Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH:16]1([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH:26][CH:2]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]3=4)=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCCC2Nc1ccc(C2CCCCC2)cc1
Reaction time: 4 h

Procedure:
A mixture of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (1.2 g, 5.9 mmol), 4-cyclohexylaniline (2.1 g, 11.8 mmol), decaborane (0.22 g, 1.8 mmol) in dry MeOH (20 mL) was stirred under nitrogen for 4 h. Solvent evaporation and chromatography (5% to 20% EtOAc in Hexane) gave methyl 5-[(4-cyclohexylphenyl)amino]-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a yellow solid. HPLC/MS: m/z=364.2 (M+1), Rt=2.83 min. 1H NMR (CDCl3): δ 7.86 (1H, s), 7.85 (1H, d, J=7.5 Hz), 7.54 (1H, d, J=7.5 Hz), 7.11 (2H, d, J=8.5 Hz), 6.68 (2H, d, J=8.5 Hz), 4.66 (1H, t, J=5.5 Hz), 3.96 (3H, s), 3.79 (1H, br s), 2.97-2.82 (2H, m), 2.46 (1H, m), 2.10-1.78 (9H, m), 1.44 (4H, m), 1.30 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH2:21].[H-].[Na+]>O=S(Cl)Cl.C1COCC1>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: COc1ccc(Cl)c(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
A solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (1.6 g, 7 mmol, 3.0 eq) in SOCl2 (20 mL) was heated at reflux for 3 h. The excess thionyl chloride was removed in vacuo and the residue obtained dissolved in THF (10 mL) and added dropwise to a solution of 2,6-dichloro-3-methoxy-aniline (450 mg, 2.3 mmol, 1.0 eq) and NaH (85 mg, 3.4 mmol, 1.5 eq) in THF (10 mL). The reaction was stirred at room temperature for 2 h then quenched by addition of aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound (200 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH:27]2[CH2:28][CH2:29][CH:23]1[CH2:24][CH:25]([NH2:30])[CH2:26]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:25]2[CH2:26][CH:27]3[N:22]([CH3:21])[CH:23]([CH2:29][CH2:28]3)[CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1C2CCC1CC(N)C2
Product: CN1C2CCC1CC(NC(=O)c1cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s1)C2

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine (71.0 mg, 0.52 mmol). The title compound was obtained as a solid (40 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.97 (2H, m), 8.52 (1H, s), 8.44 (1H, s), 3.85 (1H, m), 3.79 (2H, m), 2.64 (3H, m), 2.25 (2H, m), 2.22 (4H, m), 2.16 (2H, m). MS m/z: 475.35, 477.33 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:23][C:24]1[CH:39]=[C:38](O)[CH:37]=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:16]([O:23][C:24]1[CH:39]=[C:38]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:37]=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.221 mL) was added to an ice-cooled mixture of benzyl 2-benzyloxy-4-hydroxybenzoate (0.400 g) and pyridine (0.111 mL) in dichloromethane (1.5 mL) with stirring, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of 1 mol/L hydrochloric acid and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to afford benzyl 2-benzyloxy-4-trifluoromethanesulfonyloxybenzoate (0.555 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1.Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1.CN(C)C=O.[H-].[Na+]>O>[C:31]([C:30]1[C:25]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:23])=[C:14]([O:21][CH3:22])[CH:15]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)#[N:32]
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxyphenyl]methanol (5.00 g), 2-chloro-3-cyanopyridine (2.65 g) and N,N-dimethylformamide (150 mL) was added sodium hydride (60%, oil, 0.70 g) at room temperature and the mixture was stirred for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give crystals (6.60 g, yield 99%) of 3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N-:16]=[N+]=[N-].[Na+].O.C(Cl)Cl>CS(C)=O>[CH3:7][C:5]1([CH3:8])[CH2:6][C:2]2[NH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:3]=2[CH2:4]1
Reactant: CCOC(=O)/C=C/C1=C(Cl)CC(C)(C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c([nH]1)CC(C)(C)C2
Temperature: 75 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A 250-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 167a (17 g, 74 mmol) in DMSO (100 mL). To the solution was added sodium azide (9.6 g, 150 mmol). The mixture was then heated to 75° C. and stirred for 8 h. After cooling to rt, H2O (100 mL) and CH2Cl2 (200 mL) were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using a 100% hexane-1:1 hexane/ethyl acetate gradient to afford a 37% yield (5.7 g) of 167b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>C1COCC1>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at −25° C. was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed by isobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resulting mixture was stirred at −25° C. for 30 min and an amine or an amine salt, e.g. (S)-2-amino-1-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was then added. The mixture was allowed to gradually warm to rt. After 16 h, the solvents were removed. The residue was dissolved in AcOEt, washed twice with NH4Cl saturated solution, then twice with 10% NaHCO3 solution. The organic layer was dried over Na2SO4, filtrated and concentrated to afford the desired product, e.g. tert-butyl (2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (8.76 g, 96%) as a pale yellow oil in 88.5% purity by HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[C:11]([CH2:12][OH:13])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 3-(benzyloxy)-2-methylbenzoic acid (800 mg) in THF (10 mL) was added dropwise a 1.0 M solution of borane-THF complex in THF (6.6 mL) at room temperature over 30 min, and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction mixture under ice-cooling, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (480 mg) as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH2:11]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-:37]>C1(C)C=CC=CC=1>[I:37][CH2:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: OCCC1Cc2ccccc2C1
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCC1Cc2ccccc2C1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
A mixture of 2-(indan-2-yl)ethanol (19.3 g), imidazole (12.1 g), triphenylphosphine (34.3 g), and toluene (250 ml) was heated to 90° C. To this mixture, iodide (33.2 g) was added, and the resulting mixture was stirred at 90° C. for 20 min. The mixture was allowed to cool to room temperature. filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:4) to give an oil (28.4 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O-])=[O:7].[NH4+:12].[CH:13]([O-])([O-])OC>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[NH:12][CH:13]=[N:11]2)=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: Nc1cc(Cl)ccc1C(=O)[O-]
Reactant: COC([O-])[O-]
Solvent: CO
Product: O=c1[nH]cnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
In a 2-mL volume stainless steel pressure-resistant vessel were placed 340 mg (1.8 mmol) of ammonium 4-chloroanthranilate (prepared in the same manner as in Reference Example 2), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of methanol. The reaction was carried out at 120° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 176 mg (reaction yield: 54%) of 7-chloroquinazolin-4-one.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.CN(C)CCCN=C=NCC.[CH3:39][C:40]1([C:46]2[CH:47]=[C:48]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:45]2[CH:41]1[CH2:42][NH:43][CH2:44]2.C(N(CC)CC)C>CN(C)C=O>[NH3:2].[CH3:39][C:40]1([C:46]2[CH:47]=[C:48]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:45]2[CH:41]1[CH2:42][N:43]([C:12](=[O:14])[CH2:11][C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=1)[CH2:44]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CC(=O)N2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)c2ccccc21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.9 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-3-yl)acetic acid (117 mg, 0.62 minol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride hydrochloride (170 mg, 0.88 mmol). After stirig at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacui. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia (300:8:1) to afford the title compound as a white foam (58 mg, 20%).
Reaction SMILES: O.[OH-].[K+].[C:4]1([CH:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([O:35]C)=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(c5ccccc5)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1

Procedure:
10 ml of water and 1 g of potassium hydroxide were added to a solution of 25 ml of methanol containing 214 mg of methyl 17β-(N-diphenylmethylcarbamoyl)androsta-3,5-diene-3-carboxylate (prepared as described in Example 27). The reaction mixture was then heated under reflux for 4 hours. At the end of this time, methanol from the reaction mixture was removed by distillation under reduced pressure. The mixture was then made acidic by the addition of 1N aqueous hydrochloric acid and extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 20 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 50:50 by volume as the eluent, to give 110 mg of the title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[S:12](=[O:16])(=O)(O)O.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:8]1[C:22]2=[CH:21][S:12](=[O:16])[CH:23]=[C:17]2[CH:18]=[CH:19][CH2:20]1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Product: O=S1C=C2C=CCOC2=C1

Procedure:
The thieno[3,4-b]pyrans are prepared according-to Scheme 3. In this reaction sequence, 3,4-dibromothiophene is converted by literature procedures [Tetrahedron, 1965, 21, 3331] to 3-bromo-4-t-butoxythiophene (22) which in turn is converted to 3-lithio-4-t-butoxythiophene according to the same literature procedure. Reaction of the 3-lithio compound with a 3,3-disubstituted acryloyl acid derivative such as the methyl or ethyl ester, acid chloride, anhydride or amide derivatives at about -70° to 50° C. gives the unsaturated ketone derivative (23). Reaction of 23 with protic acid catalysts such as p-toluenesulfonic acid, sulfuric acid or the like at about 50°-250° C. neat or in inert solvents such as toluene or xylenes gives the ring-closed thieno[3,4-]pyranone derivative (24). Using reaction conditions essentially as those described for Scheme 1, reduction of the ketone gives the alcohol 25 which is dehydrated to give the olefin 26. Treatmen of the olefin (26) with N-bromosuccinimide and water in polar solvents gives the bromohydrin 27 which is converted to the epoxide 28. Reaction of 28 with the anions of various amines and amides gives the aminoalcohols 29 (R1R2 =H). Reaction of these derivatives with electrophiles such as bromine, chlorine, sulfuryl chloride or nitric acid gives the substituted derivatives 29 (R1 or R2 =Br, Cl, NO2), respectively. When the electrophiles is an acylating agent such as acetyl chloride or acetic anhydride and Lewis or protic acid catalysis is employed, the product is the acetyl acetoxy derivative 30 (R1 or R2 =acetyl) which may be converted to the aminoalcohol 29 (R1 or R2 =acetyl) by treatment with alcoholic base. ##STR10##
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[O:9]=[C:10]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[N:13]2[N:34]=[CH:35][N:36]=[C:12]2[N:11]1[CH:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:15]3[C:10](=[O:9])[N:11]([CH:37]4[CH2:42][CH2:41][N:40]([CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)[CH2:39][CH2:38]4)[C:12]4[N:13]([N:34]=[CH:35][N:36]=4)[C:14]=3[CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=2)[NH:30]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(C3CCOCC3)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCN(C3CCOCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A mixture of hydroxylammonium chloride (615 mg), sodium hydrogen carbonate (911 mg) and dimethyl sulfoxide (6 mL) was stirred at 60° C. for 30 min, a solution of 4′-({5-oxo-7-propyl-4-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (317 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (115 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (108 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=5/95→30/70 (volume ratio)] and crystallized from acetonitrile to give the title compound as colorless crystals (108 mg, 31%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-]>CO.CCOC(C)=O>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:14][CH:15]=2)[CH:9]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1

Procedure:
To a solution of 1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (203 mg, 0.695 mmol) in MeOH (6 mL) and EtOAc (6 mL), SnCl22H2O (343 mg, 1.52 mmol) was added. After the mixture was heated to reflux for 1 h, it was concentrated in vacuo. The residue was purified by HPLC to give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (145 mg). MS 267 (M+H).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:27]([C:29]1[CH:30]=[C:31]([CH2:35]O)[CH:32]=[CH:33][CH:34]=1)[CH3:28]>C(Cl)Cl>[Br:1][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:27][CH3:28])[CH:30]=1
Reactant: BrBr
Reactant: CCc1cccc(CO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Bromine (0.21 mL, 4.08 mmol) was added dropwise to a solution of triphenylphosphine (1.08 g, 4.12 mmol) and imidazole (280 mg, 4.11 mmol) in CH2Cl2 (13.5 mL) at 0° C. The mixture was allowed to warm to room temperature and then a solution of (3-ethylphenyl)methanol (˜3.05 mmol) in CH2Cl2 (3.5 mL) was added. After 1 h, the mixture was diluted with hexanes and filtered through celite, washing with excess hexanes. The filtrate was concentrated in vacuo. Purification of the crude residue by chromatography on silica gel (hexanes→10% EtOAc/hexanes, gradient) afforded 530 mg (87% over two steps) of 1-(bromomethyl)-3-ethylbenzene.