Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1=Cc2ccccc2OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 105.4 %

Procedure:
Methyl 2-(3,4-dichlorophenyl)-4-hydroxychroman-3-carboxylate (90 mg) and p-toluenesulfonic acid hydrate (24 mg, 128 μmol) were dissolved in toluene (4.0 mL) and heated to reflux. After 40 min, the solution was cooled to rt, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to provide racemic methyl 2-(3,4-dichlorophenyl)-2H-chromene-3-carboxylate as a white solid (90 mg, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.21 (s, 1 H) 6.81 (d, J=8.1 Hz, 1 H) 6.93 (t, J=7.6 Hz, 1 H) 7.17-7.25 (m, 3 H) 7.35 (d, J=8.6 Hz, 1 H) 7.44 (d, J=2.0 Hz, 1 H) 7.70 (s, 1 H).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].[CH2:13]([CH2:15]N)[OH:14].Cl>CO>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:14][CH2:13][CH2:15][N:12]=2)=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: NCCO
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(O)c1ccc(C2=NCCO2)nc1

Procedure:
Under a nitrogen atmosphere, sodium (12 mmol) is added to a flask containing 10 ml of anhydrous methanol. After the sodium has dissolved, a solution of 5-carboxy-2-cyano-pyridine (5 mmol) in 5 ml of methanol is added dropwise. The mixture is heated at 50° for 1.5 h. The mixture is allowed to cool and a solution of ethanolamine (10 mmol) in a mixture of 5 ml methanol and 1.5 of concentrated HCl is added dropwise. After addition is complete, the reaction mixture is refluxed for 2 h. The solvent is evaporated, the residue dissolved in 45 ml of hot ethanol, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 286°-287°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[N:12]=1)([CH3:10])([CH3:9])[CH3:8].O>C(O)C>[C:7]([C:11]1[N:12]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[CH:14]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: COCCc1cc(Cl)nc(C(C)(C)C)n1
Solvent: O
Solvent: CCO
Product: COCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of piperazine (45.2 g, 525 mmol) in ethanol (300 mL) was heated to reflux. A solution of 2-tert-butyl-4-chloro-6-(2-methoxy-ethyl)-pyrimidine (20 g, 87 mmol) in ethanol (50 mL) was added dropwise to the above solution. The solution was refluxed for another 3 hrs, cooled to room temperature. Then water was added and the organic layer was extracted with EA (400 mL×3). To the organic layer was added 5% citric acid (1 L), separated, and the aqueous layer was collected and adjusted to alkaline pH>8 with 2 N NaOH. The alkaline aqueous layer was extracted with EA (400 mL×3), and the organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (20 g, 82% yield) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[Li+].CCC[CH2-].[P:13](Cl)(=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O1CCCC1>[CH2:15]([O:14][P:13]([CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])([O:17][CH2:18][CH3:19])=[O:20])[CH3:16]
Reactant: CCOS(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Reaction time: 0.25 h
Yield: 117.1 %

Procedure:
A solution of ethyl methanesulfonate (4.14 mL, 40.2 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere. N-Butyllithium (20 ml, 50.0 mmol) was added slowly in 7 minutes after which stirring was continued for 15 minutes. Diethyl phosphorochloridate (4.36 mL, 30.2 mmol) was added, the reaction mixture was stirred for 2.5 h, the cooling bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was quenched with aqueous saturated ammonium chloride (150 ml) and the resulting mixture was extracted with EtOAc (2×100 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 9.20 g of a yellow oil. The oil was purified over silicagel (600 g) using a gradient of ethyl acetate (0-100%) in heptane to yield 1.75 g of the product (6.7 mol, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[N:12][OH:13])[NH2:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1c(F)cccc1Cl
Temperature: 72.5 °C
Reaction time: 16 h

Procedure:
A mixture of 15.6 g of 2-chloro-6-fluorobenzonitrile, 9.0 g of hydroxylamine hydrochloride, 7.4 g of sodium carbonate, 50 ml of ethanol and 15 ml of water was stirred at 70-75° C. for 16 h. The solvent was evaporated and the residue was stirred with tertbutyl methyl ether, and the filtrate afforded, after evaporation of the solvent, 17.6 g of the desired product of m.p. 115-120° C.
Reaction SMILES: [C:1]1([C:7]([O:9][C@H:10]2[CH2:20][O:19][C@H:12]3[C@H:13]([OH:18])[C@H:14]([O:17][C@@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C=O)C.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@H:13]1[C@@H:12]2[O:19][CH2:20][C@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@@H:11]2[O:17][C@@H:14]1[O:15][CH3:16]
Reactant: CI
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1O
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-L-glucofuranoside (1.03 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH3:32]>>[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])[CH3:32]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CCN(CC)CCCCN
Product: CCN(CC)CCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 488 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:26]([CH2:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.O>ClCCl>[O:26]([CH2:33][C:34]([NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(Cl)COc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)-piperazin-1-yl]-(2-trifluoromethyl-phenyl)methanone (105 mg, 0.300 mmol) in dichloromethane (10 mL) was added phenoxyacetyl chloride (56 mg, 0.32 mmol) followed by the addition of triethylamine (0.15 mL) at 0° C. The mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate (2×15 mL). The combined organic layer was washed sequentially with diluted HCl, sodium bicarbonate and brine solution, then dried with Na2SO4, concentrated. The residue was re-dissolved in small amount of dichloromethane and purified by column chromatography. The title compound was isolated as a white solid in 34% yield (50 mg). 1H NMR (300 MHz, CDCl3) δ 9.28, 8.38, 7.75, 7.64, 7.56, 7.35, 7.04, 4.65, 4.01, 3.68, 3.34.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:42])[C:25](=[O:41])[C:26]4[N:34]5[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:28][C:27]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[CH3:43]I>C1COCC1.C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:43])[C:24](=[O:42])[C:25](=[O:41])[C:26]4[N:34]5[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:28][C:27]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:5]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C)nc(N2CCN(c3ccc(N(C)C(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
Sodium hydride (55% dispersion in oil, 24 mg, 0.56 mmol) was added to an ice-cold solution of N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (prepared as described in Example 3, 200 mg, 0.37 mmol) in THF, and stirred for 10 minutes at 0° C. Methyl iodide (0.036 mL, 0.56 mmol) was added, the mixture warmed to room temperature and stirred for 30 min. The solvent was evaporated and the residue partitioned between ice-water and DCM. The organic layer was separated and washed successively with water, sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a residue. This was dissolved in the minimum amount of DCM and re-precipitated by addition of petroleum ether to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-N-methyl-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (120 mg, 58%) as light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH3:11])[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1cccc(F)c1
Yield: 98.8 %

Procedure:
Following a similar procedure to that described in Example (1b), 1.23 g of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3-fluorophenyl)ethyl]amine [prepared as described in step (a) above], 1.52 g of nickel chloride hexahydrate and 509 mg of sodium borohydride were reacted, to obtain 1.12 g of the title compound as a pale yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=[O:20].[Br:22]C(F)(F)C(Br)(F)F.Cl>O1CCCC1>[Br:22][C:17]1[S:16][C:15]([C:19]([OH:21])=[O:20])=[C:14]([Cl:13])[CH:18]=1
Reactant: O=C(O)c1sccc1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1sc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.8 ml) in tetrahydrofuran (75 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 30.5 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of 3-chloro-2-thiophenecarboxylic acid (3.92 g) in tetrahydrofuran (40 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise 1,2-dibromo-1,1,2,2-tetrafluoroethane (6.0 ml). The mixture was stirred at the same temperature for one hour, and then, warmed to room temperature. The mixture was poured into a diluted aqueous hydrochloric acid solution, and the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixed solvent of diisopropyl ether and hexane to give 5-bromo-3-chloro-2-thiophenecarboxylic acid (3.79 g) as a yellow solid. ESI-Mass m/Z 239/241 (M−H). (2) The above 5-bromo-3-chloro-2-thiophenecarboxylic acid was treated in a manner similar to Reference Example 94 to give 5-bromo-3-chloro-2-(4-ethylphenylmethyl)thiophene as colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C@H:8]([CH2:17][C@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][C:10](OC(C)(C)C)=[O:11].O.[OH-].[Na+]>C1COCC1>[F:7][C@H:8]([CH2:17][C@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10][OH:11]
Reactant: CCCC[C@@H](C)C[C@@H](F)CC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@@H](C)C[C@@H](F)CCO
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
In a 100 ml flask were charged dried THF and 0.7 g of lithium aluminum hydride in a nitrogen stream, followed by cooling to 10° C. or less. A solution of 4.2 g of t-butyl (3R,5R)-3-fluoro-5-methylnonanoate obtained in Step 7 in 13 ml of dried THF was added thereto over 30 minutes, and the resulting mixture was allowed to react at 30 to 35° C. for 1.5 hours. After cooling to 5° C., a mixture of 0.7 ml of water and 2 ml of THF was added thereto over 30 minutes, and 1.5 ml of a 4% sodium hydroxide aqueous solution was then added, followed by stirring at that temperature for 1 hour. The by-produced salt was removed by filtration, and calcium carbonate was added to the filtrate to dry. The solvent was removed by distillation to obtain 2.9 g (96.5%) of a crude product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[Br:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.O>CCCCCC.C1COCC1>[Br:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)[OH:19])=[CH:16][CH:15]=1
Reactant: Brc1cncnc1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Br)cc1)(c1ccc(Br)cc1)c1cncnc1
Reaction time: 16 h

Procedure:
A solution of 20 ml of 1.6N n-butyllithium in hexane is added dropwise within 30 minutes, with stirring and with the exclusion of moisture, to a solution, cooled to -75°, of 5.2 g (33 mmol) of 5-bromopyrimidine and 10.7 g (31.2 mmol) of 4,4'-dibromobenzophenone in 130 ml of THF. The reaction mixture is stirred for a further 0.5 hour at -75° and then for 16 hours at room temperature; then, while cooling with ice, it is hydrolysed by adding 20 ml of water. The organic phase is separated and diluted with ethyl acetate. The solution is washed with 2N HCl and a semi-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. The residue is purified by column chromatography (400 g of silica gel, methylene chloride/ethyl acetate 85:15) and recrystallised from ethyl acetate, m.p. 89°-90°, Rf value=0.11 (silica gel, methylene chloride/ethyl acetate 85:15).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:34][S:41]([C:38]1[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Yield: 79.4 %

Procedure:
A solution of 1-(3,5-di-O-benzyl-4-C-(hydroxymethyl)-β-D-ribofuranosyl)thymine 35 (1.48 g, 3.16 mmol), DMAP (1.344 g, 0.011 mol) and p-toluenesulphonyl chloride (1.45 g, 7.6 mmol) in dichloromethane (20 ml) was stirred for 3 h at room temperature. The reaction mixture was diluted with dichloromethane (30 ml) and washed with saturated aqueous solutions of sodium hydrogen carbonate (3×20 ml) and sodium chloride (2×25 ml). The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using methanol:dichloromethane (1:99, v/v) as eluent to give nucleoside 72 (1.95 g, 80%) as a white solid material. FAB-MS m/e 776. δC (CDCl3) 162.9, 149.8 (C-2, C-4), 145.8, 145.2 (2×Ts), 136.9, 136.8 (2×Bn), 134.3 (C-6), 132.1, 132.0, 130.0, 129.9, 129.0 128.9, 128.4, 128.3, 128.2, 128.0, 127.7 (2×Ts, 2×Bn), 111.2 (C-5), 85.3, 84.0 (C-1′, C-4′), 78.9, 78.3, 75.2, 74.3, 72.7, 69.1 (C-2′, C-3′, C-5′, C-1″, 2×Bn), 21.7 (2×CH3), 11.9 (CH3). Anal. Calcd. for C39H40N2S2O11: C, 60.30; H, 5.19; N, 3.61. Found: C, 59.95; H, 5.11, N, 3.81.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>[Cu](I)I.C1OCCOCCOCCOCCOCCOC1.C1(C)C=CC=CC=1.CN1CCCN(C)C1=O>[C:2]1([N:23]2[C:24]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: I[Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: c1ccc2c(-n3c4ccccc4c4ccccc43)cccc2c1
Temperature: 170 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
21 g (0.1 mol) of 1-bromonaphthalene, 17 g (0.1 mol) of carbazole, 950 mg (5 mmol) of copper iodide (I), 33 g (240 mmol) of potassium carbonate, and 660 mg (2.5 mmol) of 18-crown-6-ether were put into a 500 mL three-neck flask, and nitrogen substitution was carried out in the flask. To this mixture was added 80 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (abbreviation: DMPU), which was followed by stirring for 6 hours at 170° C. under nitrogen. To this reaction mixture was further added 10 g (50 mmol) of 1-bromonaphthalene, 2.0 g (10 mmol) of copper iodide (I), and 2.6 g (10 mmol) of 18-crown-6-ether, and stirring was further conducted for 7.5 hours at 170° C. Furthermore, to this reaction mixture was added 10 g (50 mmol) of 1-bromonaphthalene, and additional stirring was carried out for 6 hours at 180° C. After the reaction was completed, to this reaction mixture was added about 200 mL of toluene and about 100 mL of 1 mol/L hydrochloric acid, and then the mixture was filtered through celite. The obtained filtrate was filtered through Florisil and celite. The obtained filtrate was separated into an organic layer and an aqueous layer, and after this organic layer was washed with 1 mol/L hydrochloric acid and then with water, the organic layer was dried over magnesium sulfate. This suspension was filtered through Florisil and celite. The filtrate was concentrated to give an oily substrate, and methanol was added to this oily substrate, followed by irradiation with ultrasound to precipitate a solid. The solid precipitated was collected by suction filtration, giving 22 g of 9-(1-naphthyl)carbazole as white powder (75% yield). The Rf values (SiO2, eluent; hexane:ethyl acetate=10:1) of 9-(1-naphthyl)carbazole, 1-bromonaphthalene, and carbazole were 0.61, 0.74, and 0.24, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:18][C:15]1[N:16]=[N:17][C:12]2[CH:11]=[C:10]([C:3]3[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=3[Cl:1])[CH:20]=[C:19]([CH3:21])[C:13]=2[N:14]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(N)nc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 72.8 %

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.158 g, 0.527 mmol, 1 equiv) was diluted with 10 mL DCM and chilled to 0° C. using an ice bath. A 1.0 M solution of BBr3 in DCM (3.16 mL, 3.16 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 3-5 minutes. Additional DCM was added and this mixture was washed with sodium bicarbonate followed by brine. The organic phase was separated, dried over sodium sulfate (Na2SO4), filtered and evaporated to dryness. Solids were then diluted with minimum amount of ethyl acetate and precipitated out with hexanes. Product was filtered off and dried to yield a yellow solid (0.110 g, 73% yield). MS (ESI+): m/z 287.1, LC retention time: 2.46 min.
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[CH3:16][O:15][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[O:6][C:7]=2[C:13]([NH2:14])=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(N)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(N)c2oc(N)nc12
Temperature: 100 °C
Yield: 19.9 %

Procedure:
To a stirred solution of 100 mg (0.42 mmol) (7-amino-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester in 15 ml dioxane and 5 ml ethylene glycol was added 15 ml of a 5 N aq. sodium hydroxide solution and the mixture was heated at 100° C. for 4 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (5/95 methanol/dichloromethane, then 10/89/1 methanol/dichloromethane/triethylamine) followed by trituration in ether afforded 15 mg (20%) 4-methoxy-benzooxazole-2,7-diamine as a brown solid. ES-MS m/e (%): 180 (M+H+, 100).