Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2F)C(=O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2F)C(=O)C1

Procedure:
A solution of product from Step D (2.75 g, 8.48 mmol), tert-butyldiphenylchlorosilane (2.2 mL, 8.48 mmol), and imidazole (860 mg, 12.7 mmol) in DMF (50 mL) was stirred at 60° C. for 15 hours. The reaction was poured into EtOAc (200 mL), and washed with H2O (300×100 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-30% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][C:9]=1[F:16].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O>O1CCOCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]=3[C:10]=2[C:9]=1[F:16]
Reactant: CN1CCCCC1=O
Reactant: NNc1ccc(Cl)c(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(Cl)c(F)c3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-chloro-3-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give a mixture or regioisomeric products. For this Example, silica gel chromatography separates the title compound from the other regioisomer (Compound 6) obtained in Example 11.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@H:8]2[CH3:14])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C@@H:8]([CH3:14])[CH2:9][N:10]([C:24](=[O:28])[CH2:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([CH3:17])=[CH:27][C:26]=3[OH:25])[C@H:11]([CH3:13])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)OC(=O)CC2
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(O)c1
Yield: 79 %

Procedure:
To a solution of (2R,5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine (0.25 g, 1.12 mmol) in toluene (10 mL) was added 7-methyl-chroman-2-one (0.25 g, 1.54 mmol) and the resulting solution was heated to reflux for 48 hours. The reaction was cooled, concentrated in vacuo and purified via chromatography on silica gel to give the title compound (0.34 g).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>CN(C=O)C>[C:24]1([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:15]=2[CH2:14][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Cc1ccc(S(=O)(=O)n2c(CBr)c(-c3ccccc3)c3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(Cn3cnc4c(N)ncnc43)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a stirred mixture of 9H-purin-6-ylamine (130 mg, 0.98 mmol) in DMF (5 mL) under an argon atmosphere was added NaH (60% in mineral oil, 40 mg, 0.98 mmol). After stirring for 10 min at RT, 2-bromomethyl-3-phenyl-1-(toluene-4-sulfonyl)-1H-indole (430 mg, 0.98 mmol) in DMF (10 mL) was added and stirring continued for 15 min. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) affording the title compound as a white solid (370 mg, 77%). LCMS (Method C): RT 3.16 min [M+H]+ 495.1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@H:6]1Br)(=[O:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)CO[C@H]1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])OC[C@@H]1OC(C)=O
Yield: 80.2 %

Procedure:
4.88 g (12.2 mmol) of 2,3,4-tri-O-acetyl-α-L-xylopyranosyl bromide was dissolved in 40 ml of N,N-dimethylformamide, and 4.5 g (69.2 mmol) of sodium azide was added. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue extracted with chloroform (250 ml). The chloroform layer was washed with water (250 ml), dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Waggle C-200, 40 g) and eluted with chloroform-methanol (100:1). The eluate was crystallized from ethyl acetate-hexane to obtain 2.95 g (9.79 mmol, 68%) of 2,3,4-tri-O-acetyl-β-L-xylopyranosyl azide as a colorless needle crystal. The following are the physicochemical properties of this crystalline compound.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1)(=[O:24])[CH3:23]>C1COCC1>[Br:1][CH2:23][C:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1)=[O:24]
Reactant: CC(=O)c1ccc(C#N)cn1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)CBr)nc1
Yield: 80.5 %

Procedure:
Add pyridinium tribromide (9.2 g, 28.7 mmol) to a solution of 6-acetyl-nicotinonitrile (4.2 g, 28.7 mmol) in THF (200 mL) at room temperature. Filter off the solids and wash with minimal THF. Recrystallize the solid from EtOAc/hexane to obtain the desired intermediate as a light orange solid (5.2 g, 80%) that was used without further purification. MS (ES−) m/z: 223 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:13]([CH3:18])[CH3:14])[C:5]2=[O:12]
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a suspension of 5-bromo-1H-isoindole-1,3(2H)-dione (ABCR, 5.0 g) and triphenylphosphine (8.70 g) in tetrahydrofuran (THF) (100 mL) under nitrogen at room temperature was added di-t-butyl azodicarboxylate (7.64 g). The suspension was cooled in an ice/water bath and to this was added iso-propanol (2.032 mL). The reaction mixture was allowed to warm to room temperature to give a pale yellow solution. After 60 minutes, the solvent was removed in vacuo and the residue was dissolved in DCM (30 mL). This was applied to a 750 g silica cartridge and eluted with a gradient of 0-40% ethyl acetate in cyclohexane over 8CV. The required fractions were combined and evaporated in vacuo to give the title compound (5.27 g) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][O:33][CH:34]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1
Temperature: 80 °C

Procedure:
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.25 g (0.55 mmol) was dissolved in 2.5 ml of anhydrous dimethylformamide. To this solution was added 0.14 g (1.3 mmol) sodium carbonate, furan-3-boronic acid 0.77 g (0.68 mmol), and Pd(PPh3)4 19 mg (0.014 mmol). The reaction mixture was heated overnight at 80° C. under a nitrogen atmosphere. The mixture was quenched with water and extracted 3 times with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography with a gradient 100% hexane to ethyl-acetate: hexane 1-1, gave the desired compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>ClCCl.O=[Pt]=O>[CH3:1][C@@H:2]1[NH:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14]
Reactant: CC1=N[C@H](c2ccccc2)COC1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Product: C[C@@H]1N[C@H](c2ccccc2)COC1=O
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a solution of (5R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1.70 g, 9.0 mmol, 1.0 equiv.) in anhydrous dichloromethane (60 mL) under an atmosphere of nitrogen was added PtO2 (170 mg, 0.1 equiv.). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by recrystallisation in dichloromethane, diethyl ether and hexane to furnish the title compound as white needles (1.37 g, 80%); m.p. 82.0-83.0° C. (lit. m.p. 81.0-82.0° C.); v(max)(KBr) 3314 (N—H), 2981 (C—H), 1739 (C═O), cm−1, δH (250 MHz, CDCl3) 7.44-7.33 (5H, m, Ph); 4.42-4.23 (3H, m, CHCH2), 3.88 (1H, q, /6.76 Hz, CHCH3), 1.86 (1H, br, NH), 1.50 (3H, d, J 6.16 Hz, CH3); δc (62.5 MHz, CDCl3) 170.7, 138.0, 129.3, 127.5, 127.2, 75.4, 58.2, 55.4, 19.0 m/z (CL, NH3), 191 (M+, 7%), 147 (20%), 131 (65%), 104 (100%), 91 (20%), and 77 (12%); HRMS for C11H13NO2 requires 191.0943 found 191.0940. [α]D20 −92.9 (c 1.02 CHCl3) (lit. for the enantiomer [α]D20 +92.3 (c 0.84 CHCl3)).
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][CH2:11][NH:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:39])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[NH:38])[NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=2)[CH2:16]1)=[O:14])C1C=CC=CC=1>C(O)=O.[Pd]>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:40])=[O:8])=[O:14])[CH2:16]2)=[O:39])=[CH:24][CH:25]=1)(=[NH:30])[NH2:38]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CC(=O)N2CCCC(C(=O)NCCC(=O)OCc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: O=CO
Product: N=C(N)c1ccc(CC(=O)N2CCCC(C(=O)NCCC(=O)O)C2)cc1
Reaction time: 4 h
Yield: 77.7 %

Procedure:
535 mg of rac-N-[[1-[p-[N-(t-butoxycarbonyl)amidino]phenylacetyl]-3-piperdinyl]carbonyl]-β-alanine benzyl ester were allowed to stand in 11 ml of formic acid for 19 hours, and the mixture was treated with 134 mg of Pd/C and stirred under hydrogen for 4 hours. The solution was filtered and evaporated, the residue was dissolved in water and the solution was evaporated again. The product was stirred in acetonitrile, filtered with suction and dried, yielding 272 mg of rac-N-[[1-[(p-amidinophenyl)acetyl]-3-piperidinyl]carbonyl]-β-alanine, MS: 361 (41, M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]([NH:21]C=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[ClH:25]>CO>[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:24])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=CNC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1

Procedure:
To a solution of 2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethylformamide (13.87 g, 40.9 mmol) in methanol (100 ml) was added conc. hydrochloric acid (3.8 ml, 45.0 mmol), and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the objective substance.(13.63 g, 96%) as crystals.
Reaction SMILES: [C:1]([C:9]1[CH:20]=[C:19]([Cl:21])[C:12]2[O:13][CH:14]([C:16]([OH:18])=[O:17])[CH2:15][C:11]=2[C:10]=1[Cl:22])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].Cl>N1C=CC=CC=1>[Cl:22][CH:10]1[C:11]2[C:12]([O:13][CH:14]([C:16]([OH:18])=[O:17])[CH:15]=2)=[C:19]([Cl:21])[CH:20]=[C:9]1[C:1](=[N:24][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1C=C2C(=C(Cl)C=C(C(=NO)c3ccccc3)C2Cl)O1
Reaction time: 18 h
Yield: 99.6 %

Procedure:
A mixture of 5-benzoyl-4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid (2.5 g), hydroxylamine hydrochloride (5.2 g) and pyridine (50 ml) was stirred for 18 hours at 90°-100° C. After cooling, the mixture was rendered acidic with HCl and subjected to extraction with ether. Ether was distilled off and the residual water was removed by azeotropic distillation with benzene, yielding 2.6 g of 4,7-dichloro-2,4-dihydro-5-(α-hydroxyiminobenzyl)benzo[b]furan-2-carboxylic acid. This compound (2.6 g) was dissolved in 20 ml of anhydrous dimethylformamide, and to the ice-cooled solution, 0.9 g of 60% sodium hydride was added in small portions under stirring. After continuing the agitation for 7 hours at room temperature, the mixture was left to stand overnight. After addition of water, the mixture was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized with acetonitrile-benzene, yielding 0.9 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. The physical data of this compound were in agreement with those of the product obtained in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])(=O)=O>O1CCCC1.C1C=CC=CC=1>[Cl:17][C:9]1[C:10]([OH:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cc(-c2ccc(Cl)cc2)on1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Oc1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3-hydroxyisoxazole (50.0 g) in dry tetrahydrofuran (300 ml), a solution of sulfuryl chloride (34.5 g) in dry benzene (50 ml) was added dropwise with stirring at 5° C. The resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour and further refluxed for 3 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the solid thus obtained was recrystallized from ethanol to obtain the title compound (44.2 g, 76.8%) as colorless needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)CCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Temperature: 80 °C
Yield: 66.8 %

Procedure:
2.00 g (6.61 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 1.43 g (7.90 mmol) of ethyl 3-bromopropionate were dissolved in 10 ml of dioxane, and 1.09 g (7.89 mmol) of potassium carbonate was added to the mixed solution, and then the mixture was stirred under heating at an oil bath temperature of around 80° C. for 8 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a solvent mixture of chloroform and methanol in the volume ratio 19:1 as are eluent. The desired fraction was concentrated under reduced pressure to give 1.78 g (67%) of ethyl 3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-propionate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH3:56][C:57]([CH3:59])=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH:57]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)([CH3:59])[CH3:56]
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(C(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 14 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with acetone (0.13 mL, 10 eq) to provide the title barbituric acid (15.0 mg, 14%). MS found: (M+H)+=502.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>S(Cl)(Cl)=O>[CH2:1]([N:7]([CH2:11][CH3:12])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)[CH3:2]
Reactant: O=C(O)CCCCc1nnnn1-c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)CCCCc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 190.7 %

Procedure:
Thionyl chloride (10 ml) is added to 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (1.8 g) and the mixture is refluxed for 1 hour. After excess thionyl chloride is distilled off under reduced pressure, dry benzene is added to the residue and the remaining small amount of thionyl chloride is removed as the benzene azeotrope. The resulting residue is dissolved in dry pyridine (50 ml) and thereto is added dropwise with stirring N,N-Diethylamine (1.5 g) under ice-cooling. The mixture is stirred at room temperature for 1 hour and benzene is added to the reaction mixture. The mixture is washed with diluted hydrochloric acid, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution and dried over sodium sulfate. After benzene is distilled off, the residue is subjected to column chromatography (Kieselgel 60 produced by Merck) by eluting the column with chloroform to give N,N-di-ethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide (2.1 g), colorless liquid, nD25 =1.5303.
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24]([N:26]4[CH2:32][CH2:31][CH2:30][C:29]([F:34])([F:33])[CH2:28][CH2:27]4)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:29]1([F:33])[CH2:30][CH2:31][CH2:32][N:26]([C:24]([CH:22]2[CH2:23][N:20]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:36][CH2:35][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:21]2)=[O:25])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)N4CCCC(F)(F)CC4)C3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CN(c2c3c(nc4ccnn24)CCNCC3)C1)N1CCCC(F)(F)CC1
Reaction time: 8 h

Procedure:
To 190 mg (0.38 mmol) 10-[3-(4,4-Difluoro-perhydro-azepine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 5 mL DCM was added 0.38 mL TFA and stirring was continued overnight at room temperature. To neutralize TFA sat. NaHCO3-solution was added, the organic layer separated and dried over Na2SO4. After filtration and evaporation of the solvent was the residue purified by HPLC.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)([CH3:14])[CH3:13])[CH2:7][C:6]1=[O:23])(=O)[CH2:2][CH3:3].[CH2:24]([O:27][NH2:28])[CH:25]=C.C1C=CC=CC=1>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([S:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)([CH3:14])[CH3:13])[CH2:7][C:6]1=[O:23])[CH2:2][CH3:3])[CH3:25]
Reactant: CCC(=O)C1C(=O)CC(C(C)(C)Sc2ccc(C)cc2)CC1=O
Reactant: C=CCON
Solvent: CCO
Solvent: c1ccccc1
Product: CCONC(CC)=C1C(=O)CC(C(C)(C)Sc2ccc(C)cc2)CC1=O
Yield: 68.1 %

Procedure:
1.3 g of 2-propionyl-5-[1-(p-tolylthio)isopropyl]cyclohexane-1,3-dione was allowed to react with 0.3 g of allyloxyamine at room temperature for 15 hours in the mixture of 10 ml of benzene and 3 ml of ethanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain 1 g of the desired compound.
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4]>CC(O)C>[OH:5][C:3]([CH3:4])([C:4]([OH:5])([CH3:1])[C:2](=[O:6])[CH3:3])[C:2](=[O:6])[CH3:1]
Reactant: CC(=O)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C(C)(O)C(C)(O)C(C)=O

Procedure:
3,4-dihydroxy-3,4-dimethyl-2,5-hexanedione was prepared by photochemistry. A closed flask [Pyrex (trade mark)], which contained a solution of 20.1 g (0.23 mol) 2.3-butanedione in 81 g 2-propanol, was allowed to stand in daylight for 4.5 months. The solvent was evaporated under reduced pressure (about 20 mm Hg); traces of volatiles were removed by simultaneous evaporation with two parts of toluene of 40 ml. The semi-solid, white residue (13.9 g) was recrystallized twice with a mixture of ether and hexane in a ratio of 1:1, yielding 5.2 g colourless crystals having a melting point of 95°-96° C.