Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O>O>[C:24]1(=[O:33])[N:1]([CH:2]([CH2:3][C:4]2[N:8]=[CH:7][NH:6][CH:5]=2)[C:9]([OH:11])=[O:10])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1c[nH]cn1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a stirred solution of histidine (3.17 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 50 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. The resulting slurry is filtered and the solid washed with water and dried in vacuo (60 C, <1 mm) to afford 3.65 g (64%) of 2-phthalimido-3-(imidazol-4-yl)propionic acid as a white powder: mp 280°-285° C.; 1H NMR (dmso-d6, 250 M Hz) δ12.5 (br s, 1H), 7.90-7.60 (m, 6H), 6.80(s, 1H), 4.94 (t, 1H, J=7.8), 3.36 (d, 2H, J=7.8); 13C NMR (dmso-d6) δ 170.1, 167.1, 134.8, 134.6, 133.2, 131.1, 123.2, 116.3, 52.4, 25.8; Anal. Calculated for C14H11N3O4. Theoretical: C, 58.95; H, 3.89; N, 14.73. Found: C, 58.80; H, 3.88; N, 14.66.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@H:3]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:12][CH:13]=1)=[O:6])[NH2:4].C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH3:1][C:2]([C@H:3]1[NH:4][C:34](=[O:36])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:12][CH:13]=2)[C:5]1=[O:6])([CH3:25])[CH3:24]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)(C)C)cn2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C(C)(C)C)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-methyl-N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-valinamide (Intermediate 97, 5.2 mg) was dissolved in dry dichloromethane (0.5 mL). The reaction mixture was cooled down in an ice bath. Triethylamine (12.6 μl, 0.091 mmol) was added at 0° C. Then 0.5 mL of a solution of triphosgene in dry dichloromethane (2.47 mg, 0.0083 mmol) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. Some water was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 60/40 during 15 min and 60/40 during 10 min. This afforded the title compound (5.9 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1ccnc(F)c1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)c1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-4-methylpyridine.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1>C(OCC)(=O)C>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:38])([CH3:37])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a 50 mL round-bottom flask was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate (Int-5j, 800 mg, 1.43 mmol) and ethyl acetate (15 mL). The flask was flushed with argon and 5% palladium on carbon (100 mg) was added. The flask was sealed and degassed under vacuum. Hydrogen gas was then added via balloon. The reaction was stirred under a hydrogen atmosphere 18 hours. The reaction was then filtered through celite to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1.5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5k) (761 mg, 1.35 mmol, 95% yield) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (32.0 g, 123 mmol) in THF (650 mL) was added morpholine (21.4 g, 246 mmol), in a slow stream via an addition funnel over 15 min, and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was treated with NaBH(OAc)3 (38.4 g, 172 mmol) in portions over 40 min, was stirred at room temperature for 16 h, and then concentrated to a residue. The residue was diluted with EtOAc (400 mL), cooled to 0° C., and treated with 1 N NaOH (250 mL). The biphasic solution stirred at 0° C. for 30 min. The phases were separated and the aqueous layer was extracted with EtOAc (2×200 mL) and CH2Cl2 (2×100 mL). The organic layers were combined, washed with brine (1×300 mL), dried (Na2SO4), and concentrated to yield the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[C:24]([C:10]1[C:9]([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[N:11]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2C(C)(C)C)C2CCCCC2)cc1
Yield: 16.3 %

Procedure:
Using cyclohexyl{3-tert-butyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.52 g) synthesized in Example 13(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.34 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.13 g, 16%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc(F)c3c(N4CCOCC4)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask charged with 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (220 mg, 0.39 mmol) was added morpholine (Aldrich, 2 mL, 23 mmol) and the red solution was stirred under argon at room temperature for 10 minutes. The reaction was then quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue obtained was re-dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid at 0° C. for 1 hour. The reaction was then quenched with a saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The dark-brown material was then suspended in 0.5 N NaOH (8 mL) and heated to 90° C. for 6 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, 50% ethyl acetate in hexanes) to afford 6-fluoro-5-morpholin-4-yl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 15.1 mg, 11.6%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:17]([S:18][CH3:19])=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1.C(N(CC)CC)C.Cl>CN(C)C=O.ClCCl>[CH3:7][O:8][C:9]1[C:17]([S:18][CH3:19])=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:14][C:10]=1[C:11]([O:13][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)=[O:12]
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
133 mg (1.05 mmol) of oxalyl dichloride and three drops of N,N-dimethylformamide were added in succession to 200 mg (purity 78% by weight, 0.59 mmol) of 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoic acid in 20 ml of dichloromethane. After the elimination of gas had ceased, the mixture was heated under reflux for another 10 min. The content was then cooled to RT and freed from the solvent. 93 mg (0.83 mmol) of 1,3-cyclohexanedione were added to the residue in 20 ml of dry dichloromethane, and 152 mg (1.50 mmol) of triethylamine were then added dropwise. The mixture was stirred at RT for 16 h. For work-up, 3 ml of 1M hydrochloric acid were added to the contents. After phase separation, the organic phase was freed from the solvent. The residue was purified chromatographically, which isolated 100 mg of 3-(2-methoxy-3-methylthio-4-(trifluoromethyl)benzoyloxy)-cyclohex-2-enone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.O>C(O)(=O)C.C(O)C.C(O)(=O)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:23][C:22]1[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:9])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1cccc(F)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Under an atmosphere of nitrogen, 30 g of titanium trichloride was added portionwise (cautiously) with stirring to 200 ml of ice. The resulting solution was added all at once to a stirred solution of 10.0 g (0.0297 mole) of (3-fluorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone in 150 ml of acetic acid: ethanol (1:1) and 150 ml of acetic acid: water (1:1). After 30 min stirring, the reaction mixture was poured into one liter of water. The mixture was filtered and the resulting filter-cake was suspended in 100 ml of water. The mixture was again filtered and the filter-cake (10.0 g) was partially dissolved in 100 ml of hot methanol. The solution was basified with 25 ml of concentrated ammonium hydroxide, stirred for an additional 15 min and then diluted with 500 ml of water. The mixture was extracted three times with 75 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 50 ml of water, dried over sodium sulfate and concentrated in vacuo. The residue (6.9 g) was twice recrystallized, treating once with charcoal, from ethyl acetate-isopropyl ether to give 4.5 g (49%) of a dark gold solid, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C1(C)C=CC(S([N:21]2[C:29]3[C:24](=[C:25]([O:30][CH2:31][CH:32]4[O:34][CH2:33]4)[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=O)=O)=CC=1>C(O)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[NH:1][CH2:33][CH:32]([OH:34])[CH2:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][NH:21]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Reactant: NC1CCc2ccccc2C1
Solvent: CCO
Product: OC(CNC1CCc2ccccc2C1)COc1cccc2[nH]ccc12
Yield: 30.6 %

Procedure:
A mixture of 2-aminotetralin (5 g) and 1-[1-(p-toluenesulfonyl)-indol-4-yloxy]-2,3-epoxypropane (11.7 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is evaporated, the obtained residue is dissolved under stirring in hot isopropanol (100 ml) and the solution is made acidic by the addition of hydrochloric acid in isopropanol. The precipitate which forms is recovered by filtration, dissolved in a mixture of ethanol (250 ml) and aqueous sodium hydroxide (7.6 g in 85 ml of water). The reaction mixture is refluxed for 6 hours, the solvent is evaporated off and the residue is dissolved in ethyl acetate (200 ml). The obtained solution is washed twice with water, dried over sodium sulfate and concentrated by evaporating off the solvent. The residue is chromatographed on a silica gel column eluting with ethyl acetate. The fractions containing pure product are pooled. The solvent is evaporated and the residue is dissolved in ethyl ether (20 ml) and crystallized therefrom yielding 3.5 g of N-(1,2,3,4-tetrahydronaphth- 2-yl)-2-hydroxy-3-(4-indolyloxy)propanamine; m.p. 65°-68° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([O-:12])(=O)=[O:10].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([Cl:15])(=[O:12])=[O:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])Cc1ccccc1Br
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)Cc1ccccc1Br
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a suspension of crude sodium (2-bromophenyl)methanesulfonate (34 g) in toluene (500 mL) was added PCl5 (34 g, 0.16 mol). The resulting mixture was stirred at 100° Celsius for 4 hours before concentrating to dryness and pouring the residue onto crushed ice (150 g), stirring for 5 min, and extracting with DCM (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to dryness to give (2-bromophenyl)methanesulfonyl chloride (16.8 g, 77%). 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.45 (m, 2H), 7.29 (m, 1H), 7.18-7.01 (m, 1H), 3.97 (s, 2H).
Reaction SMILES: CN(C=O)C.CCO[CH2:9][CH3:10].[K+].[Br-:12].[Br-].BrCC[C:17]1[C:30]2[C:21](=[NH+:22][CH:23]=[C:24]3[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]3)[CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:12][CH2:24][CH2:23][N:22]1[CH2:9][C:10]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]1=2
Reactant: [Br-]
Reactant: BrCCc1cccc2[nH+]cc3ccccc3c12
Reactant: CCOCC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCN1Cc2ccccc2-c2ccccc21
Yield: 50 %

Procedure:
During the preparation of 6a, the mother liquor from the DMF/ether (25:75) solution was kept and washed thoroughly 4 times with 40 ml of water. The organic layer was then washed with brine and dried over MgSO4. The solvent was evaporated down to a dark residue. Column chromatography (Silica, DCM as elutant) afforded 5 (140 mg; 0.485 mmol) as a beige powder in a 50% yield. Rf=0.75 in 100% ethyl acetate; mp: 99-100° C.; 1H NMR (CDCl3, 400 MHz): δ 7.64 (d, 1H, J=7.60 Hz), 7.60 (d, 1H, J=7.60 Hz), 7.22 (t, 1H, J=7.60 Hz), 7.13 (t, 2H, J=7.60 Hz), 7.01 (d, 1H, J=7.60 Hz), 6.77 (t, 1H, J=7.60 Hz), 6.62 (d, 1H, J=7.60 Hz), 4.27 (s, 2H), 3.64 (t, 2H, J=7.80 Hz), 3.44 (t, 2H, J=7.80 Hz); 13C NMR (CDCl3, 100 MHz): δ 145.02 (C), 132.71 (C), 132.19 (C), 129.68 (CH), 128.55 (CH), 128.22 (CH), 125.96 (CH), 124.44 (CH), 124.22 (C), 123.59 (CH), 119.19 (CH), 112.51 (CH), 53.38 (CH2), 53.26 (CH2), 27.78 (CH2); IR (KBr, cm−1): 3429 (s), 2924 (w), 1716 (w), 1628 (s), 1601 (s), 1525 (w), 1493 (s), 1442 (s), 1340 (m), 1290 (m), 1269 (s), 1196 (s), 1022 (m), 758 (s), 725 (m), 615 (m) MS (FAB): 289 (M+H) (100), 222.1 (7), 194.1 (35), 180.1 (22), 166.1 (6), 152.1 (4), 107.2 (2), 85.7 (1), 58.1 (7); Anal. Calcd for C15H14NBr: C, 62.51; H, 4.89; N, 4.86. Found: C, 62.30; H, 4.96; N, 4.75.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](OC)=O.[NH3:24]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:8][CH2:7][CH2:6][CH:11]([CH3:10])[O:13][C:14]3[CH:23]=[CH:22][CH:21]=[C:16]4[C:15]=3[N:24]=[C:5]([NH2:1])[CH:4]=[CH:17]4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: COC(=O)c1cccc(O)c1
Reactant: N
Product: CC(CCCOc1ccc(-n2ccnc2)cc1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 4-(1H-imidazol-1-yl)phenol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 8.89 (s, 1H), 7.93 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.32 (m, 3H), 7.20 (dd, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.96 (m, 2H), 4.69 (m, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 2.23 (m, 1H), 2.12 (m, 1H), 1.94 (m, 2H), 1.48 (d, 3H); MS (DCI/NH3) m/z 389 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[C:13]([NH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH:26]=[CH:25][O:24]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>O=P(Cl)(Cl)Cl>[C:13]([NH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C@@H:23]2[O:24][C@@H:25]([O:5][CH:4]([C:6]3[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=3)[CH2:3][CH2:2][Cl:1])[CH2:26][CH2:27][CH2:28]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: OC(CCCl)c1ccc(F)cc1
Reactant: CC(=O)Nc1ccc(OCC2CCC=CO2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(OC[C@H]2CCC[C@H](OC(CCCl)c3ccc(F)cc3)O2)cc1

Procedure:
A catalytic amount (2 drops) of phosphorus oxytrichloride was added to 10 ml of an ethereal solution containing 277 mg of 3-chloro-1-(4-fluorophenyl)propanol and 330 mg of 2-(4-acetamidophenoxymethyl)-3,4-dihydro-2H-pyran and the mixture was allowed to react at room temperature for 8 days. The precipitated crystals were separated by filtration, giving 240 mg of the isomer of lesser polarity of the title compound, melting at 133°-135° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O>CC(N(C)C)=O>[NH:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]=[C:1]1[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(C=O)cc2)C1
Reactant: Nc1ccccc1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3nc4ccccc4[nH]3)cc2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
tert-Butyl 2-(4-formylphenyl)morpholine-4-carboxylate (300 mg, 1.03 mmol) was dissolved in dimethylacetamide (4.5 ml). 1,2-Diaminobenzene (134 mg, 1.24 mmol) and sodium metabisulfite (294 mg, 1.54 mmol) were added and the reaction mixture was stirred at 90° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (20 g silica gel, 40 to 70% ethyl acetate in heptane) to yield a white solid (333 mg, 85%). MS (ISP): 280.3 (100%, [M-BOC+H]+), 380.2 (20%, [M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([CH:18]=C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:22]C(C)=O>CC(C)=O.O.CCCCCC.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([CH:18]=[O:22])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirred mixture of (2-(benzyloxy)-3-nitro-6-vinylpyridine (0.5 g, 0.0019 mol) in acetone:water (1:1, 5 mL), was added OsO4 (16.39 mg, 0.000064 mol, Aldrich) and NaIO4 (1.67 g, 0.0078 mol, Aldrich). The reaction mixture was stirred for 4 h at room temperature. After completion of the reaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (5 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and purified by column chromatography, silica gel (60-120 mesh) using 5-7% EtOAc in petroleum ether as an eluent to afford the title compound. 1H NMR (400 MHz, CDCl3) δ: 10.00 (s, 1H), 8.38 (d, J=6 Hz, 1H), 7.69 (d, J=6 Hz, 1H), 7.54 (d, J=5.7 Hz, 2H), 7.41-7.37 (m, 3H), 5.69 (s, 2H).