Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNCCO.[H-].[Na+].ClC[C:10]1[C:11]2[C:16]([C:17](CCl)=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2>CN(C=O)C>[CH:12]1[C:11]2[C:16](=[CH:17][C:18]3[C:23]([CH:10]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1c2ccccc2c(CCl)c2ccccc12
Agent: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2cc3ccccc3cc2c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
That is, 2.06 g (27.0 mmol) of N-methylethanolamine was dissolved in 90 ml of anhydrous DMF in a 200 ml three-necked flask. Then, the resulting solution was cooled to −15° C. and to this, 1.08 g (27 mmol) of a 60% solution of NaH was added over 0.5 hours. After addition, the mixed solution was stirred at −15° C. for 1 hour. Then, 3.00 g (13.5 mmol) of 9,10-bis(chloromethyl)anthracene (1) was added gradually in a crystalline state. The resulting mixture was heated to −10° C. after a lapse of one hour from the completion of this addition and stirred over one night. After the completion of a reaction, DMF was distilled off under a reduced pressure, and the residue was dissolved in 200 ml of methylene chloride and insoluble matter was filtered out. 50 ml of water was added to this, and TFA was added while stirring until the pH of the solution becomes acid. After leaving at rest for 15 minutes, the solution was separated into two layers. A water phase was concentrated by repeating this operation two times and then the water phase was freeze-dried to obtain 2.43 g of quaternary anthracene salt 2 at a yield of 33%.
Reaction SMILES: [CH2:1]1[CH2:16][O:15][CH:3]([CH2:4][CH:5]=[CH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[O:2]1>C1(C)C=CC=CC=1.[Pd]>[CH2:16]1[CH2:1][O:2][CH:3]([CH2:4][CH2:5][CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[O:15]1
Reactant: N#Cc1ccc(C=CCC2OCCO2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CCCC2OCCO2)cc1
Reaction time: 2.5 h
Yield: 8.2 %

Procedure:
A solution of 3.7 g of p-(4,4-ethylenedioxy-1-butenyl)benzonitrile in 50 ml of toluene was treated with 350 mg of palladium/carbon (5%) and the mixture was hydrogenated for 2.5 hours (hydrogen consumption 385 ml). The reaction mixture was then filtered (rinsing with diethyl ether) and the filtrate was evaporated. There were obtained 308 mg (82%) of p-(4,4-ethylenedioxybutyl)benzonitrile as a colourless, partially crystallizing oil.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:2]([CH3:1])[CH2:3]3)[CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: CC1CNc2ccccc21
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Agent: Cl
Product: CC1CN(C2CCN(CCc3ccc(F)cc3)CC2)c2ccccc21
Yield: 75.6 %

Procedure:
3-Methylindoline (0.2 g) and 1-(4-fluorophenethyl)-4-piperidone (0.50 g) were treated as in Example 16 to give the title compound (0.384 g) as a pale yellow oil (yield: 7.0.7%) Next, hydrochloric acid was added thereto to give a salt followed by recrystallization from ethanol. Thus the hydrochloride (0.314 g) of the title compound was obtained as colorless crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][C@@H:13]([C:15](O)=[O:16])[NH2:14])=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[NH2:14][C@@H:13]([CH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:19][CH:18]=1)[CH2:15][OH:16]
Reactant: Cc1ccc(C[C@H](N)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@H](N)CO)cc1

Procedure:
A mixture of lithium aluminum hydride (254 mg, 6.696 mmol) in THF (20 mL) was heated at reflux for 1 h, then cooled in an ice bath. (S)-4-Methylphenylalanine (500 mg, 2.79 mmol) was added portionwise and the resultant mixture was heated at reflux for 14 h. The excess lithium aluminum hydride was decomposed by successive addition of H2O (1 mL), 10% aq. NaOH (10 mL) and H2O (2.5 mL). The mixture was filtered and the solid was washed with THF. The filtrate was concentrated in vacuo and the residue was dissolved in CHCl3 (50 mL), washed with 5% aq. NaOH (25 mL), H2O (25 mL) and brine (25 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford (2S)-2-amino-3-(4-methylphenyl)propan-1-ol as an off-white solid. 1H NMR (CD3OD, 500 MHz) δ 7.13-7.09 (m, 4H), 3.52 (dd, J=10.7, 4.6 Hz, 1H), 3.36 (dd, J=10.7, 6.9 Hz, 1H), 3.04-2.99 (m, 1H), 2.73 (dd, J=13.5, 6.2 Hz, 1H), 2.53 (dd, J=13.5, 7.7 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH2:26][CH2:25][N:24]2[CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[N:16]=[N:17][C:12]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cc1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 4-fluorophenylboronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 417.81 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 53 %

Procedure:
A round bottom flask was charged with 124a, 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (271 mg, 0.58 mmol), PdCl2(dppf) (50 mg, 0.06 mmol), K3PO4.3H2O (323 mg, 1.16 mmol), THF (15 mL), and H2O (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 124b as a yellow solid (200 mg, 53%). LCMS: [M+H]+ 651
Reaction SMILES: [CH2:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[O:11]2)=[C:6]([CH3:18])[C:5]=1[O:19][CH2:20][O:21][CH3:22])[CH:2]=[CH2:3].B.C1C[O:27]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[OH:27][CH2:3][CH2:2][CH2:1][C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8]([CH3:16])([CH3:17])[CH2:9][C:10](=[O:15])[O:11]2)=[C:6]([CH3:18])[C:5]=1[O:19][CH2:20][O:21][CH3:22]
Reactant: C1CCOC1
Reactant: C=CCc1c(C)c2c(c(C)c1OCOC)C(C)(C)CC(=O)O2
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: COCOc1c(C)c2c(c(C)c1CCCO)OC(=O)CC2(C)C
Reaction time: 0.33 h
Yield: 195.9 %

Procedure:
Compound D (4.09 g, 13.46 mmol) was dissolved in 7 mL of freshly distilled THF. Argon was passed through the mixture for 20 min. The solution was cooled in an ice-water bath. BH3—THF solution (1.0 M, 5.05 mL, 5.05 mmol) was added dropwise with stirring. After the addition, the mixture was stirred at 0° C. for 2 h. Water (about 1 mL) was added dropwise to destroy the excess borane until hydrogen evolution ceased. NaOH solution (2 N, 3.4 mL) and 30% H2O2 solution (1.7 mL, 16.2 mmol) were added. The mixture was stirred for 30 min and neutralized with 5% HCl solution. The organic compounds were extracted with EtOAc (3×50 mL), washed with water (3×30 mL), and dried over MgSO4. The solvent was evaporated, and the residue was purified on a silica gel column (EtOAc/hexanes=1/3, v/v) to give 3.19 g (70%) of the product. 1H NMR (CDCl3) δ4.91 (s, 2H), 3.63 (s, 3H), 3.60 (t, J=6.0 Hz, 2H), 2.81 (t, J=7.4 Hz, 2H), 2.56 (s, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.77 (m, 2H), 1.45 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([Br:15])=[CH:4][C:3]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Li])CCC.CN(C)[CH:30]=[O:31]>>[Br:15][C:5]1[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:2]([CH:30]=[O:31])=[C:3]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:4]=1
Reactant: CN(C)C=O
Reactant: CCCCCCSc1cc(Br)c(SCCCCCC)cc1Br
Agent: [Li]CCCC
Product: CCCCCCSc1cc(C=O)c(SCCCCCC)cc1Br
Yield: 50 %

Procedure:
BrS6 was converted to BrS6A by the same methods as Br6A and BrC6A, using butyllithium and dimethylformamide. Products were purified by column chromatography with ethylacetate:hexane (1:30) eluent followed by recrystallization from methanol. Yellow powder is collected at a yield of 50%. For BrS6A, 1H NMR (500 MHz, CDCl3): δ 10.39 (s 1H), 7.64 (s 1H), 7.61 (s 1H), 3.00 (t 2H), 2.91 (t 2H), 1.73-1.65 (m 4H), 1.46 (m, 4H), 1.34-1.28 (m 8H), 0.89 (m 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30].[NH4+].[Cl-]>CCOCC>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH:29]=[O:30])=[CH:16][N:15]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)CCSc2ccc(C#Cc3ccc(Br)cn3)cc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)CCSc2ccc(C#Cc3ccc(C=O)cn3)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.) solution of 358 mg (1.0 mmol) of 2-(4,4-dimethylthiochroman-6-yl)ethynyl-5-bromopyridine in 5 ml of anhydrous ether was added slowly under nitrogen 1.3 ml of 1.7M (2.21 mmol) tert-butyl lithium in pentune. The mixture was stirred at -78° C. for 1 h and then treated with 95 mg (1.3 mmol) of anhydrous dimethylformamide. The mixture was stirred at -78° C. for a further 0.5 hours, then warmed to 0° C. and treated with 5 ml of saturated NH4Cl solution followed by 5 ml of ether. The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) followed by high pressure liquid chromatography (Whatman M-9 Partisil 10/50 column, 15% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:55]1([O-:61])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:55]4[CH2:56][CH2:57][CH2:58][CH2:59][C@H:60]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Reactant: [O-][N+]1=CCCCC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@@H]4CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 10 %

Procedure:
To a solution of 0.500 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 100 ml of toluene is added 0.291 g of 2,3,4,5-tetrahydropyridine 1-oxide and the reaction mixture heated at reflux for 18 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.160 g of the first desired product as a foam, FAB MASS SPEC 826 (M+Na), and 0.057 g of the second desired product as a foam. FAB MASS SPEC 826 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:17]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:38][CH2:39][S:40][CH3:41])[C:34]([O:36][CH3:37])=[O:35].Cl.COC(=O)[C@H](CCSC)N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]2[CH:17]=[C:16]([NH:15][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH:24]=[CH:23][C:19]=2[C:20]([NH:32][C@@H:33]([CH2:38][CH2:39][S:40][CH3:41])[C:34]([O:36][CH3:37])=[O:35])=[O:22])=[CH:30][CH:29]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of 4-{1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]-2-(4-fluorophenyl)benzoic acid (1.67 g; 4 mmol), methyl (2S)-2-amino-4-(methylsulfanyl)butanoate, (L-methionine methyl ester hydrochloride) (0.96 g; 4.8 mmol), HOBT (0.65 g; 4.8 mmol), EDC (0.925 g; 4.8 mmol) and DMAP (0.54 g; 4.4 mmol) in dichloromethane (100 ml) was stirred at ambient temperature for 5 hours. The solution was diluted with dichloromethane (200 ml), washed with 5% aqueous sodium hydrogen carbonate solution and evaporated to dryness. The residue was purified by flash chromatography eluting with dichloromethane/ethanol 95/5 to give the title compound as a solid (1.8 g; 80%).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26]([O-:28])=O)=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26](=[O:28])[NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)NCCN(C)C)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1

Procedure:
304 mg (0.60 mmol) of mono(3,3-diphenylpropane-1-yl)4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 0.1 ml (0.91 mmol) of N,N-dimethylethylenediamine, 140 mg (0.73 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 18 mg (0.15 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=95/5) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C([N:46]1[CH:50]=[CH:49][N:48]=[C:47]1[CH2:51]Cl)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([C:21]([C:23]2[N:27]([CH2:51][C:47]3[NH:46][CH:50]=[CH:49][N:48]=3)[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:19][CH2:20]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccccc1)C(=O)c1ccccc1
Reactant: ClCc1nccn1Cc1ccccc1
Agent: Cl
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ncc[nH]2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 21.1 using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)benzamide and 1-benzyl-imidazol-2-ylmethylchloride hydrochloride to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH2:8][C:9](=O)[N:10]=[C:6]2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17].P(Cl)(Cl)([Cl:20])=O>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([Cl:20])[N:10]=[C:6]2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: CCOC(=O)C1=CC(Cl)=C(N)N2CC(=O)N=C12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)c(N)n2cc(Cl)nc12
Yield: 72 %

Procedure:
A solution of ethyl 5-Amino-6-chloro-2-oxo-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxylate (EXAMPLE 24, Step 2, 0.50 g, 2.00 mmol) in phosphorus oxychloride (4 mL) was refluxed for 4 h. After cooling, the mixture was evaporated. The obtained residue was carefully treated with water and 25% aqueous ammonia. The formed solid was collected by filtration to give 385 mg (72%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:3]=1.[F:16][C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19](N2C=CC(=O)NC2=O)[CH2:18]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[O:20][C@H:21]([CH2:22][OH:23])[C@@H:17]([F:16])[CH2:18]2)=[C:4]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(OC2CCC2)c2nc[nH]c2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(OC2CCC2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 192 h
Yield: 73.5 %

Procedure:
2-Amino-6-cyclobutoxy-9H-purine (0.50 g, 2.4 mmoles) and 2'3'-dideoxy-3'-fluorouridine (0.67 g, 2.9 mmoles) were suspended in potassium phosphate buffer (50 ml, 10 mM), pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 8 days, MeOH (150 ml) was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (92:8) as eluant. Solvent was removed and lyophilization yielded 0.57 g of 2-amino-6-cyclobutoxy-9-(2,3-dideoxy-3-fluoro-β-D-erythropentofuranosyl)-9H-purine (70%): mp 139°-140° C.;
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]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=[CH:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[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[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=[CH:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCCCCn3cnc4ccccc43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[NH:18]C(=O)C(F)(F)F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH:32]=1)(=O)=O>>[C:1]1([C:7]2[NH:18][C:10]3[C:9]([C:8]=2[C:31]2[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:33][CH:32]=2)=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(C#Cc2ccccc2)c(NC(=O)C(F)(F)F)c1
Reactant: O=S(=O)(OC1=CCC(c2ccccc2)CC1)C(F)(F)F
Product: O=C(O)c1ccc2c(C3=CCC(c4ccccc4)CC3)c(-c3ccccc3)[nH]c2c1

Procedure:
The title compound was prepared according to the procedure outlined in Example 7, employing 4-(2-phenylacetylenyl)-3-trifluoroacetamidobenzoic acid on Wang resin (prepared according to Example 3) and 4-phenylcyclohex-1-enyl trifluoromethanesulfonate; 1H NMR (DMSO-d6) δ 1.90 (m, 2 H), 2.40 (m, 3 H), 3.00 (m, 1 H), 5.90 (m, 1 H), 7.20 (m, 1 H), 7.30 (m, 5 H), 7.50 (m, 2 H), 7.75 (m, 5 H), 7.95 (m, 1 H), 11.60 (s, 1 H).