Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.[S:11]([N:21]1[C:25]2[N:26]=[CH:27][C:28]3[N:29]([C:30]([C@@H:33]4[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34]4)=[N:31][N:32]=3)[C:24]=2[CH:23]=[CH:22]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CC([O-])=O.[Na+]>O.C(Cl)Cl>[N:38]1([C@H:35]2[CH2:36][CH2:37][C@@H:33]([C:30]3[N:29]4[C:24]5[CH:23]=[CH:22][N:21]([S:11]([C:14]6[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=6)(=[O:13])=[O:12])[C:25]=5[N:26]=[CH:27][C:28]4=[N:32][N:31]=3)[CH2:34]2)[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5cccc5)C4)n23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A solution of 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) in water (3 mL) was heated at about 100° C. for about 1.5 h. The solution was cooled to ambient temperature. A suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentanamine hydro-chloride (0.10 g, 0.21 mmol, prepared using E from Preparation #B.1 and HCl) and NaOAc (0.05 g, 0.61 mmol) in DCM (5 mL) was added to the aqueous solution. The reaction mixture was stirred at ambient temperature for about 1 h followed by addition of additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol). The reaction mixture was heated to about 40° C. for about 15 h. Additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) was added and the reaction mixture was stirred at about 40° C. for about 8 h then at about 35° C. for about 48 h. The reaction was diluted with DCM (10 mL) and water (10 mL). The layers were separated and the organic layer was washed with water (2×10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give 1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.095 g, 99%) as a yellow residue: LC/MS (Table 1, Method a) Rt=2.42 min; MS m/z: 447 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[N:2]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCNc1nsc2ncccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCNc2nsc3ncccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
N1-(Isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine (100 mg, 0.48 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.23 mL, 1.34 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 4-methoxybenzoyl chloride (98 mg, 0.58 mmol) in methylene chloride (5 mL) was added drop-wise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(isothiazolo[5,4-b]pyridin-3-ylamino)propyl)-4-methoxybenzamide (54 mg). 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.55 (t, 1H), 8.45 (d, 1H), 8.18 (s, 1H), 7.82-7.85 (m, 2H), 7.41 (dd, 1H), 7.26-7.36 (m, 2H), 3.95 (s, 3H), 3.40-3.42 (dd, 2H), 3.39-3.40 (dd, 2H), 1.82-1.95 ppm (m, 2H). MW=342 confirmed by LC-MS, tr=10.82 min (Method Y) MH+=343.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:6]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:7]1=[O:8])[CH:4]=[CH2:5].[CH2:18]([OH:23])[CH:19]([OH:22])[CH2:20]Cl>CO>[CH2:3]([N:6]1[C:16]2[C:11](=[C:12]([O:17][CH2:20][CH:19]([OH:22])[CH2:18][OH:23])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:7]1=[O:8])[CH:4]=[CH2:5]
Reactant: OCC(O)CCl
Reactant: C=CCN1C(=O)CCc2c(O)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCN1C(=O)CCc2c(OCC(O)CO)cccc21
Yield: 44 %

Procedure:
0.4 g of potassium hydroxide was dissolved in 40 ml of methanol, and 1.0 g of 1-allyl-5-hydroxy-3,4-dihydrocarbostyril and 1.5 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 6 hours. The mixture was then worked up in the same manner as described in Example 3 and recrystallized from ethyl acetate to give 0.6 g of 1-allyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 96° - 97.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)ncc1N
Temperature: 80 °C
Yield: 88.9 %

Procedure:
A mixture of 2-chloro-4-methoxy-5-nitropyridine (208 mg, 1.10 mmol), ammonium chloride (295 mg, 5.52 mmol) and iron powder (246 mg, 4.41 mmol) in ethanol (5 mL) and water (0.5 mL) was heated at 80° C. for 18 h. The mixture was cooled and filtered through a Celite cartridge and washed through with methanol. The combined filtrate and washing was evaporated, and the residue partitioned between DCM (10 mL) and water (10 mL), the organic phase was washed further with water (10 mL), and the aqueous washes were combined and extracted with DCM (3×5 mL). The organic extracts were combined and filtered through a hydrophobic frit, and the solvent was removed by evaporation to give the product as an off-white solid (155 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H); 6.71 (s, 1H); 3.90 (s, 3H); 3.71 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[CH2:13][CH3:14].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:45](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[N:45]=[CH:12]2
Reactant: CCc1c(Br)ccc(NC(C)=O)c1C
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1c(Br)ccc2c1cnn2C(C)=O

Procedure:
To a solution of 3.72 g of the acetamide prepared in Example 212b in 31.5 ml chloroform were added 4.1 ml of acetic anhydride and 2.85 g of potassium acetate, and 192 mg of 18-crown-6 and 3.4 g of isopentyl nitrite were then added dropwise. The reaction mixture was heated for 20 hours under reflux and after cooling diluted with 200 ml ethyl acetate. The organic phase was washed with 20 ml sodium carbonate solution and once with saturated sodium chloride solution. After drying over sodium sulphate and filtration, this was concentrated in vacuo and the crude product thus obtained purified by column chromatography on silica gel with hexane/0-50% ethyl acetate. Yield: 3.78 g of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:13][OH:14])[CH2:8]2
Reactant: NO
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1C2CC3CC(C2)CC1C3
Yield: 90.9 %

Procedure:
To 30 g of 2-adamantanone (Aldrich Chem. Co.) in 100 mL of methanol was added 50 g of hydroxylamine hydrochloride and 92 g of sodium acetate trihydrate and the mixture was refluxed for 2 hours. The mixture was concentrated in vacuo, the residue was distributed between 250 mL of dichloromethane and 50 mL of water. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 30 g of crude 2-adamantanone oxime. This was dissolved in 100 mL of chloroform and 135 g of PPE (polyphosphate ester, prepared by refluxing phosphorus pentoxide with diethyl ether in chloroform, as described by G. Schramm, H. Groetsch, and W. Pollmann, Angew. Chem., Internat. Ed., 1,1 (1962)) was added carefully. When the exothermic reaction ceased, the mixture was refluxed for 5 minute. Then it was cooled in ice, diluted with 500 mL of water and stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 16.6 g of the crude lactam product. This was dissolved in 250 mL of chloroform and 11 mL of phosphorus oxychloride was added dropwise in 30 minutes. After stirring for additional 1 hour at room temperature, to this stirred mixture was added 25 mL of triethylamine and a solution of 16 g of 4,6-dichloro-2-aminobenzonitrile (4,6-dichloroanthranilonitrile) which was prepared by the methodology shown in Example 11.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>>[C:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)=[CH:7][CH:6]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-acetylpiperizine according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.3(dd, 1H, J=1.8 and 8.7 Hz), 7.9(s, 1H), 7.84(d, 1H, J=7.5 Hz), 7.74(d, 1H, J=8.7 Hz), 7.54(m, 2H), 7.31(s, 1H), 6.99(d, 1H, J=7.5 Hz), 6.84(d, 1H, J=8.1 Hz), 6.76(d, 1H, J=11.7 Hz), 4.32(t, 2H, J=5.7 Hz), 3.66(t, 2H, J=5.4), 3.5(t, 2H, J=5.4 Hz), 3.28(m, 4H), 3.0 (t, 2H, J=5.7 Hz), 2.65(m, 4H), 2.05(s, 3H), 1.62-1.8(m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1cccc(S)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)CSc2cccc(OC)c2)cc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
3-Methoxythiophenol (50.0 g, 0.356 mol) was dissolved in 700 mL of ethanol. To this mixture was added (20 g, 0.36 mol) of potassium hydroxide pellets. A total of (82.5 g, 0.36 mol) of 2-bromo-4'-methoxyacetophenone was added in small portions to keep the temperature of the reaction at approximately 25° C. The reaction was allowed to proceed at ambient temperature for three hours. The reaction was terminated by evaporation of the alcohol, which resulted in obtaining a brown oil. The oil was partitioned between 2 L of water and 1.5 L of diethylether. The ether layer was separated and washed with water, dried with anhydrous magnesium sulfate, and evaporated to a solid. The solid was crystallized from a mixture of diethylether:petroleum ether (3:1) to yield 78.5 g of the title compound as a 5 pink crystalline solid. mp 53° C.-54° C. EA calculated for C16H16O3S: C, 66.64; H, 5.59; O, 16.64; S, 11.12. Found: C, 66.55; H, 5.87; O, 16.82; S,10.86.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:33][C:34]=1[CH3:35]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[N:31]=[C:32]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:33][C:34]=5[CH3:35])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-chloromethyl-5-methyl-2-phenyloxazole, to give the desired product as a brown solid (71%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.C(Cl)Cl>C1COCC1>[CH:1]1([C:4]2[N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To the solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (0.4 g, 0.99 mmol, 1.0 eq) in dry THF (50 mL), NaH (0.4 g, 60% dispersion in oil, 10.0 mmol, 10.0 eq) was added by portions. The reaction mixture was stirred at rt for 1 h. Then, BOC2O (0.26 mL, 1.19 mmol, 1.2 eq) was added to the reaction mixture and the resulting reaction was stirred at rt for 2 h. CH2Cl2 was added and organic layer was washed (water), dried and concentrated. The residue was purified by silica gel chromatography (hexane as eluant) to afford tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (0.32 g, 60.3%). LC-MS (m/z): 504.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 0.81-0.85 (m, H), 1.09-1.15 (m, 2H), 1.67 (s, 1H), 2.49 (m, 1H), 6.86 (s, 2H), 7.50-7.60 (m, 3H), 8.41-8.44 (m, 2H), 9.40 (s, 1H), 10.46 (s, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])[C:8]([C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[C:9]([CH3:15])[NH:10]2)([CH3:3])[CH3:2].C.[H][H]>[Pd].C(O)C>[CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:34])([F:35])[F:33])[C:8]([C:16]([OH:18])=[O:17])=[C:9]([CH3:15])[NH:10]2)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Reaction time: 0.5 h

Procedure:
Three g (6.2 mMol) Benzyl (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate are hydrogenated at normal pressure and at ambient temperature with the use of 1.5 g. 10% palladium on active charcoal in 100 ml. ethanol. The take up of hydrogen is finished after 30 minutes. The catalyst is filtered off, the solvent is distilled off in a vacuum and the colorless, crystalline residue is recrystallized from diisopropyl ether/ethyl acetate. There is obtained (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid in the form of colorless crystals with a melting point of 164°-166° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].C([O-])(=O)C.[K+].C([O-])([O-])=O.[K+].[K+].CCO>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][OH:33])([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2(CO)CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 145 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
A 25 mL round bottom flask charged with a mixture of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (900 mg, 1.316 mmol), potassium acetate (388 mg, 3.95 mmol), K2CO3 (182 mg, 1.316 mmol), EtOH (1 ml, 17.13 mmol), N,N-dimethylacetamide (6 mL) and stirred in a pre-heated oil bath (145° C.) for 3 h. After cooling the reaction was quenched with 1 N HCl (3 mL), diluted with EtOAc (100 mL) and washed with water (3×25 mL). The combined aqueous layers were extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to afford a brown solid which was crystallized from ethanol (˜30 mL) to give the title compound (250 mg, 0.448 mmol, 34.1% yield) as white crystals. 1H NMR (500 MHz, CDCl3) δ: 9.59 (1H, t, J=5.95 Hz), 7.24 (1H, d, J=7.63 Hz), 7.16-7.22 (1H, m), 6.94 (1H, t, J=9.00 Hz), 4.76 (1H, d, J=15.26 Hz), 4.58-4.65 (1H, m), 4.42-4.49 (1H, m), 3.48-3.57 (3H, m), 3.37-3.47 (1H, m), 3.05 (3H, s), 3.04 (3H, s), 3.01 (3H, s), 2.26 (3H, d, J=1.53 Hz), 2.08-2.16 (3H, m), 1.77-1.85 (1H, m), 1.67-1.74 (2H, m), 1.41-1.51 (1H, m). LCMS (M+H)=530.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10]O2)=[CH:4][CH:3]=1.NC(N)=[S:13].O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][S:13]2)=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: Fc1ccc(C2CO2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(C2CS2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-(4-fluoro-phenyl)-oxirane (1.38 g, 10.0 mmol), thiourea (760 mg, 10.0 mmol) and silica gel (200 mg) in CH2Cl2 (10 mL) was stirred at room temperature for 12 hours. Water (20 mL) was added to the suspension and the mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)[CH:10]=2)[N:3]=1.[Cl:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O.CO.C(Cl)Cl>[Cl:21][C:22]1[N:26]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH:20]=[CH:19][N:18]=[N:17]4)[CH:10]=3)[N:3]=2)[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Clc1ncnc(Nc2cccc(Cn3ccnn3)c2)n1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Clc1nc2ccccc2n1-c1ncnc(Nc2cccc(Cn3ccnn3)c2)n1
Temperature: 70 °C

Procedure:
(4-Chloro-[1,3,5]triazin-2-yl)-(3-[1,2,3]triazol-1-ylmethyl-phenyl)-amine (552.7 mg, 1.921 mmol) is combined with 2-chlorobenzimidazole (381 mg, 2.497 mmol) and K2CO3 (372 mg, 2.689 mmol) in AcCN (10 ml) and heated at 65-75° C. for 2 to 20 h. The reaction mix is cooled to RT and diluted with MeOH and CH2Cl2. The inorganic salts are filtered off and the organic solution is concentrated under reduced pressure. The crude is treated with AcCN (5-8 ml), forming a precipitate. The precipitate is filtered and dried, giving [4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3-[1,2,3]triazol-1-ylmethyl-phenyl)-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][Cl:20]>CC(=O)CC.CCOC(C)=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:18][CH2:19][Cl:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a mixture of 3-nitrophenol (5.0 g, 35.94 mmol), K2CO3 (7.45 g, 53.9 mmol), in 2-butanone at 85° C. 1-bromo-2-chloroethane (1.723 mL, 71.88 mmol) was added and stirred for 24 h. The mixture was cooled to rt and reduced in vacuo, then diluted with EtOAc (200 mL) and water (200 mL) and separated. The aqueous layer was extracted twice with EtOAc (200 mL) and the combined organic layers were dried over MgSO4 and reduced in vacuo onto silica. Purified via column chromatography using gradient of EtOAc/Hexanes to afford a yellow oil that solidified upon standing to afford 4.22 g (58% yield) of desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.8 (m, 1H), 7.7 (t, J=2.4 Hz, 1H), 7.6 (t, J=8.2 Hz, 1H) 7.4 (dd, J=8.2, 2.6 Hz, 1H), 4.4 (m, 2H), 4.0 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1ccnc(N)c1
Product: COc1ccc(CCNc2cc(C)ccn2)cc1

Procedure:
Similarly prepared from 4-methoxyphenyl acetic acid and 2-amino-4-picoline.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:3][CH:2]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH:14]1([C:17]([N:9]2[CH2:10][CH:11]3[C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=4)([CH2:12]3)[CH2:8]2)=[O:18])[CH2:16][CH2:15]1
Reactant: Cc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)C1CC1
Product: Cc1ccc(C23CC2CN(C(=O)C2CC2)C3)cc1

Procedure:
In a like manner 1-(p-tolyl)-3-azabicyclo[3.1.0]-hexane (Example 36) is reacted with cyclopropanecarbonyl chloride to give 3-cyclopropanecarbonyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane which is reduced as above to give 3-cyclopropylmethyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 180°-182° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([SH:11])[N:5]2[N:4]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.N>C(#N)C>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:11][C:10]3[N:5]4[N:4]=[C:3]([CH2:2][OH:1])[N:13]=[C:6]4[N:7]=[C:8]([CH3:12])[CH:9]=3)[CH2:28][S:27][C@H:22]12
Reactant: Cc1cc(S)n2nc(CO)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In 130 ml of acetonitrile were suspended 11.08 g of 2-hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine and 15.38 g of 7-aminocephalosporanic acid, and 24.6 ml of boron trifluoride - ethyl ether complex was added thereto and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was ice-cooled, 300 ml of water was added thereto and pH thereof was adjusted to 2 with conc. aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and with acetone, and then dried to obtain 18.5 of the title compound.