Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH:14]O.Cl>[OH-].[Na+]>[NH2:9][C:10]1[C:2]([Cl:1])=[CH:3][C:4]([F:13])=[CH:5][C:6]=1[C:7]([OH:12])=[O:14]
Reactant: OO
Reactant: O=C1Nc2c(Cl)cc(F)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)cc(F)cc1C(=O)O
Reaction time: 1 h

Procedure:
A solution of 7-chloro-5-fluoro-1H-indole-2,3-dione (270 mg) in 1 M sodium hydroxide solution (5 mL) was treated with 30% hydrogen peroxide (5 mL) via dropwise addition. After one hour of stirring, the reaction was acidified with HCl to pH 1, and extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, and concentrated in vacuo to provide 200 mg of 2-amino-3-chloro-5-fluoro-benzoic acid.
Reaction SMILES: [C:1](=[O:19])([S:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH3:2].[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:4][SH:3]=[C:1]([OH:19])[CH3:2])[CH2:10][CH2:9]1
Reactant: CC(=O)SC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)=[SH]C[C@H]1CC[C@H](N)CC1
Yield: 98.9 %

Procedure:
A mixture of S-({trans-4-[(tert-Butoxycarbonyl)amino]cyclohexyl}methyl) ethanethioate (0.20 g, 0.70 mmol) in methylene chloride (1.6 mL) was treated with trifluoroacetic acid (0.54 mL, 7.0 mmol) at room temperature for 2 h. The reaction mixture was evaporated to dryness to give the desired product (0.21 g, 100%). LCMS calculated for C9H18NOS (M+H)+: m/z=188.1. Found: 188.1.
Reaction SMILES: CS(O)(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([OH:26])=[O:25])([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:11][CH2:10]2.[CH2:27](O)[CH3:28]>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:11][CH2:10]2
Reactant: O=C(O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Reactant: CCO
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
Methane sulfonic acid (12 mL) was added to a solution of 1E (8 g, 26.5 mmol) in ethanol (50 mL), and the mixture was stirred at room temperature for 12 h. Ethanol was removed from reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate and washed with brine solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 20% ethyl acetate in hexanes to give the title compound (6 g, 56%) as a syrup. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=9.2 Hz, 1H), 6.75 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.1 (q, J=6.8 Hz, 2H), 3.0-2.8 (m, 4H), 2.62-2.5 (m, 2H), 2.4 (m, 1H), 2.3 (m, 1H), 1.23 (t, J=7.2 Hz, 3H). ESI-MS m/z: 331 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[N+:8]([C:7]1[C:2](=[O:1])[N:3]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cccnc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 25 °C
Yield: 75.1 %

Procedure:
2-Hydroxy-3-nitro-pyridine (75 g, 0.535 mole) and 1400 mL of anhydrous tetrahydrofuran were stirred at 0° C. using a mechanical stirrer. Lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 683.5 mL) was slowly added over 30 minutes. The deep brown reaction mixture was stirred for 30 additional minutes and then t-butyl bromoacetate (109.6 g, 0.561 mole) was slowly added over 30 minutes. The reaction mixture was warmed to 25° C. overnight. The organic solvents were removed under vacuum and the residue was dissolved in 2 liters of ethyl acetate and 500 mL of water. The organic phase was dried with magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica gel using a methylene chloride:ethanol gradient, 100:0 to 98:2, to yield 102.1 g (75 %) of the title compound as a yellow-orange solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[Br:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=3)[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Yield: 42.3 %

Procedure:
4-{[(4-Bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (322 mg, 42%) was prepared from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 450 mg, 2.0 mmol), 4-bromophenol (346 mg, 2.0 mmol) and Ph3P (629 mg, 2.4 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.512 mL, 2.6 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 2H, J=9.1 Hz), 6.76 (d, 2H, J=8.9 Hz), 4.28-4.18 (m, 2H), 3.79 (d, 2H, J=6.2 Hz), 3.14-3.04 (m, 2H), 2.94-2.82 (m, 1H), 2.10-1.94 (m, 1H), 1.97-1.87 (m, 2H), 1.49-1.36 (m, 2H), 1.28 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 380/382 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]I)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:17]=[O:18])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(CCCCI)cc1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2C=O)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A suspension of 1-tert-butoxy-4-(4-iodobutyl)benzene (10.0 g), 2-formyl-1H-imidazole (3.47 g) and potassium carbonate (4.16 g) in DMF (100 ml) was stirred at 70° C. for 17 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazole-2-carbaldehyde as a pale brown oil. Sodium borohydride (1.25 g) was added to a solution of the compound in methanol (200 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water, concentrated and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; hexane:ethyl acetate=1:3 to ethyl acetate) to give the titled compound (8.29 g) as a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][CH:13]=O.Cl.[CH2:16]([O:18][NH2:19])[CH3:17]>C(O)(C)C>[CH2:16]([O:18][N:19]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1)[CH3:17]
Reactant: O=CNc1cnc2ccccc2c1Cl
Reactant: CCON
Agent: Cl
Solvent: CC(C)O
Product: CCOn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
A solution of 4-chloroquinolin-3-ylformamide (5.0 g, 24 mmol), O-ethylhydroxylamine hydrochloride (2.95 g, 30.2 mmol), and isopropanol (75 mL) was heated at reflux overnight, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was stirred with dichloromethane (150 mL) and saturated aqueous sodium carbonate (50 mL) for 15 minutes. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 2% methanol in dichloromethane containing 5 mL of aqueous ammonium hydroxide per liter of eluent) to provide 2.45 g of 1-ethoxy-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[CH2:10][NH2:11])=[O:6])[CH:2]=[CH2:3].Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:10][NH:11][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH3:13])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cl
Reactant: C=CCOC(=O)NCC(CN)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 11.4 g of crude 2-(N-allyloxycarbonylaminomethyl)-3-(t-butyldimethylsilyloxy)butylamine in 67 ml of tetrahydrofuran and 56 ml of water was added 2.8 ml of allyl chloroformate dropwise, while keeping pH 8-8.5 with 4N sodium hydroxide solution. The reaction mixture was extracted three times with chloroform, and the combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by column chromatography on silica gel (hexane:ethyl acetate=1:1) gave 5.34 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)- 3-t-butyldimethylsilyloxybutane.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Propenoyl chloride (668 mg, 600 ul, 7.4 mMole) was added dropwise to an ice-cold solution of ethyl 3-aminobenzoate (2.0 gm, 12 mMole) in 10 ml of acetone. The solution was stirred for 30 minutes on ice and then for 30 minutes at room temperature. 50 ml of water was added and the yellowish oil was separated by decantation. It was washed with water and then dissolved in 15 ml of diethl ether. This solution was washed with 10% (w/v) sodium bicarbonate, water and then dried over anhydrous sodium carbonate. The ether was evaporated and a white creamy product was crystallized from ethanol. The overall yield was 37%, and the melting point of the product was 93° C. to 94° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), 4-aminothiophenol (8.8 g, 68 mmol) and K2CO3 (11.8 g, 85 mmol) in DMF (150 mL) was heated at 90° C. for 1.5 hours, cooled to room temperature, and then poured into H2O (450 mL) under stirring. The aqueous mixture was extracted with AcOEt (400 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give the crude product as orange crystal. The crude product was suspended in 150 mL of i-Pr2O and stirred at room temperature for 1 hour. The crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. for 3 days under reduced pressure to give purified title compound as orange crystal (18.6 g, 90%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[N:6]=[CH:5][C:4]([C:3]([N:31]5[CH2:36][CH2:35][S:34][CH2:33][CH2:32]5)=[O:2])=[CH:9][CH:8]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:23])[F:21])[O:18][N:17]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1)N1CCSCC1
Yield: 51 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (70 mg, 0.17 mmol), was converted, using thiomorpholine instead of cyclopropanemethylamine, to the title compound (42 mg, 51%) which was obtained as a colourless oil. MS: m/e=486.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[CH2:33]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:34]#[CH:35]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:35]#[C:34][CH2:33][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)acetic acid ethyl ester (300 mg; 0.56 mmol), 4-prop-2-ynyl-morpholine (280.4 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 300 mg; 92%. HPLC-MS: m/z: 580.7 (M+H)+; Rt: 2.16 min.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[CH:6]=[CH:7][C:8](=[O:10])[CH:9]=1)[CH2:2][CH3:3].C[O:13][C:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH:15]=1.Cl>C1C=CC=CC=1.CO>[OH:11][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][C:8]2[O:10][C@H:16]3[CH2:15][C:14](=[O:13])[CH2:19][CH2:18][C@H:17]3[C:7]=2[CH:6]=1
Reactant: CCCC1=CC(=O)C=CC1=O
Reactant: COC1=CC=CCC1
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: CCCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@@H]1O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
A solution of 1.08 g (7.2 mmol) of 2-propyl-1,4-benzoquinone and 2.20 g (20.0 mmol) of 1-methoxy-1,3-cylcohexadiene in 20 mL of benzene was heated at reflux for 2 h. The solution was concentrated in vacuo and the residue dried under high vacuum to afford a pale yellow oil. This material was dissolved in 20 mL of methanol and to that solution was added 1 mL of 2.0M HCl. The solution was stirred at room temperature for 6 hours, then was concentrated to about 5 mL volume. This was partitioned between ethyl acetate and water and the aqueous layer was washed with two portions of ethyl acetate. The organic extracts were sequentially washed with water and NaCl solution, combined, dried over magnesium sulfate, and concentrated. The residue was crystallized from ether-hexane to afford 0.764 g white crystals, 43%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]=[CH:27][NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[CH:27][N:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1nc[nH]n1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3ncnn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-1,2,4-triazole
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:19][CH:18]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:34][NH2:35]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[CH:19][CH:18]=4)[NH:35][N:34]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(/C=C/c1ccc(OCc2ccccn2)cc1)CC(=O)/C=C/c1ccc2[nH]ccc2c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: C(=C/c1cc(/C=C/c2ccc3[nH]ccc3c2)n[nH]1)\c1ccc(OCc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
In 0.34 mL of acetic acid was dissolved 15 mg (35 μmol) of (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione. To this solution was added 34 μL (0.70 mmol) of hydrazine monohydrate at room temperature and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was neutralized with a saturated sodium bicarbonate aqueous solution and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol). The resulting solid was washed with an organic solvent to give 3.5 mg (24% yield) of the title compound as a pale yellowish white powder with the following properties.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[O:9][C:10]3[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CS([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)(=O)=O.C(=O)([O-])[O-].O>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([O:1][C:2]2[C:3]([C:8]3[O:9][C:10]4[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[N:22]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Oc1cccnc1-c1nc2c(o1)CCCC2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Oc2cccnc2-c2nc3c(o2)CCCC3)n1

Procedure:
0.12 g 2-(3-hydroxy-2-pyridyl)-4,5,6,7-tetrahydrobenzoxazole, 0.12 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.21 g pottasium carbonate were suspended in 3 ml DMF, and the resulting suspension was subjected to a reaction for 2 hours at 60° C. After completing the reaction, the suspension reacted was added with water and then extracted with ethyl acetate. The extract was then washed with saturated saline solution. The organic layer obtained was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.18 g.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]C([O-])(C)C.[K+].IC.C(OC(N[C@H](C1(C)CCCCC1)C(O)=O)=O)(C)(C)C>C(Cl)Cl>[CH3:9][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)[O-]
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1(C)CCCCC1
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: CC1(C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A flame-dried 500-mL round-bottomed flask capped with a rubber septum was charged with anhydrous CH2Cl2 (150 mL) via cannula and cyclohexanecarboxaldehyde (12) (9.09 mL, 75 mmol, 1.0 equiv) via syringe under N2. The flask was cooled in an ice bath for 10 min, the septum was removed, and t-BuOK (10.9 g, 97.5 mmol, 1.3 equiv) was added in one portion with rapid stirring. The septum was replaced, and iodomethane (14.0 mL, 225 mmol, 3.0 equiv) was added in one portion via syringe. The mixture was stirred at 0° C. under N2 for 30 min. The mixture was then allowed to warm to room temperature and stirred an additional 2 h. The resulting pale yellow, heterogeneous mixture was filtered through a 10-cm diameter medium porosity fritted disk funnel, and the cake was washed with CH2Cl2 (3×15 mL). The filtrate was washed with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was distilled under reduced pressure (1 torr) while maintaining the receiving flask between −20 to −40° C. (bp <30° C.). The distillate was a clear, colorless oil that contained (1-methyl)cyclohexanecarboxaldehyde (13) and 1.25 equiv CH2Cl2, as determined by 1H-NMR analysis: 13.2 g total, ˜7.2 g (1-methyl)cyclohexanecarboxaldehyde (57 mmol, 76% yield). The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]#C)[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:24]=[C:17]([CH3:18])[O:16][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: C#CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cc(Cc2cnc(N)nc2N)c2cc(C)oc2c1OC

Procedure:
A mixture of 2,4-diamino-5-[3,4-dimethoxy-5-(2-propynyloxy)benzyl]pyrimidine (1.18 g, 3.75 mmol), potassium carbonate (0.518 g, 3.75 mmol) and sulfolane (10 mL) was heated to 220°-230° under nitrogen over a period of 20 minutes and then maintained at this temperature for an additional 15 minutes. The resulting dark mixture was cooled and the precipitate was adsorbed on silica gel. The title compound was eluted with MeOH:CH2Cl2 /1:9 as an off-white powder, after recrystallization from 95% ethanol; mp 209°-212°. Anal. Calcd for C16H18N4O3.1/2H2O: C, 59.43; H, 5.92; N, 17.33. Found: C, 59.22; H, 5.97; N, 17.31.