Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[OH:10][C:9]1[C:2]([O:1][CH3:11])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(O)cccc1C=O
Yield: 61.7 %

Procedure:
2,3-Dihydroxybenzaldehyde (1.00 g, 7.24 mmol), potassium carbonate (1.00 g, 7.24 mmol) and iodomethane (0.59 ml, 1.34 g, 9.4 mmol) in dry DMF (10 ml) were stirred at ambient temperature for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N aqueous sodium hydroxide (3×). The basic extracts were combined and acidified by addition of 3N hydrochloric acid, then extracted with ethyl acetate. The ethyl acetate layer was washed with water (4×), brine and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 3-hydroxy-2-methoxy-benzaldehyde (0.68 g, 62%) as a yellowish-tan solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][C:41]([NH2:43])=[S:42])[CH2:4][CH2:3]2.C(N(CC)C(C)C)(C)C.Br[CH2:54][C:55](=O)[C:56]([CH3:59])([CH3:58])[CH3:57].O>CN(C=O)C>[C:56]([C:55]1[N:43]=[C:41]([NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[S:42][CH:54]=1)([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)C(=O)CBr
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(N)=S)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(Nc3nc(C(C)(C)C)cs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-thioureido-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (150 mg, 0.249 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.217 mL, 1.244 mmol) and 1-bromopinacolone (0.056 mL, 0.373 mmol). The reaction mixture was stirred at rt overnight. After 18 h, the reaction mixture was poured into a separatory funnel containing H2O (5 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to white solid. The material was redissolved in DCM (3 mL), MeOH wash added and concentrated to remove most of the DCM. The resulting white precipitate was filtered, washed with cold MeOH, and dried in a vacuum oven to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(4-tert-butylthiazol-2-ylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (154.0 mg, 0.225 mmol, 91% yield) as a white solid. LC/MS: m/e 683.4 (M+H)+, 2.88 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.95 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 6.06 (s, 1H), 5.31 (d, J=4.6 Hz, 1H), 4.88 (s, 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.93 (s, 3H), 2.72 (d, J=13.7 Hz, 1H), 2.68-2.62 (m, 1H), 2.55 (dd, J=8.1, 12.7 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 2.07-1.98 (m, 1H), 1.92-1.83 (m, 1H), 1.82-1.76 (m, 1H), 1.74 (s, 3H), 1.73-1.66 (m, 2H), 1.61 (s, 1H), 1.57-1.49 (m, 3H), 1.49-1.40 (m, 4H), 1.40-1.31 (m, 3H), 1.29 (s, 9H), 1.27-1.21 (m, 1H), 1.18-1.12 (m, 1H), 1.10 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=1.C(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O.CN(C)C=O>CCCCCC>[Cl:16][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][N:10]=1
Reactant: O=c1ncc(-c2ccccc2F)n[nH]1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccccc1-c1cnc(Cl)nn1

Procedure:
A suspension of 42.4 g. of 6-(o-fluorophenyl)-1,2,4-triazin-3(2H)-one in 350 ml. of chloroform is refluxed overnight, cooled in an ice bath, and 350 ml. of phosphorus oxychloride followed by 2.6 g. of N,N-dimethylformamide are added. The mixture is refluxed for 4.5 hours, cooled and concentrated to a brown oil. This oil is dissolved in methylene chloride, poured onto ice and made basic, giving a brown solid. The mixture is filtered and the filtrate is passed through a silica gel column giving a crystalline solid. This solid is heated with hexane and filtered giving crystals. Recrystallization from hexane gives a tan solid which sublimes on heating giving 3-chloro-6-(o-fluorophenyl)-1,2,4-triazine as tan crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:17]=1OC.O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([O:36]C)=[O:35].[C:38]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([OH:36])=[O:35])=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:16][C:17]=1[CH3:38]
Reactant: COC(=O)Cc1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(CO)cc1OCc1nc(-c2ccccc2)oc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2CC(=O)O)cc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 8 h

Procedure:
To a mixture of [4-methoxy-3-[(5-methoxy-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (0.95 g), methyl 2-(2-hydroxyphenyl)acetate (0.50 g), triphenylphosphine (0.95 g) and tetrahydrofuran (15 mL) was dropwise added a solution (40%, 1.74 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol (10 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid (5 mL), extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[2-[4-methoxy-3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization with ethanol-hexane gave colorless plate crystals (0.52 g, 37%). melting point: 154-155° C.
Reaction SMILES: [Br:1][C:2]1[C:19]([OH:20])=[N:18][C:5]2[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:20][C:19]1[C:2]([Br:1])=[CH:3][C:4]2[CH:10]([CH3:11])[CH2:9][N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[CH2:7][CH2:6][C:5]=2[N:18]=1)(=[O:23])=[O:21]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(Br)cc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(OS(=O)(=O)C(F)(F)F)c(Br)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-2-ol (30.0 mg, 85.0 μmol), Tf2O (50 μl), K2CO3 (18 mg) and DCM (1 ml) was stirred for 16 h at room temperature. The mixture was extracted with sat. aq. NaHCO3, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to yield 11.0 mg (26%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate. A mixture of methylamine (50 μl), 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl trifluoromethanesulfonate (11.0 mg, 22.7 μmol), and THF (1 ml) was heated to reflux for 15 h. The reaction mixture was parted between sat. aq. NaHCO3 and EtOAc. The organic layer was dried, concentrated in vacuo and purified with column chromatography to give 5.2 mg (62%) of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 486.2 (M+H+). A mixture of 3-bromo-N,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine (5.2 mg, 14.2 μmol), K2CO3 (15 mg), MeOH (1 ml) and H2O (100 μl) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 2.1 mg (55%) of 3-bromo-N,5-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine. MS (ESI) m/z 271.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.Cl.[NH2:13][NH:14][C:15]([NH2:17])=[O:16]>O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[N:13][NH:14][C:15]([NH2:17])=[O:16]
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1C=NNC(N)=O
Yield: 93.8 %

Procedure:
In 180 ml. of hot water, 9.3 grams (0.06 mole) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde is slurried while 6.7 grams (0.06 mole) of semicarbazide hydrochloride is added portionwise. After 15 minutes of heating, the mixture is cooled in a refrigerator overnight. The solid is then collected and washed with water and methanol, respectively, to give a yellow product, melting point 272°-273° C. (dec.). After drying at 100° for 2 hours under reduced pressure, 11.94 grams of 1-methyl-5-nitro-2-imidazolecarboxaldehyde semicarbazone is obtained. This semicarbazone (6.35 grams or 0.03 mole) is added to 10 grams of anhydrous sodium acetate in 50 ml. of glacial acetic acid and 1.25 ml. of bromine is added with continuous stirring. The mixture is heated gradually to give a nearly clear red solution at 50° C. which becomes increasingly turbid with time. After heating at 75° ± 3° for 3 hours, the mixture is cooled and poured on ice. The yellow solid is collected, washed with water, then with methanol, and dried under reduced pressure at 70°C. for 3 hours to give 5 grams of crude 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-oxadiazole, melting point 284°-287° C. (dec.). This material is dissolved in boiling dimethylformamide, ethanol added, and the mixture cooled to give yellow crystals, melting point 291°-293° C. (dec.).
Reaction SMILES: O[C:2]1([C:17]2[O:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=1.NC(C(O)=O)CCSC>CS(O)(=O)=O>[OH:15][C:11]1[CH:10]=[C:9]([CH2:8][CH:3]2[C:2]([C:17]3[O:18][C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:21]=3)=[CH:7][CH2:6][CH2:5][CH2:4]2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CC2CCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Product: Oc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 43.4 %

Procedure:
A suspension of 2-[(1RS,2SR)-1-hydroxy-2-[(3-methoxyphenyl)methyl]cyclohexyl]-4,5-diphenyloxazole (2.23 g) and DL-methionine (7.56 g) in methanesulfonic acid (33.0 ml) was stirred at 60° C. for 17 hours, then another DL-methionine (7.56 g) and methanesulfonic acid (33.0 ml) was added thereto. The mixture was stirred at the same temperature for 23 hours and poured into ice-water. The resulting aqueous mixture was extracted three times with ethyl acetate. The extracts were combined, washed with sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-diethyl ether (100:20)) over silica gel. The first eluate afforded 2-[6-[(3-hydroxyphenyl)methyl]-1-cyclohexen-1-yl]-4,5-diphenyloxazole (897 mg) as paste.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[CH3:13][O:14][CH2:15]Cl>C(#N)C.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(S)cc1
Reactant: COCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: COCSc1ccc(CC(=O)OC)cc1
Yield: 78.9 %

Procedure:
A solution of (4-mercapto-phenyl)-acetic acid methyl ester (500 mg, 2.7 mmol) and chloromethyl methyl ether (331 mg, 4.1 mmol) in acetonitrile (3 mL) and pyridine (1 mL) was heated under reflux for 16 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in ethyl acetate (10 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×25 mL) and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded (4-methoxymethylsulfanyl-phenyl)-acetic acid methyl ester (482 mg, 77.6%) as a clear oil: EI-HRMS m/e calcd for C11H14O3S (M+) 226.0664, found 226.0664.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([Cl:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 98.5 %

Procedure:
A solution of 3-amino-6-chlorobenzotrifluoride (1.045 g, 5.34 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.250 g (98.5%) of 3-acetamido-6-chlorobenzotrifluoride. 1H NMR (CDCl3): δ 2.193 (s, 3H); 7.420 (d, 1H, J=8.7 Hz); 7.726 (m, 2H), 7.804 (s, 1H).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=CC=[CH:15][CH:14]=2)=[C:7](OC(=O)C)[C:6]=1[O:23]C(=O)C)(=O)C.[C:27]([O-:30])(=O)[CH3:28].[NH4+].C[OH:33]>>[C:8]1([CH:11]=[CH:12][C:13]2[CH:18]=[CH:28][C:27]([OH:30])=[CH:15][CH:14]=2)[CH:7]=[C:6]([OH:23])[CH:5]=[C:10]([OH:33])[CH:9]=1
Reactant: CC(=O)[O-]
Reactant: CC(=O)Oc1ccc(C=Cc2ccccc2)c(OC(C)=O)c1OC(C)=O
Reactant: CO
Agent: [NH4+]
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
2.10 g (6.0 mmol) triacetoxystilbene were dissolved under reflux in 19.3 ml methanol and 39 ml ammonium acetate solution (25%) was added to the solution. The reaction mixture was stirred for three hours at the same temperature and afterwards the methanol was distilled off. By cooling to 5° C. the product crystallized and could be filtered off. 1.33 g (5.82 mmol, 97%) resveratrol were obtained as a pure compound. The mother liquor was purified by extraction with methyl-butyl-ether and neutralized with ammonia. After concentration under reduced pressure the solution was used again for the described reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[C:16]([C:17]([C:27]#[N:28])=[C:18]4[S:22][C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[C:19]=24)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].O[C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33]C)=[O:32].BrBr>>[Br:9][C:6]1[CH:5]=[C:4]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([C:27]#[N:28])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:3]=[C:2]([Br:1])[C:7]=1[O:8][C@@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Reactant: N#Cc1c2ccccc2c(-c2cc(Br)c(O)c(Br)c2)c2c1sc1ccccc12
Agent: BrBr
Product: N#Cc1c2ccccc2c(-c2cc(Br)c(O[C@@H](Cc3ccccc3)C(=O)O)c(Br)c2)c2c1sc1ccccc12

Procedure:
Prepared from 11-(3, 5-dibromo-4-hydroxy-phenyl)-benzo[b]naphtho[2,3-d ]thiophene-6-carbonitrile (Example 58) and (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 97). White solid: mp 176-178° C.: NMR (CDCl3); δ8.36 (ddd, J =8,1,1 Hz, 1 H), 7.85 (d, J=8 Hz, 1 H), 7.77 (ddd, J=8, 8, 2 Hz, 1 H), 7.58 (d, J=2 Hz, 1 H), 7.61-7.54 (m, 2 H), 7.56 (d, J=2 Hz, 1 H), 7.47 (ddd, J=8, 8, 1 Hz, 1 H), 7.41 (ddd, J=8, 1, 1, 2 H ), 7.36-7.26 (m, 3 H), 7.20 (ddd, J=8, 8, 1, 1 H), 6.75 (ddd, J =8, 1, 1 Hz, 1 H), 5.46 (t, J=7 Hz, 1 H), 3.59 (d, J=7 Hz, 2 H); MS (-FAB): [M-H]-, 2 bromine isotope pattern, 654 (2%), 656 (4%) 658 (2%); Anal. Calc. for C32H19Br2NO3S: C, 58.47, H, 2.91, N, 2.13 Found: C, 58.23, H, 2.69, N, 2.03.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH3:21][C:22]1[N:23]=[C:24]([CH2:28][O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@@H:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C@@H:17]3[OH:18])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(CBr)n1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1cccnc1)CO2
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2cccnc2)CO3)n1

Procedure:
By the method of Example 5, 0.50 g (1.95 mmol) of trans-3-(3-pyridylmethyl)-4,6-chromandiol and 400 mg (2.15 mmol) of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using ethyl acetate as eluant to yield purified title product, o.14 g (20%), m.p. 66°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1.C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:37][C:5]1[C:4](=[O:22])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)O)c1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(N)c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (6.00 g, 19.1 mmol), DPPA (6.16 mL, 28.6 mmol) and Et3N (3.99 mL, 28.6 mmol) in toluene (60 mL) was heated to 100° C. for 2 h. To the mixture was added 8 M NaOH aqueous solution (23.8 mL) at 0° C. The mixture was stirred at room temperature for 3 h, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc/i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (3.57 g, 66% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.83 (3H, s), 6.31 (2H, s), 7.64-7.79 (2H, m), 8.13 (2H, s), 8.64 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:49][C:50]1[CH:58]=[CH:57][CH:56]=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[CH:56][CH:57]=[CH:58][C:50]=2[Br:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: CC(O)c1ccccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccccc4Br)cc3)c2cc1OC
Temperature: 25 °C
Yield: 57.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (88 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (145 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-bromo-α-methylbenzyl alcohol (90 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (89 mg, yield 54%).
Reaction SMILES: ClC1C=CC(C=[N:9][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH2:15][C:16]#[CH:17])[C:11]([O:13][CH3:14])=[O:12])=CC=1.Cl>C(OCC)C.O>[NH2:9][C:10]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH2:15][C:16]#[CH:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: C#CCC(N=Cc1ccc(Cl)cc1)(C(=O)OC)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C#CCC(N)(C(=O)OC)c1ccc(OC)cc1
Yield: 92.6 %

Procedure:
962 mg of the compound prepared in Stage 2 are stirred at AT in 14 mL of ethyl ether and 3.5 mL of 1 N hydrochloric acid for 18 hours. The mixture is diluted with water and the product is extracted with ethyl acetate. The solvent is dried over magnesium sulphate and evaporated to produce 584 mg of product, in the form of colourless oil (Yd=92%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][NH:21]2>CC#N>[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:11]1[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:9]2[N:10]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: C1NC2CNC1C2
Solvent: CC#N
Product: Nc1nc(N2CC3CC2CN3)nc2nc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.7 mmol, 1 eq.; see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and 2,5-diaza-bicyclo[2.2.1]heptane (5 eq.) were suspended in 10 mL of CH3CN. The mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with water, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (95% CH2Cl2, 4% MEOH, 1% Et3N) to afford 5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: OC1CCc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c(c1)C(OC1CCCCO1)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
6-Bromoindan-1-ol (3.01 g) and dihydropyrane (1.78 g) are dissolved in dichloromethane (50 ml), and thereto is added pyridinium p-toluenesulfonate (178 mg), and the mixture is stirred at room temperature for 1.5 hour. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 6-bromo-1-tetrahydropyranyloxyindane (4.10 g).