Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[C:5]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:6]=2[N:7]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[Cl:12][C:10]1[N:9]=[CH:8][C:6]2[N:7]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]3)[C:3](=[O:19])[N:4]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[C:5]=2[CH:11]=1
Reactant: OCCN1CCNCC1
Reactant: CCCOCCn1c(=O)c(Cl)nc2cnc(Cl)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOCCn1c(=O)c(N2CCN(CCO)CC2)nc2cnc(Cl)cc21
Yield: 83 %

Procedure:
A solution of 3,7-dichloro-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one (200 mg, 0.66 mmol), 1-(2-hydroxyethyl)piperazine (117 mg, 0.90 mmol, Aldrich) and triethylamine (0.27 mL, 1.94 mmol) in THF (3 mL) was stirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give 7-chloro-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one. (218 mg, 83% yield). 1H NMR (CDCl3) δ 8.48 (1H), 7.34 (1H), 4.33-4.30 (2H), 4.04-4.00 (4H), 3.76-3.72 (2H), 3.69-3.65 (2H), 3.38-3.34 (2H), 2.67-2.64 (4H), 2.62-2.58 (2H), 1.55-1.48 (2H), 0.87-0.82 (3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(C)=O)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Yield: 95.6 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-acetyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (303 mg, 0.5 mmol), phenylboronic acid (122 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (326 mg, 1.0 mmol) to obtain 4-[3-[6-(5-acetyl-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (288 mg, 96%) as a colorless oil: ES(+)-HRMS m/e calcd for C37H46O7 (M+Na)+ 625.3136. found 625.3133.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(O)CCCOc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: O=C1CCCOc2cc(Br)ccc21
Temperature: 110 °C
Yield: 50.1 %

Procedure:
To a stirred suspension of polyphosphoric acid (PPA, ca. 60 g) and celite (ca. 40 g) in 100 mL toluene was added crude 4-(3-bromophenoxy)butanoic acid 7 (ca. 58 mmol) in one portion, 10 mL toluene rinse (FIG. 1). The resultant suspension was heated at 110° C. for 5 hr. The toluene was decanted through a plug of celite and the remaining slurry was washed repeatedly with toluene and ethylacetate. The eluent was concentrated and purified by flash column chromatography (4:1 hex:EtOAc) to give 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (7 g, ca. 50% y). 1H NMR (DMSO-d6, 500 MHz) 7.55 (d, J=8.5 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.35 (dd, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.14 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH3:27][CH:28]([NH2:32])[CH2:29][O:30][CH3:31]>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:32][CH:28]([CH3:27])[CH2:29][O:30][CH3:31])=[CH:20][N:19]=3)=[O:17])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: COCC(C)N
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)COC)cn2)CC1
Yield: 82 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-methoxyisopropylamine. And then, the product was recrystallized with isopropanol and hexane to give a desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH2:29].[OH2:30].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].O>C(#N)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:27])(=[O:30])=[O:29])[N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O
Reactant: CSc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(S(C)(=O)=O)n1
Yield: 89.9 %

Procedure:
A suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(1H)-one 0.28 g, 0.0006 mol), and magnesium monoperoxyphthalate hexahydrate 90.6 g, 0.0012 mol) in acetonitrile (8.0 ml) and water (2.0 ml) was stirred at room temperature for 16 h. The resulting clear solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and water (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to afford the title compound (0.27 g, 90%) as a pale yellow substance: 1H NMR (CD3OD/400 MHz) δ 8.91 (d, 1H, J=5.2 Hz), 7.63 (d over m, 2H, J=5.2 Hz), 7.03 (m, 2H), 6.58 (s, 1H), 5.54 (s, 2H), 5.33 (s, 2H), 3.28 (s, 3H), and 2.49 (s, 3H); 19F NMR (CD3OD/400 MHz) δ−111.58 (m), −115.98 (m);ES-HRMS m/z 500.0113 (M+H C19H17N3O4BrSF2 requires 500.0086).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:12][CH2:13][CH2:14][CH2:15][SH:16].[OH-].[K+]>COCCOC>[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: SCCCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1cc([N+](=O)[O-])ccc1SCCCCl
Yield: 16.5 %

Procedure:
2-amino-4-nitro-fluorbenzene (500 mg, 3.2 mmol), 3-chloro-1 propanethiol (354 mg, 3.2 mmol), and potassium hydroxide (269 mg, 4.8 mmol) were mixed together in ethylene glycol dimethyl ether (6.4 mL) and heated at reflux for 72 hours. The reaction was filtered and the filtercake washed with chloroform. The filtrate was concentrated and purified by flash column chromatography on 10 g if silica gel and eluted with 3% methanol in chloroform to give 2-[(3-chloropropyl)sulfanyl]-5-nitrophenylamine (130 mg, 17%). 1H NMR (CDCl3, 300 MHz): δ7.49-7.48 (m, 2H), 7.38 (dd, 1H, J=7.7 Hz, J=7.7 Hz), 4.55 (s-broad, 2H), 3.64 (t, 2H, J=6.2 Hz), 3.03 (t, 2H, J=7 Hz), 2.00 (q, 2H, J=7 Hz) ppm. Mass Spec (ESI):264 (base M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>O>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:9]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CCCC(NC(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CCCC(N)C1)C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{1-[2-(6-Chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (160 mg, 0.30 mmol) was added into a 4N solution of HCl in dioxane (2 mL, 8 mmol), followed by water (0.5 mL). The resulting mixture was stirred at RT for 2 hours, then concentrated under vacuum. The residue was taken up with water (5 mL) and a 1N aqueous solution of NaOH (15 mL), then extracted with DCM (2×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum. After purification by crystallization from ACN, the title compound was obtained as a white powder (46 mg, 35%). 1H NMR (DMSO-d6) δ 7.47-7.31 (m, 4H), 4.83 (s, 1H), 4.81 (s, 1H), 4.52 (s, 1H), 4.47 (s, 1H), 3.42 (br s, 2H), 2.85 (s, 1.5H), 2.80 (s, 1.5H), 2.70-2.43 (m, 5H), 2.23-2.09 (m, 1H), 1.88-1.74 (m, 1H), 1.65-1.52 (m, 1H), 1.46-1.31 (m, 2H), 1.25 (s, 2H), 1.02-0.83 (m, 1H), 0.83-0.65 (m, 1H). HPLC (max plot) 99.4%, Rt 2.21 min. UPLC/MS: (MS+) 439.3 ([M+H]+). Melting point: 165-170° C. (ACN).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>CO>[N+:30]([C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:23]([CH2:3][CH2:2][C:1]#[N:4])[C:20]1[CH:19]=[CH:18][CH:17]=[CH:22][CH:21]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: N#CCCN(c1ccccc1)c1ccccc1[N+](=O)[O-]

Procedure:
Acrylonitrile (210 ml) and 40% benzyltrimethylammoniumhydroxide in methanol (1.5 ml) were added to 2-nitrodiphenylamine (100 g), and the mixture was refluxed with heat for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to thereby obtain 47.7 g of the titled compound as a red solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.BrC1C=CC([C@H]2C[C@@H]2C[OH:24])=CC=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][CH2:12][OH:24])=[CH:4][CH:3]=1
Reactant: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The alkene intermediate from Example 29F (1.64 g, 7.35 mmol) was converted to the alcohol by the method of Example 26F, followed by chromatography (7.3 hexane/ethyl acetate) provided the title compound. 1H NMR (300 MHz, CDCl3): δ 0.96-0.79 (m, 2H), 1.00-1.14 (m, 1H), 1.54-1.76 (m, 3H), 4.91-4.97 (m, 1H), 3.76 (t, J=6 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 258 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[N:22]=3)[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.CCO>[OH:28][CH2:27][C:23]1[N:22]=[C:21]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C=O)n3)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(CO)n3)c2)cc1

Procedure:
A suspension of 4′-(4-methoxyphenyl)-2,2′:6′2″-terpyridine-6-carboxaldehyde (8.93 mmol) in a mixture of 70 mL of THF and 70 mL of absolute EtOH is treated with 1 g of NaBH4 and then heated to reflux for 15 minutes under N2. After cooling, the organic solvents are removed, the residue is heated for 30 minutes at reflux in dilute NaHCO3, cooled, filtered, washed with H2O, then dried to give the desired product.
Reaction SMILES: Br[C:2]1[N:3]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][CH3:17])[N:5]=2.[CH3:26][O-:27].[Na+]>CO.[Cl-].[NH4+]>[CH3:18][C:14]([CH3:19])([CH2:15][CH2:16][CH3:17])[CH2:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:27][CH3:26])[N:3]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:11])[N:7]=1
Reactant: CCCC(C)(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
To a solution of 8-bromo-2-[(2,2-dimethylpentyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (475 mg) in dry MeOH (3.92 mL) was added sodium methoxide solution (0.649 mL, 30% wt. in MeOH). The reaction mixture was stirred at reflux for 5 h. The reaction was cooled and concentrated in vacuo to give an orange residue. The residue was taken up in saturated ammonium chloride solution (25 mL) and was extracted with EtOAc (25 mL). The organic layer was separated and washed with water (15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange solid (323 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=[O:2].[N:11]#[C:12][NH2:13].Cl.[OH-].[Na+]>C(O)(=O)C>[N+:1]1([O-:2])[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:12]([NH2:13])[N:11]=1
Reactant: N#CN
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2ccccc2[n+]([O-])n1
Temperature: 70 °C
Yield: 77.5 %

Procedure:
A mixture of 10 g 2-nitroaniline and 20 g cyanamide is heated for 5 min to 100° C., cooled, mixed with 25 ml conc. hydrochloric acid and carefully heated to 70° C. After subsidence of the vigorous reaction, one cools to room temp., adds dropwise thereto 50 ml semiconce. caustic soda lye, heats for 30 min to 100° C., cools, filters and washes the precipitate with hot glacial acetic acid. There remain 9.1 g of title compound (78% of theory) of the m.p. 272°-274° C.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].[CH2:14]([O:21][C:22]1[C:35]2[C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:27](=[O:45])[C:26]=2[CH:25]=[C:24]([CH2:46][OH:47])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl([O-])=[O:49].[Na+].Cl[O-].[Na+].P(=O)(O)(O)O>C(#N)C.O>[CH2:14]([O:21][C:22]1[C:35]2[C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:27](=[O:45])[C:26]=2[CH:25]=[C:24]([C:46]([OH:49])=[O:47])[CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2cccc(OCc3ccccc3)c2C(=O)c2c(OCc3ccccc3)cc(CO)cc21
Reactant: [O-][Cl+][O-]
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c2c(c1)C(=O)c1cccc(OCc3ccccc3)c1C2=O
Temperature: 35 °C
Yield: 98 %

Procedure:
10 g (0.06 moles) of radical 2,2,6,6-tetramethyl-1-piperidinyl-oxyl (TEMPO) and 1160 ml of an aqueous solution of 120 g (1 mole) of sodium dihydrogen phosphate and 180 g (1 mole) of disodium hydrogen phosphate are added in sequence to a suspension of 333 g (0.74 moles) of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone in 1660 ml of acetonitrile. The reaction mixture is heated to 35° C. and a solution of 167 g (1.5 moles) of sodium chlorite 80% in 513 ml of water is added dropwise in 40-50 minutes, maintaining the temperature around 35-40° C. 20 ml of aqueous sodium hypochlorite 10-12% are then dripped in and the reaction is heated to 60-65° C. for three hours. It is cooled to room temperature and 1400 ml of water are added. Phosphoric acid 85% is dripped in until reaching a pH of 2.8-3.2. The solid obtained is filtered and washed with water (350 ml×2). The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 337 g (yield 98%) of crude dibenzylrhein.
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([C:9]3[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[N:20]([CH3:24])[CH:19]=[CH:18]5)[CH:14]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.O>[CH:1]1([C:4]2[O:8][C:7]([C:9]3[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[N:20]([CH3:24])[CH2:19][CH2:18]5)[CH:14]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-(1-methyl-1H-indol-5-yl)-pyridin-2-ylamine (160 mg, 0.48 mmol) in TFA at 0° C. was added triethylsilane (0.2 mL, 1.20 mmol) drop-wise over a period of 5 min, and stirred for 2 h at 0° C. The reaction mixture was diluted with water (20 mL) and neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:7]=1.[Cl:30]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:30][C:11]1[C:6]([NH:5][CH2:4][C:3]([N:2]([CH3:29])[CH3:1])=[O:28])=[N:7][C:8]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[N:9][C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: CC(=O)O
Product: CN(C)C(=O)CNc1nc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
A mixture of N,N-dimethyl-2-[6-phenyl-2-(4-trifluoromethyl-phenyl)-4-pyrimidinylamino]acetamide (15.9 g), N-chlorosuccinimide (6.4 g) and acetic acid (80 ml) is stirred at 90° C. for 1.5 hour. The reaction mixture is concentrated under reduced pressure, and water and chloroform are added to the residue. The mixture is neutralized with an aqueous sodium hydroxide solution (1 mol/L), and the chloroform layer is separated. The chloroform layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to give the desired compound (16 g).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([S:55][C:56]2[C:61](O)=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:52]=[CH:53][CH:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([S:55][C:56]2[C:61]([O:14][CH2:13][CH2:12][CH2:11][C:10]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[OH:4])=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: COCOc1cnccc1CCCO
Reactant: Oc1cccnc1Sc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOc1cccnc1Sc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (1.59 g, 9.2 mmol) obtained in Example 2 and triphenylphosphine (2.78 g, 10.6 mmol) are dissolved in THF (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (1.85 g, 9.2 mmol) and 2-(3-bromo-phenylthio)-3-pyridinol (2.00 g, 7.1 mmol) obtained in Reference Example 1 under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 15% aqueous hydrochloric acid solution (10 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/ethyl acetate), and further recrystallized from diethyl ether to give the title compound (1.98 g) as colorless crystals, m.p. 169-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][C:24]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:27])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: O=C1CCCC2CN(Cc3ccccc3)CC12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)CCCC2CN(Cc3ccccc3)CC21
Yield: 84.1 %

Procedure:
To a suspension of 55.63 g of 2-methoxyphenylmagnesium bromide in 250 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 20.16 g of (3aRS,7aSR)-2-Benzyl-4-perhydroisoindolone in 250 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, treated with 300 cm3 of saturated aqueous ammonium chloride solution, taken up in 200 cm3 of ethyl ether and washed with 300 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8.8 cm, height 41 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 1000 cm3 fractions. Fractions 4 to 27 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 24.96 g of (3aRS,4RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained in the form of white crystals melting at 106° C.