Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([F:20])[CH:27]=[C:26]([F:28])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cc(F)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-difluoroaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.94 (d, 1H, J=3.3 Hz), 7.20–7.11 (m, 3H), 7.02 (s, 1H), 6.92–6.90 (m, 2H), 6.65. (s, 1H), 6.39 (tt, 1H, J=2.4 and 9.0 Hz), 4.31 (s, 4H); 19F NMR (282 MHz, CDCl3): −31142, −47002; LCMS: purity: 97%; MS (m/e): 375(MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].CC1C=C(C=C(C)C=1)CC1NC(=O)NC(=O)C=1C(C)C.BrC(C(C)C)C(O)=O.BrC(CC)C(O)=O.[C:55]([O:58][CH2:59][CH2:60][CH2:61][O:62][CH2:63]OC(=O)C)(=[O:57])[CH3:56].C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.[Cl-].[Na]>C(#N)C.ClCCl>[CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[N:7]([CH2:63][O:62][CH2:61][CH2:60][CH2:59][O:58][C:55](=[O:57])[CH3:56])[C:8]=1[CH2:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1)[CH3:2]
Reactant: CCc1c(Cc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OCCCOCOC(C)=O
Agent: CC(C)C(Br)C(=O)O
Agent: CCC(Br)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CCc1c(Cc2cc(C)cc(C)c2)n(COCCCOC(C)=O)c(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of 5-ethyl-6-(3,5-dimethylbenzyl)uracil (645 mg, 5 mmol) (prepared as described for the preparation of 6-(3,5-dimethylbenzyl)-5-isopropyluracil in the above Example 1-A but in replacing the 2-bromo-3-methylbutanoic acid by the 2-bromobutanoic acid) and 1-acetoxy-3-acetoxymethoxypropane (prepared as described in the above Example 1-B) (950 mg, 5 mmol) in ethanenitrile (25 ml), were added hexamethyldisilazane (810 mg, 5 mmol) and chlorotrimethylsilane (545 mg, 5 mmol). After 10 minutes under stirring at 20° C., it was added dropwise thereto, in 10 minutes, a solution of tinIV chloride (782 mg, 2.4 mmol) in ethanenitrile (7 ml). After 14 h under stirring, it was added to the reaction medium dichloromethane (70 ml) and an aqueous saturated sodium hydrogenocarbonate solution (70 ml). The organic phase was separated by decantation and the aqueous phase was extracted with dichloromethane (3×50 ml). The collected organic phases were washed with saturated sodium hydrogenocarbonate solution (25 ml), with water (25 ml) and with an aqueous saturated sodium chloride solution (25 ml). The organic phase was dried over sodium sulfate, concentrated, and subjected to a flash column chromatography on silica gel (ethyl acetate/petroleum ether 1:1) to give 0.85 g (87%) of 5-ethyl-1-(3-acetoxypropyloxymethyl)-6-(3,5-dimethylbenzyl)uracil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: Cc1ccccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccccc1OCCCBr
Reaction time: 24 h
Yield: 44.1 %

Procedure:
To a solution of 2-methylphenol (0.0954 g, 0.924 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (1.00 mL, 9.85 mmol) followed by Cs2CO3 (0.469 g, 1.44 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0934 g, 44.1%). EI-MS Rt (2.45 min).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH:5]=[CH:6][C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:14])=[CH:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccn(-c2ccccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(-c2ccn(-c3ccccn3)c2)c1
Temperature: 84 °C

Procedure:
2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol), 3-cyanophenylboronic acid (0.59 g, 4 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in a mixture of DME (18 mL) and H2O (2 mL) and degassed for 15 min with Ar (g). The reaction mixture was then heated at 84° C. for 18 h. At this time, a further 0.25 eq. of 3-cyanophenylboronic acid (0.15 g, 1 mmol) was added and heating was continued. After a total of 42 h, the reaction mixture was cooled to rt, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (3:7) to afford a white waxy solid that was further purified by liquid chromatography on silica gel eluting with dichloromethane to afford 3-(1-pyridin-2-yl-1H-pyrrol-3-yl)benzonitrile as a colorless oil. 1H NMR (CD3Cl, 300 MHz) δ 8.49-8.52 (1H, m), 7.66 (1H, ddd), 7.47-7.51 (2H, m), 7.33-7.39 (3H, m), 7.24 (1H, ddd), 6.91 (1H, d), 6.51-6.52 (1H, m), 6.43 (1H, dd). MS (ESI) 246 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14]C)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCc1c(C(=O)OC)ccc(OC)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(C(=O)OC)ccc(O)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
2.0 g of methyl 2-ethyl-4-methoxy-3-methylbenzoate are dissolved in 50 ml of DCM in a 100 ml round-bottomed flask, and BBr3 is carefully added dropwise at 0° C. The mixture is left to stir at RT for 4 hours. The solvent is distilled off in vacuo, methanol is carefully added to the residue at 0° C., and the mixture is evaporated again in a rotary evaporator. This operation is repeated a further twice, giving 1.88 g of methyl 2-ethyl-4-hydroxy-3-methylbenzoate as oil, which is employed for the next step without further purification; MS-FAB (M+H+)=195,2; Rf (polar method): 1.96 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.[C:13](OC(=O)C)(=O)[CH3:14]>>[CH3:13][C:14]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C(=O)O)c1
Product: COc1ccc2nc(C)oc(=O)c2c1
Yield: 77 %

Procedure:
A solution of 5-methoxyanthranilic acid (7.8 g, 46.5 mmol) was refluxed in acetic anhydride (60 mL) for 2 h15 before being cooled and concentrated under reduced pressure. The crude residue was then concentrated twice in the presence of toluene before being filtered and washed with ether to yield to the title compound (6.8 g, 77% yield) as a beige solid; LC/MS: m/z 192 [M+H]+, Rt 1.69 min.
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[C:31]([OH:33])=O)[CH:27]=[CH:28][CH:29]=1.C(O)(=O)C.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([CH2:60][NH:61][C:62](=[O:71])[C@@H:63]([NH2:70])[CH:64]2[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N1CCOCC1)C>CN(C)C=O>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([CH2:60][NH:61][C:62](=[O:71])[C@@H:63]([NH:70][C:31](=[O:33])[CH:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=2)[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[CH:64]2[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H](N)C2CCCCC2)CC1
Reactant: N#Cc1ccc(CC(C(=O)O)c2cccc(Br)c2)cc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H](NC(=O)C(Cc2ccc(C#N)cc2)c2cccc(Br)c2)C2CCCCC2)CC1
Temperature: 22 °C
Reaction time: 15 h

Procedure:
At 4° C., TOTU (1.59 g, 4.84 mmol) was added to a solution of 2-(3-bromo-phenyl)-3-(4-cyano-phenyl)-propionic acid (1.6 g, 4.84 mmol), 4-[(2-(S)-amino-2-cyclohexyl-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester acetic acid salt (2.0 g, 4.84 mmol), and N-ethylmorpholine (1.2 ml, 9.68 mmol) in dimethylformamide (80 ml). The mixture was stirred at 22° C. for 15 hours, then evaporated in vacuo and stirred with sodium bicarbonate solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo at 40° C. to give the desired product, which was used without further purification. MS m/z 665.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:14])=[CH:7][C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:14])=[CH:7][C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C
Yield: 102.9 %

Procedure:
7-Hydroxy-4,8-dimethylcoumarin (91.075 g, 0.479 mol), anhydrous K2CO3 (302.9 g, 2.190 mol), and allyl bromide (217.1 mL, 2.51 mol) were added to 2.5 L of reagent grade acetone. The milky mixture was refluxed for eight hours with overhead stirring, filtered, and the filtrate was concentrated to dryness with the rotary evaporator to obtain 7-allyloxy-4,8-dimethylcoumarin (113.5 g, 0.493 mol, 103%). The crude product melted at 94.0°-100° C. (lit. mp 108° C.) and was used in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.O1C=CCC[CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[CH:19][CH:20]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Yield: 93 %

Procedure:
According to the method described for the synthesis of 207d, 206e (18.2 g, 63.8 mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH2Cl2 (300 mL) to give 207e (22.0 g, 93%) as an oil, which was used without further purification. 1H NMR (CDCl3): δ 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m, 1H). 13C NMR (CDCl3): δ 142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MO: 369.1429, found: 369.1451.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])[CH2:7][CH2:6][CH2:5]2
Reactant: CCCS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCCN2
Product: CCCS(=O)(=O)N1CCCc2cc(Br)ccc21
Yield: 43.2 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 6-bromo-1,2,3,4-tetrahydroquinoline (0.40 g, 1.89 mmol) and propanesulfonyl chloride (0.31 mL, 2.8 mmol) to provide 6-bromo-1-(propylsulfonyl)-1,2,3,4-tetrahydroquinoline (0.26 g). MS (ES) m/z 317.6; HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(C)C)(C)C.[C:41]1([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:48][NH2:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:18]=1
Reactant: 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
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(Di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 ml) under an atmosphere of argon. Diisopropylamine (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 ml) and 0.1M HCl (250 ml). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.05 (s, 1H), 7.30-7.10 (m, 10H), 6.00 (m, 1H), 5.70 (m, 2H), 5.60 (m, 1H), 5.20 (m, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 3.65 (m, 1H), 3.05 (m, 1H), 2.00 (m, 1H), 1.70 (m, 1H), 1.40 (s, 18H), MS (ES+) m/e 631 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([CH2:19][CH2:20][CH2:21][OH:22])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)[CH:27]=[CH:26][N:25]=[CH:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:23]1([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:22][CH2:21][CH2:20][CH2:19][C:10]3[N:11]=[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)=[CH:33][CH:34]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OCCCc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: Oc1ccc(Cn2ccnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2ncc(CCCOc3ccc(Cn4ccnc4)cc3)nc2-c2ccccc2)cc1
Yield: 34 %

Procedure:
3-(5,6-Diphenyl-2-pyrazinyl)-1-propanol (950 mg), 4-(1H-imidazolylmethyl)phenol (570 mg), and triphenylphosphine (860 mg) were suspended in anhydrous tetrahydrofuran (30 mL). A 40% solution (1.56 g) of diethyl azodicarboxylate in toluene was added dropwise to the resultant suspension under ice cooling, and the resultant mixture was stirred at room temperature for one hour. Ethyl acetate was added to the mixture, and the ethyl acetate layer was washed sequentially by a 10% aqueous solution of sodium hydroxide, water, and saturated saline. The washed product was dried over sodium sulfate anhydrate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column and crystallized from ether, to thereby yield 500 mg of Compound (1R) of the present invention as colorless crystals (yield 34.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[F:11][C:12]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:23]2[C:22]([F:26])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:11])[CH:24]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Reactant: COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ncc(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A mixture of 5-chloro-6-methoxypyridin-3-ol (Preparation 77, 100 mg, 0.627 mmol), tert-butyl 2,4,5-trifluorobenzoate (Preparation 6, 147 mg, 0.633 mmol), and potassium carbonate (260 mg, 1.88 mmol) in DMSO (5 ml) was stirred overnight at 25° C. under a nitrogen atmosphere. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with aqueous sodium hydroxide solution (1.0 M, 30 mL), brine (2×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 5% EtOAc in heptane to afford the title compound as a white solid (65 mg, 28%):
Reaction SMILES: [NH2:1][C:2]1[C:32]([N:33]([CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH3:34])=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[C:15]([F:25])[CH:14]=1)=[O:11])=[O:5].[CH:41](OCC)(OCC)OCC>>[F:25][C:15]1[CH:14]=[C:13]([NH:12][C:10]([C:9]2[CH:8]=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[C:32]([N:33]([CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])[CH3:34])[CH:31]=[CH:30][CH:29]=4)[N:1]=[CH:41]3)[CH:28]=[CH:27][CH:26]=2)=[O:11])[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(C)CCCN(C)c1cccc(C(=O)Nc2cccc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)c2)c1N
Product: CN(C)CCCN(C)c1cccc2c(=O)n(-c3cccc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)c3)cnc12

Procedure:
Using an analogous procedure to that described in Example 1, 3-{2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with triethyl orthoformate. The reaction product was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound Mass Spectrum: M+H+559.
Reaction SMILES: C(OCCOCCO)CCC.[BH4-].[Na+].[O:14](C)[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:15]([OH:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCOCCO
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCO
Temperature: 25 °C
Yield: 98 %

Procedure:
13.5 g (0.083 mole) of diethylene glycol monobutyl ether was added dropwise to a mixture consisting of 1.6 g (0.042 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.027 mole) of methyl caprate at 95° C. over two hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for two hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, n-decanol was obtained in 98% yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: NCc1ccncc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccncc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-aminomethylpyridine (0.14 mL, 1.4 mmol). Purification using silica gel, eluting with 3:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 117 as a white solid (m.p. 283-284° C.).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH3:19])([CH3:18])[C:13](=[O:20])[C:12]3([CH3:22])[CH3:21])[CH3:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH3:18])([CH3:19])[CH:13]([OH:20])[C:12]3([CH3:22])[CH3:21])[CH3:8])=[CH:23][CH:24]=1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc2c(c1)C(C)(C)C(=O)C2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=Cc1ccc(O)cc1)c1ccc2c(c1)C(C)(C)C(O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A solution of 1 g of 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanone in 10 ml of tetrahydrofuran is added dropwise while cooling with ice to a suspension of 100 mg of lithium aluminium hydride in 5 ml of tetrahydrofuran and the mixture is subsequently left to stir at room temperature for 2 hours. After the dropwise addition of 50 ml of 2N hydrochloric acid at 0° the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated. After filtration of the crude product over silica gel (elution agent hexane/ethyl acetate=1:1) it is recrystallized from ethyl acetate/hexane and there are obtained 500 mg of 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanol in colourless crystals, m.p. 148°-149°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](SC)=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:16].O.[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH2:19])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:16]
Reactant: NN
Reactant: CSc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: O
Solvent: CCO
Product: NNc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 90 °C
Yield: 77.7 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-3-(methylthio)-1,2,4-triazine (1.15 g, 0.00383 mol) and hydrazine hydrate (0.74 mL, 0.015 mol) in ethanol (50 mL) was heated at 90° C. for 20 h. After cooling, the formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (0.845 g, 77.6%).