./1.2-1.4 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]2[C:15](=[O:16])[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=3[NH:12][C:13]=2[CH:21]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1cc(Cl)ccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(C(F)(F)F)ccc2Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of Example 5B (0.3 g, 0.91 mmol) and TsOH.H2O (0.35 g, 1.82 mmol) in toluene (50 mL) was heated to reflux for 20 hours using a Dean-Stark trap to remove water. The reaction was cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.21 g (81%) of the desired product. MS (DCI) m/e 313 (M+H)+, 330 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.48 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.29-7.35 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.5, 2.1 Hz, 1H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CBr)c1ccncc1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide and isolated as light-red solid. MS(m/e): 402.3 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].C[C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1.[CH3:25]S(C)=O>O>[CH3:25][C:7]1([NH:6][C:3](=[O:5])[CH3:4])[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:19]([C:18]2[CH:23]=[CH:24][CH:15]=[CH:16][CH:17]=2)=[O:22])=[CH:9][CH2:8]1
Reactant: CS(C)=O
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1(C)C=CC(OCC(=O)c2ccccc2)=CC1
Reaction time: 1 h

Procedure:
65% Sodium hydride (2.2 g, 0.06 mole) was added to dimethylsulfoxide (60 ml), and a solution of 4-acetamidophenol (XV: R=CH3) (7.6 g, 0.05 mole) in dimethylsulfoxide (20 ml) was dropwise added thereto. After cooling to 5° to 10° C., a solution of 4-methylphenacyl chloride (XVI: X=Cl) (8.4 g, 0.05 mole) in dimethylsulfoxide (20 ml) was added dropwise thereto over 1 hour. Thereafter the reaction was carried out at 15° C. for 8 hours. The reaction mixture was diluted with water, and the precipitated crystals were filtered and recrystallized from acetone to obtain 7.9 g of 4-methyl-α-(4-acetamidophenoxy)acetophenone (XIII: R=CH3) as white crystals (yield, 55.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH3:30].[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:28])[CH3:30])=[CH:36][CH:37]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: CC(C)NCCCc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)NCCCc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Product: Cl
Reaction time: 5 h
Yield: 110.4 %

Procedure:
A stirred solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl) piperazine (10 g) and 4-[3-(1-methylethyl)aminopropyl]phenol (4.5 g) in 100 ml dimethylsulfoxide containing sodium hydroxide (0.94 g) in water (7 ml) was stirred at 55°-60° for 5 hours. The crude trihydrochloride salt obtained after the usual work-up was crystallized from methanol-acetonitrile to yield 4.5 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[3-(1-methylethyl)aminopropyl]phenoxy]ethyl]piperazine trihydrochloride, mp 216°-218°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:3]=1.C(Cl)[Cl:22]>FC(F)(F)C(O)=O>[ClH:22].[ClH:22].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[N:3]=1
Reactant: Cc1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(N2CCNCC2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
The product from the previous step (tert-butyl 4-(4-methylpyrimidin-2-yl)piperazine-1-carboxylate) was dissolved in a one-to-one mixture of trifluoroacetic acid and DCM (8 ml) and stirred at room temperature for three hours. The volatiles were removed under reduced pressure, the residue was dissolved in DCM and evaporated. The residue was dissolved in THF (10 ml), HCl in dioxane (4N, 2 ml) was added and the resulting precipitate was collected by repeated centrifugation, dekantation and washing with THF to yield 107 mg of a solid (0.30 mmol, 71%). MS (APCI) m/z=179.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16](SC)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]O.O[O:26][S:27]([O-:29])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([S:27]([CH3:23])(=[O:29])=[O:26])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc(S(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g) in a 10:1 mixture of methanol and water (25 ml) was added oxone® (potassium peroxymonosulfate; 4.1 g). The resulting suspension was stirred at room temperature for 16 hrs. After diluting with water (100 ml), product was extracted into ethyl acetate (100 ml×3) and combined organics were washed with brine (100 ml), dried over MgSO4 and concentrated in vacuo to give 4-(6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (1.01 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)COC)C3)cc1

Procedure:
Compound dt was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-methoxyacetyl chloride. LC-MS: m/z=+469 (M+H)−.
Reaction SMILES: [CH:1](=[N:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[O:10]1[C:12]([CH3:14])([CH3:13])[CH2:11]1>O1CCCC1>[CH2:1]([N:5]1[CH2:11][C:12]([CH3:14])([CH3:13])[O:10][CH:6]1[CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)CO1
Reactant: CCCC=NCCCC
Solvent: C1CCOC1
Product: CCCCN1CC(C)(C)OC1CCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
A mixture of 1 mmol of N-butylidenebutylamine, 2 mmol of 1,2-epoxy-2-methylpropane, 0.05 mmol of Cp*2Sm(THF)2, and 1 ml of tetrahydrofuran was stirred at room temperature for 5 hours. Products in a reaction mixture were isolated through column chromatography to yield 3-butyl-5,5-dimethyl-2-propyl-1,3-oxazolidine in yield of 53%.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].O[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21]>C(O)C>[Br:21][CH2:20][CH2:19][CH2:18][CH2:3][CH2:2][O:1][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])[C:9]#[N:10]
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: BrCCCCCBr
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(OCCCCCBr)c(OCCCCCBr)c1

Procedure:
Another example of a diamidine derivative is a diamidine trimer having a meta-para linkage. The meta-para oligomer is synthesized by nucleophilic substitution of one bromine atom in 1,5-dibromopentane (used in large excess) by both oxygen atoms of a 3,4-dihydroxybenzonitrile sodium ethoxide containing ethanol solvent giving the 3,4-Bis-(5-bromo-pentyloxy)-benzonitrile. This benzonitrile is dissolved in ethanol and added to a solution containing 2 equivalents of 4-hydroxybenzonitrile and sodium ethoxide in ethanol providing the 3,4-Bis-[5-(4-cyano-phenoxy)-pentyloxy]-benzonitrile. Reaction of 3,4-Bis-[5-(4-cyano-phenoxy)-pentyloxy]-benzonitrile with ethanol and hydrogen chloride in toluene converts all cyano groups in the starting materials to the imidate which is isolated but not purified. The tris imidate compound is reacted with ammonia saturated ethanol to yield the desired tris amidine.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21](SC)=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1.ClCCl.Cl[C:31]1C=CC=C(C(OO)=O)C=1.[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+]>CN(C)C(=O)C>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([S:41]([CH3:31])(=[O:45])=[O:43])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CSc1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a mixture of 1-[4-(difluoromethoxy)phenyl]-6-[5-(methylthio)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole (3.22 g, 8.60 mmol), dichloromethane (24 mL) and N,N-dimethylacetamide (24 mL) was added m-chloroperbenzoic acid (5.15 g, 21.5 mmol), and the resulting mixture was stirred at 50° C. overnight. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (2.23 g, yield 64%) as colorless crystals.
Reaction SMILES: [Br-].C(N([P+](N(CC)CC)(N(CC)CC)N(CC)CC)CC)C.[F-:23].[K+].[N+](C1C=CC=CC=1C)([O-])=O.Cl[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1>CN1CCCC1=O.C1(C)C(C)=CC=CC=1>[F:23][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1.[CH:40](=[O:41])[C:39]1[CH:42]=[CH:43][CH:36]=[CH:37][CH:38]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [F-]
Agent: CCN(CC)[P+](N(CC)CC)(N(CC)CC)N(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(F)cc1
Product: O=Cc1ccccc1
Reaction time: 24 h

Procedure:
At 60° C., a solution of 12.0 g (0.03 mol) of tetrakis(diethylamino)phosphonium bromide in 12 g of N-methylpyrrolidone (NMP), 174.3 g (3 mol) of potassium fluoride, 4.1 g (0.03 mol) of nitrotoluene and 18 ml of xylene are successively added to 421.7 g (3 mol) of 4-chlorobenzaldehyde (4-CBAL). The reaction mixture is dried by azeotropic distillation of the xylene under reduced pressure. After 24 hours at 1 90° C., the formation of 4-fluorobenzaldehyde (4-FBAL) and of benzaldehyde produced by dehalogenation, and the conversion of the reaction are determined by gas chromatography.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[N:12][CH2:13][CH2:14][CH2:15][OH:16])[C:9]3[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C(Cl)Cl>[S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)([O:16][CH2:15][CH2:14][CH2:13][N:12]=[C:10]1[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN=C1c2ccccc2CSc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN=C2c3ccccc3CSc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0 G. of 3-{ (dibenzo[b,e]thiepin-11(6H)-yliden)-amino}-1-propanol in 30 ml. of absolute pyridine are treated at 0° C. within 1 hour with 9.0 g. of p-toluenesulfonyl chloride. The solution is stirred at 0° C. for 1 hour and subsequently left to stand at 0° C. for 16 hours. The mixture is then diluted with methylene chloride and treated with water. The organic phase is washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. There is obtained crude 3-{(dibenzo[b,e]thiepin-11(6H)-yliden)-amino}-propyl tosylate which is used in the reaction described in the first paragraph of this Example without further purification.
Reaction SMILES: N[C@@H](C(C)C)[C@@H](C1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].BrCCCCBr.[O:36]([CH2:40][CH2:41]Br)[CH2:37][CH2:38]Br>CCOC(C)=O.CCCCCC>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:41][CH2:40][O:36][CH2:37][CH2:38]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOCCBr
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Agent: CC(C)[C@H](N)[C@H](O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: BrCCCCBr
Solvent: CCCCCC
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCOCC1
Yield: 95 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenylethanol, and replace 1,4-dibromobutane with (BrC2H4)2O. Column chromatography (Silica gel 50 g, eluent is n-Hexane:EtOAc=4:1) is used to purify the coarse product and a white solid (1.34 g) is obtained. The yield is 95% and the other analysis includes:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:29][CH2:28][C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ncc(CN)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (400 mg, 1.41 mmol) and (2-methylpyrimidin-5-yl)methanamine (400 mg, 3.25 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by preparative HPLC (100×20.2 mm, C18 column; 40-60% CH3CN-water [10 mM Et2NH]) to yield a light brown solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC(C)=CC=2)=CSC=1[C:36](OC)=[O:37].[CH:40](OCC)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:36][O:37][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][C:20]([CH3:40])=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccc(C)cc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccc(C)cc4)csc3c2=O)cc1
Yield: 70 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(p -tolyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), p-anisidine (91.63 mg, 0.74 mmol), and acetic acid (0.1 ml) were used to give 98.3 mg (0.28 mmol, 70% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)[O:17][CH2:16]1.C1C[O:29]CC1.CCCCCC>>[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)([OH:29])[CH2:20][CH2:19]2)[O:17][CH2:16]1
Reactant: O=C1CCCCC12OCCO2
Reactant: N#Cc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Yield: 70 %

Procedure:
4-Bromobenzonitrile was treated in THF-hexane with n-butyllithium at -100° C. Cyclohexanedione monoethylene ketal was added at -100° to give 70% yield of 11.