Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][NH:8]C(=O)C1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH2:24][C:25]([OH:27])=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.ClC(OCC(C)C)=O.C(OC(=O)CN)(C)(C)C.Cl>C(OCC)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][NH:8][C:25](=[O:27])[CH2:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: CC(C)(C)OC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=O)Cc1ccccc1

Procedure:
Following the procedure described for benzoyl-glycine-t-butyl ester, a solution of phenylacetic acid (11.44 grams) in ethyl acetate (approx. 100 ml) was activated by the mixed anhydride method using N-methylmorpholine (11.66 ml) followed by isobutyl chloroformate (10.89 ml) at -20° C. and coupled with glycine t-butyl ester.HCl (14.04 g) in methylene chloride (approx. 150 ml) which had been neutralized by addition of N-methylmorpholine (11.66 ml). After work-up, the product was obtained as an oil which was used for the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=O)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Br.[NH:34]([C:36]1[S:37][CH2:38][CH2:39][N:40]=1)[NH2:35].C([O-])(=O)C.[Na+]>C(#N)C.CO>[S:37]1[CH2:38][CH2:39][NH:40][C:36]1=[N:34][N:35]=[C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[N:12]([CH2:11][CH2:10][N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: NNC1=NCCS1
Reactant: CC(=O)N1CCN(CCn2c3ccccc3c(=O)c3ccccc32)CC1
Agent: Br
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CO
Product: CC(=O)N1CCN(CCn2c3ccccc3c(=NN=C3NCCS3)c3ccccc32)CC1

Procedure:
A suspension of 3.5 g of 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone in 100 ml of acetonitrile is treated with 1.7 ml of oxalyl chloride, suction filtered after 0.5 hour and the suction filter material (9-chloro-10-[2-(4-acetyl-1-piperazinyl)ethyl]acridinium chloride) is washed successively with acetonitrile and ether. A mixture of the substance obtained is heated to boiling under reflux with 2 g of 2-hydrazino-2-thiazoline hydrobromide, 2.5 g of sodium acetate and 100 ml of methanol and evaporated after 15 minutes. The residue is treated with water, made alkaline with sodium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried and evaporated, whereupon the residue is crystallized from methanol. After recrystallization from n-butanol, there is obtained 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone (2-thiazolidinylidene)hydrazone of melting point 256°.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:12]1[C:23](=[O:48])[CH:24]([N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[C:35]([C:37]([O:39]CC3C=CC=CC=3)=[O:38])[CH:36]=[C:29]2[C:28]1=[O:47])[CH2:25][CH3:26])=O)C1C=CC=CC=1>CO.[Pd]>[C:37]([C:35]1[CH:36]=[C:29]2[C:28]([N:27]([CH:24]([CH2:25][CH3:26])[C:23]([N:12]3[CH:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15][NH:11]3)=[O:48])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=1)=[O:47])([OH:39])=[O:38]
Reactant: CCC(C(=O)N1C(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1)N1C(=O)c2ccc(C(=O)OCc3ccccc3)cc2C1=O
Agent: [Pd]
Solvent: CO
Product: CCC(C(=O)N1NCCC1C(=O)OC(C)(C)C)N1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 97.4 %

Procedure:
24.97 g of tert.butyl 1-benzyloxycarbonyl-2-(5-benzyloxycarbonyl-2-phthalimidobutyryl)-3-pyrazolidinecarboxylate were dissolved in 250 ml of methanol and hydrogenated over 2 g of 10% palladium-on-carbon. The catalyst was removed by filtration and the filtrate was evaporated to give 16 g (98%) of tert.butyl 2-(5-carboxy-2-phthalimidobutyryl)-3-pyrazolidinecarboxylate (2 diastereomers) in the form of a gum.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][NH:40]2)=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C:60]([O:64][C:65](=[O:74])[CH2:66][C@@H:67]1[CH2:70][C@H:69]([C:71](O)=[O:72])[CH2:68]1)([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][N:40]2[C:71]([C@@H:69]2[CH2:68][C@H:67]([CH2:66][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:74])[CH2:70]2)=[O:72])=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HATU (147 mg, 0.39 mmol) was added to a solution of (R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (120 mg, 0.32 mmol), DIEA (0.110 mL, 0.64 mmol) and cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (72.5 mg, 0.34 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over-magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (162.1 mg, 0.285 mmol, 88%) as a white solid.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].N[C:7]1([O:16]O)[CH2:12][CH:11]([CH3:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]1>>[CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:13][CH:11]1[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7](=[O:16])[CH2:12]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Solvent: CCCC=O
Product: CC1CC(=O)CC(C)(C)C1

Procedure:
Butyraldehyde (28.8 g.) in petrol (100 c.c.) was cooled to below 0° and with stirring treated with 1-amino-1-hydroperoxy-3,3,5-trimethylcyclohexane (33 g.; 93% pure). When the solid had dissolved the aqueous phase was removed and the petrol solution dried with magnesium sulphate overnight at 0°. The working up as in Example 4 gave butyraldehyde, dihydroisophorone and the same peroxide (33.0 g.) b.p. 96° - 98°/0.6 mm. as in Example 4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[OH-].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:21]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)(=[O:22])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)N3CCOCC3)c3cc(F)ccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1c[nH]c2ccc(F)cc12)N1CCOCC1
Yield: 94.9 %

Procedure:
A solution of 5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole (1.3 g) in MeOH (50 mL)/5 N KOH (3 mL) is heated to reflux for 1 h. The reaction mixture is concentrated in vacuo. The residue is diluted with water (30 mL) and acidified with 10 N aqueous HCl to pH 4. The mixture is extracted with EtOAc. The organic layer washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole (0.8 g, 95%) as a solid. MS: 285 (M+H).
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
The compound obtained in Example 12-2 (351.3 mg) was dissolved in methanol (3.5 ml) and THF (3.5 ml). After the addition of 1 mol/l aqueous solution of sodium hydroxide (3.5 ml), the mixture was stirred for 2 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in distilled water (1.2 ml) and aqueous solution of hydrochloric acid (1 mol/l) was added to adjust the pH to 4. The mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain the target compound (277.9 mg) as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10]COS(C)(=O)=O)=O)(C)(C)C.[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[C:32]1[C:33](=[O:52])[NH:34][C:35](=[O:51])[N:36]([CH2:39][C:40]2[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=2[F:50])[C:37]=1[CH3:38].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:62][CH:63]([CH3:65])[CH3:64])(=[O:61])[CH3:60]>O.CN(C=O)C>[NH2:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][N:34]1[C:33](=[O:52])[C:32]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:24]=2[F:23])=[C:37]([CH3:38])[N:36]([CH2:39][C:40]2[C:45]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=2[F:50])[C:35]1=[O:51].[C:59]([O:62][CH:63]([CH3:65])[CH3:64])(=[O:61])[CH3:60]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccccc1
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)[nH]c2=O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Temperature: 55 °C

Procedure:
Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester 1d (19.7 kg), 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (16.5 kg), potassium carbonate (powder, 325 mesh, 13.4 kg) and DMF (101 L) were charged to a reactor. The mixture was stirred at 55° C. After reaction completion, the reactor was cooled to 20° C. and isopropyl acetate (132 L) was charged, followed by water (157 L). After agitation and settling, the layers were separated and the organic layer washed with water (87 L). After agitation and settling, the water layer was removed. To the organic layer was charged methanesulfonic acid (11.2 kg) and the reactor contents were heated to 60° C. for 1-2 hours. The reactor contents were cooled to 20° C. and a solution of potassium carbonate/water (26.8 kg/140 L) was added slowly, agitated, and then allowed to settle prior to separation of layers. The organic layer was treated with a solution of 85% phosphoric acid/H2O (22.6 kg/236 kg). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous layer was washed with isopropyl acetate (2×167 kg) and the layers were separated. A solution of potassium carbonate/water (36.1 kg/139 kg) was added slowly to the aqueous layer. Isopropyl acetate (206 kg) was charged; the mixture was agitated and then allowed to settle. The aqueous layer was removed and the organic layer was concentrated to provide a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in isopropyl acetate (125.4 kg, 30.7 kg contained, 86% yield) for use in the next step. LCMS (ESI) m/z 546.2 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:33])(=[O:32])[NH2:34])=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(N)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Sulfamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4-hydroxybenzenesulfonamide (available from TCI America, Portland, Oreg., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.06 (m, 4H), 2.94-3.04 (m, 2H), 4.02-4.10 (m, 2H), 4.98-5.04 (m, 1H), 7.45 (s, 2H), 7.53-7.55 (m, 2H), 7.93-7.95 (m, 2H), 8.34 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=475.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:32][CH:33]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.2 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% 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 column chromatography to give the title compound as a colorless solid (0.58 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[N:13]2)=[C:4]([F:19])[CH:3]=1.Br[CH2:21][CH2:22][CH2:23][F:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:16](=[O:17])[N:15]([CH2:21][CH2:22][CH2:23][F:24])[C:14]([CH3:18])=[N:13]2)=[C:4]([F:19])[CH:3]=1
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1CCCF
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A stirred solution of 1.8 g (0.006 mole) of 1-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 1.8 g (0.013 mole) of 1-bromo-3-fluoropropane and 0.30 g (0.010 mole) of potassium carbonate in dimethylformamide was heated at 55°-65° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into ice-water. The mixture was extracted with diethyl ether and the extract dried with magnesium sulfate. The extract was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using 9:1 methylene chloride:heptane as eluant. The appropriate fractions were combined and concentrated under reduced pressure to give 1.0 g of 1-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C[Li].[C:28](=[O:30])=[O:29]>C(OCC)C.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: c1ccc(Oc2cccc(Oc3ccccc3)c2)cc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 11 parts of 1,3-diphenoxybenzene and 40 parts of tetrahydrofuran is added 1 part of methyllithium (as a 1.82 M solution in diethyl ether) while the mixture is cooled in an ice bath. The resulting solution is heated under reflux for 2 hours and then is poured slowly onto 500 parts of dry ice. After the mixture has warmed to room temperature, 100 parts of water are added, and the tetrahydrofuran is evaporated. After the aqueous solution is extracted with 50 parts diethyl ether, it is then acidified with concentrated hydrochloric acid. The white solid which forms is collected to yield 12 parts of 2,6-diphenoxybenzoic acid. The compound is purified by recrystallization from acetonitrile to give 8 parts of pure material, M.P. 164°-165°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 31.6 %

Procedure:
Step 1 A solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.00 g, 6.32 mmol), phenol (0.714 g, 7.59 mmol) and triphenylphosphine (1.824 g, 6.95 mmol) in DCM (21.07 mL) was treated with diisopropyl azodicarboxylate (1.48 mL, 7.59 mmol) and the mixture was stirred at rt for 5 days. The mixture was concentrated and the residue was purified by column chromatography, eluting with a gradient from hexane to 80:20 hexane-EtOAc). The crude product was dissolved in EtOAc and the solution was washed twice with 1 M aqueous sodium hydroxide and brine, dried and concentrated to provide 8-phenoxy-1,4-dioxaspiro[4.5]decane as a colorless liquid (0.468 g, 32%). 1H NMR (500 MHz, chloroform-d) δ 7.16-7.24 (2H, m), 6.81-6.89 (3H, m), 4.30-4.38 (1H, m), 3.85-3.93 (4H, m), 1.80-1.90 (6H, m), 1.50-1.59 (2H, m).
Reaction SMILES: C([O-])=O.[NH4+].CN(C)/[CH:7]=[CH:8]/[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[N+:18]([O-])=O>CO.CCOC(C)=O.[Pd]>[S:13]1[C:9]2[CH:8]=[CH:7][NH:18][C:10]=2[CH:11]=[C:12]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]ccc2s1
Temperature: 25 °C

Procedure:
10% Pd/C (0.4 eq.) and ammonium formate (6 eq.) were added to a 0.1M solution of methyl 5-[(E)-2-(dimethylamino)ethenyl]-4-nitrothiophene-2-carboxylate in MeOH/EtOAc 1:1, and the mixture was heated to reflux for 30 min; after cooling to RT the flask was flushed with nitrogen a few times, then the reaction mixture was filtered and the solution evaporated i. vac. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4, and concentrated i. vac. The crude product (50% over two steps) was used as such. 1H-NMR (400 MHz, CDCl3, 300 K, δ) 8.44 (bs, 1H), 7.72 (s, 1H), 7.21 (bs, 1H), 6.50 (bs, 1H), 3.91 (s, 3H); MS (ES+) m/z 182 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][N:18]2[C:28]3[C:29]4[C:20]([CH2:21][CH2:22][S:23][C:24]=4[N:25]=[C:26]([N:30](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:27]=3)=[N:19]2)[C:11]=1[CH3:45].NC1N=C(Cl)C(C(O)CC=C)=C(Cl)N=1>ClCCl>[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][N:18]2[C:28]3[C:29]4[C:20]([CH2:21][CH2:22][S:23][C:24]=4[N:25]=[C:26]([NH2:30])[N:27]=3)=[N:19]2)[C:11]=1[CH3:45]
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SCC3)c1C
Agent: C=CCC(O)c1c(Cl)nc(N)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SCC3)c1C
Reaction time: 2 h
Yield: 85 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate of Step 10) of Example 1 (59 mg) and dichloromethane (2 mL) under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for two hours. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was dissolved in ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain the title compound (26 mg, 85%) as a solid.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: COc1ccnc(Cl)n1
Product: COc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-methoxypyrimidine. MS (ESI) mass calcd. for C24H24N4O2, 400.48; m/z found, 401.2 [M+H]+.