Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+:5].[CH3:6][O:7][CH2:8][C:9]1[CH2:30][S:29][C@@H:12]2[C@H:13]([NH:16][C:17](/[C:19](/[C:23]3[N:27]=[C:26]([NH2:28])[S:25][CH:24]=3)=[N:20]\[O:21][CH3:22])=[O:18])[C:14](=[O:15])[N:11]2[C:10]=1[C:31]([OH:33])=[O:32].CN(C)C(=O)C.CC(C)=O>O.CO>[CH3:6][O:7][CH2:8][C:9]1[CH2:30][S:29][C@@H:12]2[C@H:13]([NH:16][C:17](/[C:19](/[C:23]3[N:27]=[C:26]([NH2:28])[S:25][CH:24]=3)=[N:20]\[O:21][CH3:22])=[O:18])[C:14](=[O:15])[N:11]2[C:10]=1[C:31]([O-:33])=[O:32].[Na+:5]
Reactant: COCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: O
Product: COCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
1.01 g of sodium acetate was dissolved in a mixture of 1 ml of water and 5 ml of methanol, and 5.0 g of cefpodoxime was added thereto, followed by addition of 15 ml of N,N-dimethylacetamide. The mixture was stirred at room temperature for 30 minutes and then, 100 ml of acetone was added thereto. The solution was stirred for 20 minutes and filtered. The filtered solid was washed with 50 ml of acetone and then with 30 ml of isopropyl ether, and vacuum-dried at room temperature to give 5.04 g of pale yellow cefpodoxime sodium salt (yield: 96%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1.[NH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1.CN(C)C=O>[N:33]1([NH:32][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([N:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]([C:11]([N:8]4[CH2:9][CH2:10][CH:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH2:7]4)=[O:12])[CH2:14][CH2:15]3)=[CH:24][CH:25]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Reactant: NN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(NN1CCCCC1)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
0.4 g of 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoic acid, 0.19 g of 1-aminopiperidine, 0.26 g of hydroxybenzotriazole, 0.37 g of EDC.HCl and 7 ml of a dioxane/dimethylformamide 5/2 mixture are introduced into a 100 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture is stirred at ambient temperature for 20 h and concentrated under vacuum. The residue is chromatographed on silica gel eluted with a dichloromethane/acetone/methanol/NH4OH 88/10/2/0.2 and then 82/15/3/0.3 mixture. After triturating in ethyl ether, 0.28 g of N-(piperidin-1-yl)-4-{4-[3-(1H-pyrazol-4-yl)pyrrolidine-1-carbonyl]-3,4-dihydro-2H-quinoxalin-1-yl}benzamide is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([CH3:9])[C:2]([NH:1][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1nc(Cl)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(Cl)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of 3-amino-6-chloro-2-picoline (2.0 g, 14.0 mmol) and methanesulfonyl chloride (1.92 g, 16.8 mmol) in pyridine (40 ml) was stirred for 1 hour at room temperature. After removal of the solvent, the resulting crude product was purified by silica gel column chromatography, eluting with hexane/EtOAc (3:2), to afford 1.70 g (55% yield) of the title compound as pale yellow solids.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[S:2]([O:19][CH2:18][CH2:17][O:16][C:15]1[CH:20]=[CH:21][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:7]([Cl:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
2.6 g (0.0227 mol) of methanesulphonyl chloride are run over the course of 5 minutes, at about +10° C., into a solution of 6 g (0.0227 mol) of 2-[4-(4-chlorophenoxy)-phenoxy]-1-ethanol (CRL 40,293) in 11 ml of pyridine and the mixture is then stirred for 1 hour at ambient temperature. Thereafter the reaction mixture is poured onto ice and acidified to Congo Red with concentrated hydrochloric acid. After extracting the insoluble matter with ethyl acetate, washing the organic phase obtained with water and drying it over dry sodium sulphate, evaporation of the solvent gives 7.8 g of a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:20][C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1ccc(Br)cc1
Product: Brc1ccc(OCc2ccc3ccccc3c2)cc1
Yield: 99 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with 4-bromophenol to give 4-(naphth-2-ylmethoxy)bromobenzene (99%), m.p. 104°-106° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:11]=[N:12][C:13](Cl)=[C:14]([Br:16])[CH:15]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:33]([F:36])([F:35])[F:34])=[C:23]([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:11]=[N:12][C:13]([N:30]3[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:23]4[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=4[C:33]([F:36])([F:35])[F:34])[CH2:28][CH2:29]3)=[C:14]([Br:16])[CH:15]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reactant: O=S(=O)(NCCC1CC1)c1cnc(Cl)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1COCCO1
Product: O=C(c1cc(F)ccc1C(F)(F)F)N1CCN(c2ncc(S(=O)(=O)NCCC3CC3)cc2Br)CC1
Yield: 31.9 %

Procedure:
To a stirred solution of 5-bromo-6-chloro-pyridine-3-sulfonic acid (2-cyclopropylethyl)amide (0.432 g, 1.272 mmol) in dioxane (15.0 mL) was added (5-fluoro-2-trifluoromethylphenyl)piperazin-1-yl-methanone (0.386 g, 1.399 mmol), potassium carbonate (0.703 g, 5.080 mmol) and tetrabutyl ammonium bromide (0.042 g, 0.130 mmol). The resulting mixture was stirred at reflux for 48 h, filtered and then concentrated in vacuo. The crude product was purified by column chromatography, eluting with a solvent gradient of 35% ethyl acetate and 65% hexane to yield the desired product (0.235 g, 32%). 1H NMR (300 MHz, CDCl3) δ 8.59-8.58, 8.16-8.15, 7.74-7.69, 7.24-7.18, 7.08-7.04, 4.97-4.93, 4.03-3.85, 3.60-3.55, 3.43-3.33, 3.07-2.99, 1.41-1.34, 0.60-0.53, 0.43-0.37, 0.025-0.015. 13C NMR (75 MHz, CDCl3) δ166.1, 162.6, 145.4, 141.1, 130.5, 129.6, 129.5, 116.7, 116.4, 114.9, 114.7, 110.3, 48.8, 48.6, 46.9, 43.5, 41.6, 34.5, 8.2, 4.2. MS (ES+) m/z 581 (M+1).
Reaction SMILES: [S:1]1[CH:5]2[CH2:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:10][C:11](N(C)C)=[O:12].[OH-].[K+].Cl>C(O)C.[Cu]>[C:11]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)(=[O:12])[CH3:10]
Reactant: CC(=O)N(C)C
Reactant: C1=CCC2SC=CC2=C1
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cc2ccccc2s1
Yield: 70 %

Procedure:
The amino ester (2) was converted to the diazonium salt and reduced by boiling in ethanol containing finely divided copper to give the pure ester (3). Hydrolysis of the ester with aqueous ethanolic KOH followed by acidification with 5M HCl, gave the acid (4) in approximately 70% yield. The acid was converted to the corresponding acid chloride (5) by reaction with SOCl2.
Reaction SMILES: [CH:1]([C:13]([O:15]C)=O)([C:9]([O:11]C)=O)[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]1(/[CH:23]=[CH:24]/[C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C[O-].[Na+].CO>CCO>[OH:15][C:13]1[N:26]=[C:25](/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:27][C:9](=[O:11])[C:1]=1[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Reactant: N=C(N)/C=C/c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1c(O)nc(/C=C/c2ccccc2)[nH]c1=O
Temperature: 25 °C

Procedure:
3-Ethyl 1,1-dimethyl 1,1,3-propanetricarboxylate (1.65 g, 7.1 mmol) and (2E)-3-phenyl-2-propenimidamide (1.04 g, 7.11 mmol) were combined in EtOH (36 mL). Triethylamine (1.98 mL, 14.2 mmol) was added and the solution was heated at reflux for 3 h with no change based on LCMS. The solution was cooled to room temperature and treated with NaOMe in MeOH (1.0 mL, 5.33 mmol, 25% wt solution) and the solution was refluxed for an additional 4 h. Another portion of NaOMe in MeOH (1.0 mL, 5.33 mmol, 25% wt solution) was added and the solution was refluxed for 16 h. After this time, a yellow precipitate had formed which was filtered off The mother liquor was acidified to pH2 with 1N HCl, and the solution was concentrated under vacuum. The resulting material was combined with the yellow solid and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:15])(O)[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].NC(N)CS(F)(F)[F:29].[OH-].[K+].C(OCC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([F:29])([CH3:15])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: NC(N)CS(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of 1-(6-Bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)-2-methylpropan-2-ol (19.8 g, 49.8 mmol) in DCM (150 mL) was cooled with a dry-ice acetone bath to −73° C. (Diaminoethyl)sulfur trifluoride (6.9 mL, 52.3 mmol) was added dropwise over 2 min; the temperature rose to −62° C. The resulting solution was stirred in the bath for a further 1 hr, then at ambient temperature for 1 hour. The reaction mixture was poured into a separatory funnel containing cold 10% KOH (250 mL), and then diethyl ether (500 mL) was added. After shaking, the organic layer was washed with brine (150 mL), dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 85/15 hexanes/EtOAc as eluent. Fractions containing product were pooled and the solvent removed under reduced pressure to afford the title compound as an orange oil (13.4 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][CH:9]([C:13](C)(C)[O:14][SiH2]C(C)(C)C)[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH:23](N(C(C)C)CC)(C)C.CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([CH:9]([CH2:13][OH:14])[CH:10]([CH3:11])[CH3:12])[CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(NCC(=O)OC(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)C(CO)N(C)CC(=O)OC(C)(C)C

Procedure:
{[1-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-propyl]-amino}-acetic acid tert-butyl ester (1.9 g, 6.1 mmol) and diisopropylethylamine (4.2 mL, 24 mmol) were dissolved in DMF (15 mL). A solution of MeI (0.45 mL, 7.3 mmol) in DMF (100 mL) was slowly added over 15 min. The reaction was stirred for 2½ h. The solvent was removed in vacuo. The residue product was dissolved in EtOAc (100 mL) and the solution was washed with water (20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was dissolved in acetonitrile (45 mL) and Et3N 3HF (2 mL, 12.3 mmol) was added. The reaction was stirred for 16 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (100 mL) and washed with saturated sodium bicarbonate solution (25 mL) and saturated sodium chloride solution (25 mL). The organic phase was dried over magnesium sulfate and the solution was slowly filtered through 5 g of silica gel. The filtrate was evaporated in vacuo. Yield: 1.1 g, 78%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
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: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccnc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of 2-chloro-4nitropyridine (0.40 g, 2.56 mmol), pyridin-3-ylboronic acid (0.408, 3.32 mmol), tetrakis(triphenylphosphinepalladium(0) (0.18 g, 0.15 minol) and sodium carbonate (0.489 g, 4.6 mmol) in acetonitrile (9 mL) and water (9 mL) was heated at 80° C. overnight. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on basic alumina to give 4-nitro-2,3′-bipyridine (350 mg, 70%) as a pale yellow solid. LCMS: (FA) ES+ 202.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32](=[O:35])[NH:33][CH3:34])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C(NCC)C.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32](=[O:35])[N:33]([CH3:36])[CH3:34])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: CNC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A solution of {(3,5-bis-trifluoromethyl-benzoyl)-[4-(2-chloro-phenyl)-pyridin-3-yl]-amino}-acetic acid (0.15 g, 298 μmol, example 102, intermediate), HATU (136 mg, 358 μmol) and diethylamin hydrochloride (29.2 mg, 358 μmol) in DMF (2 mL) was treated with DIPEA (116 mg, 156 μL, 895 μmol) and stirred at room temperature for 1.75 h. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed twice with water and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow foam (0.127 g; 80%). MS (ESI): m/z=530.12 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N1CCCCC1.[CH2:14]([S:21][C:22]1[CH:27]=[C:26]([N:28]([CH:36]2[CH2:38][CH2:37]2)C(=O)OC(C)(C)C)[N:25]2[N:39]=[CH:40][C:41]([CH:42]=O)=[C:24]2[N:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C.O>[CH2:14]([S:21][C:22]1[CH:27]=[C:26]([NH:28][CH:36]2[CH2:37][CH2:38]2)[N:25]2[N:39]=[CH:40][C:41](/[CH:42]=[C:7]3/[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]/3)=[C:24]2[N:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(C)OC(=O)N(c1cc(SCc2ccccc2)nc2c(C=O)cnn12)C1CC1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Temperature: 80 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
Hydantoin (67 mg, 0.67 mmol) and piperidine (66 μL, 0.67 mmol) were added to tert-butyl 5-(benzylthio)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (95 mg, 0.22 mmol) dissolved in ethanol (1.1 mL). The reaction was heated at 80° C. After 15 h, the reaction was cooled to r.t., diluted with water (5 mL), and the precipitate was collected and washed with 1:1 ethanol:water (10 mL) and then ethanol (3 mL). The bright yellow solid was dried in vacuo to give (Z)-5-((5-(benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (75 mg, 66%). LCMS (ES): >95% pure, m/z 507 [M+1]+.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C@H:17]([CH3:18])[O:16]1>CCCCCC.CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:16])([C@H:17]([S:3][CH2:4][CH2:5][OH:6])[CH3:18])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: OCCS
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](SCCO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 74 %

Procedure:
70 mg (1.60 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were washed with hexane, and then suspended in 3 ml of dimethylformamide. 187 mg (2.4 mmole) of 2-mercaptoethanol were added to the resulting suspension under an atmosphere of nitrogen, whilst ice-cooling, and the mixture was stirred for 10 minutes. At the end of this time, 200 mg (0.80 mmole) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (prepared as described in European Patent Publication 332 387, the disclosure of which is incorporated herein by reference) were added to the mixture, and the resulting mixture was stirred at 50°-60° C. for 30 minutes. The mixture was then cooled after which it was diluted with ethyl acetate. It was then washed with a saturated aqueous solution of sodium chloride; and the solvent was then removed by distillation under reduced pressure. The crude product thus obtained was purified by column chromatography through 10 g of silica gel, using a 4:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford 195 mg of the title compound. A pure specimen melting at 89°-90° C. was then obtained by recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:11]=[C:10]([CH2:18][CH2:19][CH3:20])[N:9]=1>O1CCOCC1>[CH:15]1([NH:14][C:12]2[N:13]=[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[N:11]=2)[CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: CCCc1nc(Cl)nc(NC2CC2)n1
Solvent: C1COCCO1
Product: CCCc1nc(NC2CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
45 ml (0.45 mole) of morpholine dissolved in 200 ml of dioxane are added to a solution containing 43 g (0.163 mole) of 2-chloro-4-cyclopropylamino-6-n-propyl-1,3,5-triazine in 300 ml of dioxane, while maintaining the mixture at room temperature. After the addition, the mixture is heated under reflux for one to two hours. The reaction mixture is then allowed to return to room temperature and the precipitate is filtered off. The filtrate is concentrated and the residue is redissolved in dichloromethane. The solution is washed with water. The organic phase is separated off and dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent: 98.5:1.5 (v/v) dichloromethane-ethanol) and the product is finally recrystallized from diethyl ether. 36.2 g of 2-cyclopropylamino-4-morpholino-6-n-propyl-1,3,5-triazine are obtained. Yield: 85%. M.P.: 104° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:12]=1[OH:20]>>[NH2:17][C:16]1[C:11]([CH3:10])=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:20][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: ClCCN1CCCC1
Agent: Cl
Product: Cc1c(N)cccc1OCCN1CCCC1

Procedure:
By the method of examples 2 and 3, 1-(2-chloroethyl)pyrrolidine hydrochloride and 2-methyl-3-nitrophenol were converted into the title compound.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:37]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=1)(=[O:39])=[O:38]>>[C:1]([C:9]1[O:10][C:11]2[CH:35]=[CH:34][CH:33]=[CH:32][C:12]=2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:37]([C:40]3[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=3)(=[O:39])=[O:38])=[C:22]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:21]=2)=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)c(C3CCCC3)c2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(C(=O)c5ccccc5)oc5ccccc45)cc3)cc2C2CCCC2)cc1O

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-3-cyclopentyl-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 105-108° C.; MS m/e 694 (M−H)+;
Reaction SMILES: CI.[NH:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][N:5]=[N:4]1.[CH2:18](N(CC)CC)C>C(#N)C>[CH3:18][N:6]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[N:3][N:4]=[N:5]1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Solvent: CC#N
Solvent: CI
Product: Cn1nnnc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of methyl iodide (34.1 ml, 0.5 mol) in acetonitrile (100 ml) was added dropwise, over lh, to a solution of 4-(1H-tetrazol-5-ylmethyl)nitrobenzene (20.5 g, 0.1 mmol), and triethylamine (18.7 ml, 0.25 mol), in acetonitrile (500 ml), at room temperature. The mixture was stirred for 3h, the solvent removed under vacuum and residue dissolved in EtOAc (500 ml). The solution was washed with water (2x) and brine (1x) and the solvent evaporated. The crude product was chromatographed through silica-gel eluting with EtOAc/hexane (1:1)→EtOAc (100%) to give 2 components. The more polar product (7.9 g) was identified as the desired 1-methyl substituted tetrazole. The less polar product (7.0 g) was identified as being the 2-substitution product; 5 (360 MHz, CDCl3, more polar isomer) 3.94 (3H, s, CH3), 4.40 (2H, s, CH2), 7.42 (2H, d, J=8.7 Hz, Ar--H), 8.21 (2H, d, J=8.7Hz, Ar--H).