Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:31].[O:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:38][CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:31]
Reactant: CS(=O)(=O)c1nccc(-c2ccn(C(c3ccc(Cl)c(F)c3)c3cnco3)c(=O)c2)n1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1C(c1ccc(Cl)c(F)c1)c1cnco1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A microwave tube was charged with a solution of 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (53 mg, 0.12 mmol) in DMA (1.2 mL). Tetrahydro-2H-pyran-4-amine (35 mg, 0.35 mmol) was added neat by syringe. The reaction was put into a microwave apparatus and heated to 120° C. After 1 hour, the solution was diluted to 30 mL with ethyl acetate and washed with a water/brine mixture (4×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. TLC in ethyl acetate showed complete loss of starting material and a new spot of nearly the same rf. The crude product was loaded onto a Biotage 12M column with ethyl acetate and eluted. Product containing fractions were pooled and concentrated to an oil, 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20 mg, 36%). 1H NMR (400 MHz, CDCl3) 8.40 (d, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.43 (dd, 1H), 7.31 (d, 1H), 7.22 (br s, 1H), 7.08 (s, 1H), 7.00 (m, 2H), 6.90 (s, 1H), 6.83 (dd, 1H), 5.20 (br d, 1H), 4.11 (m, 1H), 4.01 (m 2H), 3.55 (m, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=483.0.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17](=[O:19])[CH3:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[BH4-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]([OH:19])[CH3:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
To a stirred suspension of 1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanone (0.47 g, 1.29 mmol) in ethanol (8 mL) and THF (8 mL) was added sodium borohydride (49 mg, 1.30 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and aqueous sodium bicarbonate and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic fractions were dried (Na2 SO4), filtered and concentrated in vacuo to give 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanol (0.50 g, quantitative). LCMS RT=3.20 min, [M+H]+=368/370
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[H-].[Na+].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.O>[Br:1][C:2]1[N:6]([S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a solution of 5-bromo-1H-pyrrole-3-carbaldehyde (3.50 g) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 1.21 g) at room temperature, and the mixture was stirred for 10 min. Benzenesulfonyl chloride (4.27 g) was added, and the mixture was further stirred for 1 hr, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→7:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 5.4 g, 85%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9](S(C(F)(F)F)(=O)=O)[S:10]([C:13]([F:16])([F:15])[F:14])(=O)=[O:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([O:8][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cccnc1Br
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cccnc1Br)C(F)(F)F
Temperature: 23 °C
Reaction time: 1.25 h
Yield: 94 %

Procedure:
To a solution of 2-bromo-3-hydroxypyridine [CAS 6602-32-0, commercially available] (25.0 g, 144 mmol) in anhydrous pyridine (145 mL) at −10° C. (ice/NaCl) was drop wise added Tf2O (24.2 mL, 147 mmol) keeping the temperature below −5° C. (30 min). The cooling bath was removed and mixture was allowed to reach 23° C., stirred at 23° C. for 75 min, poured into sat. NaHCO3-sol., extracted with DCM, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by vacuum distillation: bp 65° C. (0.82 mbar) (42 g colorless oil, with some solid); triturated with hexane, filtered the undesired solid off, washed with hexane, collected the mother liquor, evaporated the solvent to give the title compound as a colorless liquid (41.52 g, 94%). MS (TOF ESP) 306 [(M+H)+], 307.85 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:20])=[O:9]
Reactant: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1C
Yield: 82 %

Procedure:
To 5-methoxy-2-methyl-4-nitrobenzoic acid (1.27 g, 6 mmol) in methanol (15 mL) was added thionyl chloride (0.44 mL, 6 mmol) dropwise. The mixture was heated to reflux for 3 h and then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave methyl 5-methoxy-2-methyl-4-nitrobenzoate (1.11 g, 82%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=226 at 3.92 min. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.60 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[C:12]3[C:24](=[O:38])[N:25](CC4C=CC(OC)=CC=4OC)[CH2:26][C:11]=3[C:10]=2[F:39])[CH2:6][CH2:5][O:4][CH2:3]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[C:12]3[C:24](=[O:38])[NH:25][CH2:26][C:11]=3[C:10]=2[F:39])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cnn3ccccc23)c2c(c1F)CNC2=O
Temperature: 60 °C
Yield: 44.2 %

Procedure:
To a 25 mL round bottom flask with a stir bar was added 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-2-(2,4-dimethoxybenzyl)-7-fluoro-4-(pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (85 mg, 0.160 mmol) in TFA (5 mL). The mixture was heated at 60° C. for 1.5 h and then cooled to RT. The mixture was concentrated and purified via preparative HPLC to give a TFA salt of the title compound as a white solid (27 mg, 44.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.85 (m, 1 H), 2.12-2.14 (m, 1 H), 3.65-3.73 (m, 2 H), 3.81-3.82 (m, 1 H), 3.93-3.95 (m, 1 H), 4.01-4.03 (m, 1 H), 4.43 (s, 2 H), 4.53-4.55 (m, 1 H), 7.04 (t, J=6.83 Hz, 1 H), 7.13 (d, J=4.88 Hz, 1 H), 7.49 (t, J=8.05 Hz, 1 H), 7.94 (br s, 1 H), 8.36-8.42 (m, 2 H), 8.78 (d, J=6.83 Hz, 1 H), 9.33 (s, 1 H). [M+H] calc'd for C19H19FN6O2, 383; found, 383.
Reaction SMILES: C(O[C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[CH:38]1[CH:43]=[N:42][CH:41]=[N:40][CH:39]=1.C[Si](N[Si](C)(C)C)(C)C.Cl[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl>CC#N>[C:8]([O:7][C@H:6]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@@H:5]1[C:41]1[N:42]=[CH:43][CH:38]=[CH:39][N:40]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: c1cncnc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(OC[C@@H]1O[C@H](c2ncccn2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
To a mixture of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (1 mol) and pyrimidine base (1 mol) in anhydrous MeCN are successively added HMDS (1 mol), ClSiMe3 (0.8 mol) and SnCl4 (1.2 mol). The resulting clear solution is refluxed for 1 hour when TLC indicates completion of the reaction. The solvent is evaporated and the residue dissolved in EtOAc, washed with NaHCO3 and H2O. The EtOAc layer is dried, filtered and evaporated to give the crude product, which is either crystallized or purified on a silica gel column to obtain the pure 2,3,5-tri-O-benzoyl-β-L-ribofuranosyl pyrimidine compounds. These compounds are stirred with NH3 /MeOH to give pure β-L-ribofuranosyl pyrimidines after purification and crystallization.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][NH:12][CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:17][CH2:18]1
Reactant: O=C1CCc2ccccc2C1
Reactant: CN1CCN(CCCN)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CN1CCN(CCCNC2CCc3ccccc3C2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
A neat mixture of 2-tetralone (0.552 g, 3.78 mmol), 1-(3-aminopropyl)-4-methylpiperazine (0.713 g, 4.54 mmol, 1.2 eq), and titanium (IV) isopropoxide (1.44 g, 5.67 mmol, 1.5 eq) was heated at 80° C. for 3 hours. The mixture was cooled to 0° C., diluted with 5 mL of MeOH, and then treated with NaBH4 (0.143 g, 3.78 mmol, 1 eq, adding portionwise). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, treated with water (3 mL) and then MeOH (30 mL), filtered through Celite. The filtrate was concentrated in vacuo, and the residue was redissolved in water (25 mL) and extracted with CHCl3 (3×25 mL). The combined CHCl3 extracts were dried (MgSO4) and concentrated to give [3-(4-methyl-piperazin-1-yl)-propyl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine as a dark brown oil (0.721 g, 67%). The crude intermediate was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:35](=[O:36])[O:37][CH3:38])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (207 mg, 0.608 mmol) in dichloromethane (10 mL) was added three equivalent of triethyl amine (0.252 mL, 1.8 mmol), followed by methyl chloroformate (0.071 mL, 0.91 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-ylcarbamate (272), (181 mg 75%). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[Cl:12][C:13]1[C:14]([C:34]#[C:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:15][C:16]2[N:20]=[C:19](S(C)(=O)=O)[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:17]=2[CH:33]=1>C1COCC1>[Cl:12][C:13]1[C:14]([C:34]#[C:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:15][C:16]2[N:20]=[C:19]([O:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]([OH:4])=[O:11])[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:17]=2[CH:33]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(C#Cc3ccccc3)c(Cl)cc21
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(COc1nc2cc(C#Cc3ccccc3)c(Cl)cc2n1COCC[Si](C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (18.0 mg, 60% suspension in mineral oil, 0.45 mmol). In a separate vial, a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (79.0 mg, 0.600 mmol) in THF (2.0 mL) was combined with a solution of compound 49-2 (138.0 mg, 0.300 mmol), and added dropwise to the 20 mL scintillation vial containing NaH. The resulting mixture was stirred at rt for 5 min, then cooled in a ice bath (0° C.) and quenched by a dropwise addition of water (6 mL). The mixture was allowed to warm up to rt and stirring was maintained for 5 min. The mixture was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and evaporated to dryness in vacuo. The residue was dissolved in ACN (4 mL) and added to a vial containing 5% aqueous LiOH (1 mL). The resulting mixture was stirred at 65° C. for 1 h, then acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and evaporated to dryness in vacuo. The crude product was used in the next step without further purification. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C26H31ClN2O4Si 498.2, observed m/e 499.0 (M+H)+ (Rt 3.78. 3.87 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[C:24](OCC)(=[O:26])C>CO.CCCCCC>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:26][CH3:24])[CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc2c(c1)CN(Cc1ccccc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 2-benzyl-5-bromo-2,3-dihydro-isoindol-1-one (0.065 g, 0.22 mmol), 30% sodium methoxide-methanol (0.06 mL, 0.33 mmol), and CuBr (0:004 g, 0.03 mmol) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-methoxy-2,3-dihydro-isoindol-1-one (0.03 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.86 (s, 3H), 4.22 (s, 2H), 4.78 (s, 2H), 6.82-7.29 (m, 7H), 7.79 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[CH2:28](OCC)C>C(OCC)(=O)C>[C:17]1([CH3:27])[CH:18]=[CH:19][C:20]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1.[CH3:15][N:2]([CH3:1])[CH:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:28])[C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: CC(CCOc1ccc(Cl)nc1)N(C)C
Reactant: CCOCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(OCCC(C)N(C)C)cnc1Cl
Reaction time: 0.08 h

Procedure:
A solution of the product 45A (63 mg, 0.26 mmol) in ethyl acetate (1 mL) was treated with p-toluenesulfonic acid monohydrate (49 mg, 0.27 mmol) and stirred for 5 minutes. Then ethyl ether (30 ml) was added and stirred for an additional 5 minutes. The ether was decanted and the procedure was repeated. The residue was then dried under vacuum to provide 48 as a white solid. MS (CI/NH3) m/e 243(M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.39 (d, J=7 Hz, 3H), 2.09 (m, 1H), 2.33 (m, 1H), 2.37 (s, 3H), 2.38 (s, 3H), 2.87 (s, 6H), 3.70 (m, 1H), 4.15-4.27 (m, 2H), 7.35 (d, J=8 Hz, 2H), 7.37 (d, J=4 Hz, 1H) 7.68 (d, J=8 Hz, 2H), 7.87 (d, J=3 Hz, 1H). Analysis calculated for C12H19N2ClO.1.3C7H8O3S.H2O: C, 52.30; H, 6.53; N, 5.78; Found: C, 52.00; H, 6.33; N, 6.10
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:15]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2>[O-2].[Mn+2].ClCCl>[CH3:1][C:2]1([CH3:34])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:15]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(CO)cc4)ccc3-c3ccccc3)ccc21
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C=O)cc4)ccc3-c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
640 mg (1.4 mmol) of the alcohol obtained in Example 51, 2.50 g (28.7 mmol) of manganese oxide and 50 ml of dichloromethane are mixed together in a 500 ml round-bottomed flask. The reaction medium is stirred for twenty hours at room temperature, the manganese oxide is then filtered off and the dichloromethane is evaporated off. The residue obtained is purified by chromatography on a column of silica eluted with a mixture composed of 80% heptane and 20% ethyl acetate. After evaporation of the solvents, 90 mg (14%) of the expected compound are collected in the form of a white powder with a melting point of 120-122° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:34]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:23]1[CH:22]=[C:21]([CH:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[CH:8][CH:9]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[NH:25][C:24]=1[C:26]1[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=1
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cnc(-c2[nH]c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)cc2Cl)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution (5 mL) of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (300 mg) in tetrahydrofuran was added N-chlorosuccinimide (82.3 mg) at 0° C., and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (210 mg). The mixture of the obtained positional isomers was dissolved in hexane-2-propanol (700:300, volume ratio, 18.8 mL), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRY LTD.). Using hexane-2-propanol (700:300, volume ratio) as a mobile phase, the solution was eluted at flow rate 60 mL/min and at 30° C., and the both fractions were separated at retention times 41.0 min and 55.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate, and the insoluble material was filtered off. The filtration was concentrated to give the title compound (93.2 mg, yield 29%) as a colorless amorphous solid. MS: 521 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[OH-].[Na+].C1COCC1>CN(C=O)C>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(COc2ccccc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Yield: 23.4 %

Procedure:
A mixture of 5.0 g (0.025 mol) 4-phenoxymethylphenol, 5.35 g (0.025 mol) 2-chloromethylquinoline hydrochloride and 30 ml (2N, NaOH) in 50 ml DMF and 100 ml THF was stirred at 60° C. bath temperature for a period of 3 hours. The reaction mixture was poured into wast and extracted with ether. The ether extract was washed with water, dried and concentrated to dryness to obtain solid. Recrystallization from acetonitrile yielded (2.0 g) product, m.p. 100°-111° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]=1.CO>CN(C)C=O.O>[Cl:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:21]=[C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:19]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc2[nH]c3ccccc3c12
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Clc1cccc2c1c1ccccc1n2-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Yield: 64.3 %

Procedure:
In a stream of nitrogen, a 100 mL three-necked flask was charged with 0.53 g (13.4 mmol) of sodium hydride (oily, 60%). 15 mL of dehydrated dimethylformamide was added to the content, and the mixture was stirred. To the thus-obtained slurry, a solution of 2.2 g (11.2 mmol) of 4-chlorocarbazole in 15 mL of dehydrated dimethylformamide was dropwise added, and the mixture was stirred for 30 minutes. To the thus-obtained reaction mixture, a solution of 3.0 g (11.2 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine in 40 mL of dehydrated dimethylformamide was dropwise added. The reaction mixture was stirred at room temperature for 2 hours, and, 10 mL of methanol and then 100 mL of pure water were added to terminate the reaction. A white powder deposited upon the addition of pure water was collected, and washed with pure water and then with ethanol. The thus-obtained powder was recrystallized from o-xylene to give 3.1 g (7.2 mmol) of 4-chloro-9-(4,6-diphenyl-1,3,5-triazin-2-yl)carbazole as a white crystal (yield: 64%).