Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40]>CO>[C:39]([NH:43][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:22])[CH:21]=[C:12]([C:11]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[O:13]2)=[CH:18][CH:17]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1

Procedure:
3′,4′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 29 (2.5 g, 4.9 mmol) and tert-butyl amine (1.05 mL, 9.8 mmol) in dry methanol (160 mL) were reacted in a similar manner to that described under 34 to afford 37. Yield 2.4 g (85%); mp 159-161° C.; MS (FAB) 580 (M+1); IR (KBr) 3400, 1633; 1H NMR (200 MHz, CDCl3) δ 8.08 (d, J=8.7 Hz, 1H), 7.50-7.28 (m, 12H), 7.02-6.93 (m, 3H), 6.60 (s, 1H), 5.23 (s, 4H), 4.10-3.98 (m, 3H), 2.90 (dd, J=5.9 Hz, 3.8 Hz, 1H), 2.71 (dd, J=5.9 Hz, 7.3 Hz, 1H), 2.47 (s, 2H), 1.14 (s, 9H). Analysis Calcd for C36H37NO6: C, 74.59; H, 6.43; N, 2.42 Found: C, 73.36; H, 6.62; N, 2.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[F:19])[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 590.1 %

Procedure:
A mixture of 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g, 2.1 mmol), zinc dust (8.14 g, 125 mmol) and ammonium chloride (6.66 g, 125 mmol) in THF (160 mL) and MeOH (160 ml) was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was partitioned between EtOAc (50 ml) and a mixture of water and saturated NaHCO3 (aq) (1:1; 50 ml). The mixture was extracted with EtOAc (2×50 ml). The combined organic extracts were dried (Na2SO4) and evaporated to yield 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (3.18 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, 1H), 7.24-7.19 (m, 1H), 7.00 (s, 1H), 6.94-6.92 (m, 1H), 6.74-6.69 (m, 1H), 5.54 (brs, 2H); MS (ESI) m/z: 257.0 (M+H+).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].S>C(O)C>[C:1]1([C:7]2[S:36][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1
Agent: S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Yield: 142.8 %

Procedure:
In a 1-liter steel autoclave fitted with a mechanical stirrer, a thermometer and a pressure gauge were placed 32 g (0.09 mole) of 1,2-diphenyl-4-p-methoxyphenylbutane-1,4-dione, 100 ml of xylene, 20 g (0.045 mole) of phosphorus pentasulfide and 130 g of hydrogen sulfide. The mixture was stirred and heated 3 hours at 157°-162° C. (1190-1220 psig). The vessel was cooled and the hydrogen sulfide vented into an aqueous sodium hydroxide trap. The semisolid residue was stirred with 150 ml of absolute ethanol. Filtration gave 23 g (72%) of crude product, m.p. 130°-132° C. and a second crop of 3.7 g (11.6%) m.p. 124°-126° C. The two crops were combined and recrystallized from a mixture of 30 ml of dioxane and 60 ml of absolute ethanol to give 22 g (69%) of pure product m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([O:13][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC[C@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC[C@H]1CC[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl trans-2-(3-ethoxy-3-oxopropyl)-5-hydroxypiperidine-1-carboxylate (625 mg, 2.07 mmol, step 3 of Example 5) and triethylamine (252 mg, 2.49 mmol) in dichloromethane (9.0 mL) was added methanesulfonyl chloride (285 g, 2.49 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then stirred at room temperature for 20 h. The mixture was quenched with water (30 mL), extracted with dichloromethane (30 mL×4). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 790 mg (quant.) of the title compound as a yellow oil. The resulting residue was used for the next reaction without purification.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:26])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[I:26][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][C:10]=2[CH:12]=1
Reactant: OCCc1ccc2oc(-c3ccccc3)cc2c1
Reactant: O=C1CCC(=O)N1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
2-(2-Phenyl-benzofuran-5-yl)ethanol (11.18 g; 46.9 mmol) was dissolved in DCM (170 ml) and N-iodinesuccinimide (NIS; 11.31 g; 50.27 mmol) and triphenylphosphine (15.39 g; 52.67 mmol) was added under stirring. After keeping the reaction mixture at RT over night the reaction was extracted two times with 6% aqueous NaHCO3 solution and the organic layer was dried over Na2SO4. After filtering and removal of the solvent pure title compound was obtained after crystallization from methanol/DCM/cyclo-hexane. The mother liquor was collected and purified on silica gel (cyclohexane/ethylacetate 95/5 as mobile phase).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH3:16])([O-:15])=[O:14].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 300 g of cinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-phenylbutanoic acid methyl ester.
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:27](=[O:28])[NH:26][C:21]1[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Et3N (1.7 mL) was added to an ice-cold solution of (S)-proline methyl ester hydrochloride (1.31 g) and 3,5-dichlorophenylisocyanate (1.97 g) in CH2Cl2 (40 mL). The mixture was stirred for 3 hours. It was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/3) afforded (S)—N—[N-(3,5-dichlorophenyl)carbamoyl]proline methyl ester (2.27 g). mp. 110-112° C.; MS (m/z) 339 (M++Na). (2) A solution of the compound obtained above (14.3 g) in toluene (100 mL) containing p-toluenesulfonic acid (0.5 g) was refluxed for 2 hours. The solution was diluted with EtOAc and was washed with satd. NaHCO3, water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: CHCL3/MeOH: 10/1) and recrystallization from EtOH afforded 8.87 g of (S)-3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione. mp. 169° C.; MS (m/z) 307 (M++Na). (3) A solution of n-BuLi (2.2 mL) in hexane (1.6 N) was added to a solution of diisopropylamine (0.381 g) in THF (5 mL) at −78° C. After 15 minutes, a solution of the compound obtained above (0.894 g) in THF (8 mL) was added to the mixture. HMPA (8 mL) and additional THF (8 mL) were added to the mixture. After 35 minutes, a solution of 4-(bromomethyl)benzonitrile (0.697 g) in THF (8 mL) was added and the mixture stirred for 30 minutes at that temperature. The mixture was slowly warmed to room temperature, stirred for 30 minutes and finally quenched with 0.5 N HCl (10 mL). The mixture was diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2, Chromatotron) afforded the titled compound (0.833 g). MS (m/z) 422 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21](OC)OC.[OH:26][CH:27]([CH:29]([OH:31])[CH3:30])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]1[O:31][CH:29]([CH3:30])[CH:27]([CH3:28])[O:26]1
Reactant: COC(OC)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reactant: CC(O)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(c2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc2Cl)OC1C

Procedure:
30 g of 3-(4-chloro-3-dimethoxymethylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.1 g of 2,3-dihydroxybutane and 0.3 g of p-toluenesulfonic acid were dissolved in 100 ml of anhydrous toluene, and the stirred solution was refluxed for 7 hours in the absence of water. For working up, the solution was washed in succession with water and 10% strength NaHCO3 solution, dried over Na2SO4 and evaporated down.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7]Cl)(=[O:5])=[O:4])[CH3:2].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>>[CH2:1]([S:3]([CH2:6][CH2:7][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCS(=O)(=O)CCCl
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
Mix 2-chloroethyl ethyl sulfone (1.2 g, 7.66 mmol) and piperidine (2 mL, 20 mmol). Stir at room temperature for 2 hours. Treat with 5N sodium hydroxide, extract with ethyl acetate (3×50 mL) and dry (MgSO4). Concentrate in vacuo to yield 1.3 g yellow oil which crystallizes. Purify by silica gel chromatography (ethyl acetate) to yield 550 mg (35%) of the title compound as a clear oil which crystallizes; mp 45°-47° C.
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH:4]([CH3:6])[CH3:5])[CH3:3].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1>[S:8]([NH:7][C:2]([CH3:3])([CH:4]([CH3:6])[CH3:5])[CH3:1])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(C)(C)N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of 1.2 g (0.012 mole) 2,3-dimethyl-2-butylamine in 20 mL pyridine, a solution of 1.9 g (0.010 mole) tosylchloride in 20 mL pyridine was added dropwise in a glacial water bath, stirred for 3 hours in that bath and 1 hour at room temperature, then heated for 2 hours in a bath at temperature of 95-100° C. The solvent was distilled off in vacuum. Toluene was added to the residue, then distilled off the solvent in vacuum. The residue was dissolved in water and extracted with toluene (×4). The toluene extract was washed with water once, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled off the solvent. The residue was recrystallized from isopropanol to give a colorless columnar crystal 1.1 g, mp 80-89° C., recrystallized from isopropanol once again to give a white crystal 0.8 g, mp 88-89° C. Elemental analysis for C13H21NO2S (%): Calculated C, 61.14; H, 8.29; N, 5.48. Found C, 61.11;, H, 8.37;, N, 5.55. 1H-NMR(CDCl3; ppm) 0.91(d, J=6.8 Hz, 6H, 2CH3), 1.17(s, 6H, 2CH3), 1.82(M, 1H, CH), 2.47(s, 3H, CH3), 7.32(d,J=8.0, 2H,2Ar—H), 7.82(d, J=8.0, 2H, 2Ar—H′). MS(M/z) 255 (M+), 172(B).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])=[CH:11][S:12][CH:13]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])=[CH:11][S:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cscc1C(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cscc1C(=O)Nc1ccccc1
Yield: 102.3 %

Procedure:
4-(tert-butoxycarbonylamino)-N-phenylthiophene-3-carboxamide (300 mg, 0.94 mmol) in CH2Cl2 (3 ml) was treated with TFA (0.36 ml, 4.71 mmol) at room temperature for 2.5 hours. The solvent was evaporated, the residue was dissolved in methanol/HCl, ether was added to the solution, the precipitate was recovered to give title compound (210 mg, 87%) which was used as is in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:27]=[N:26]C=2C=1.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:26][NH2:27])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: ClCCl
Product: NNC(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 445.7 %

Procedure:
A mixture of (R)-tetrahydrofuran-2-carboxylic acid (5.00 g, 43.1 mmol, 1.00 equiv), EDCI (12.4 g, 64.6 mmol, 1.50 equiv) and HOBt (8.70 g, 64.4 mmol, 1.50 equiv) in dichloromethane (100 mL) was stirred for 30 min at 25° C. To the mixture was then added hydrazine (2.00 g, 62.4 mmol, 1.50 equiv) dropwise. The resulting mixture was stirred overnight at 25° C. The solids were removed by filtration, and the filtrate was concentrated in vacuo to furnish 25.0 g (crude) of (R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH3:19]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:16][C:17]#[C:18][CH3:19])[CH:3]=1)[CH3:14]
Reactant: CC#CCBr
Reactant: CCOC(=O)CSc1cccc(O)c1
Product: CC#CCOc1cccc(SCC(=O)OCC)c1
Yield: 100 %

Procedure:
Ethyl{[3-(2-butynyloxy)phenyl]sulfanyl}acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl [(3-hydroxyphenyl) sulfanyl]acetate (3.87 g, 18.3 mmol) and 4-bromo-2-butyne (2.66 g, 20 mmol); 5.16 g yellow oil. Yield 100%; MS(EI): 264.1 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(CCN)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CCNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylphenethylamine hydrochloride (1 g) in dichloromethane (20 ml) was added triethylamine (0.94 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (1.29 g) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with further dichloromethane (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-(2-[4-acetylphenyl]ethyl)4-methylphenylsulphonamide, 1.58 g, as a yellow crystalline solid: m.p. 124°-126° C.; NMR(d6DMSO) δ 7.84(2H,d), 7.63(3H,m), 7.37(2H,d), 7.29(2H,d), 2.98(2H,q), 2.75(2H,t), 2.55(3H,s), 2.39(3H,s); m/e 318(M+H)+.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH2:42][CH3:43])=[C:36](B(O)O)[CH:37]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH2:42][CH3:43])=[C:34]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Product: CCOc1ccc(Cl)cc1C1=COCCN1C(=O)OC(C)(C)C
Yield: 24 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 5-chloro-2-ethoxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (24% yield); 1H-NMR (d6-DMSO) 1.05 (9H, brs), 1.26 (3H, t), 3.62 (2H, t), 3.92 (2H, q), 4.15 (2H, t), 6.21 (1H, s), 6.90 (1H, d), 7.09 (1H, m), 7.22 (1H, dd); 13C-NMR (d6-DMSO) 14.9, 27.7, 63.9, 67.05, 67.1, 111.9, 126.9, 127.3, 132.0; MS ES(+) 240.0 (M++1); Anal. Calcd for C17H22ClNO4: C, 60.09; H, 6.53; N, 4.12. Found: C, 59.60; H, 6.46; N, 4.35. IR λmax=1701, 1394 cm−1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:27][CH2:26][CH2:25][N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN(CCN)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCN(C)c2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N-methyl-N-(2-pyridyl)-1,2-ethanediamine (326 mg, 2.16 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL), the resulting precipitate was collected by filtration and washed with water. The obtained solid was recrystallized from EtOH to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[2-[methyl(2-pyridyl)amino]ethylamino]-4-oxoquinoline-3-carboxylic acid (303 mg, 48%) as yellow needles.
Reaction SMILES: Cl[C:2]1[C:3]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:4]=2[N:5]=[C:6]([N:8]([CH3:10])[CH3:9])[N:7]=1.[CH3:22][NH:23][CH3:24]>C(O)C>[CH3:9][N:8]([C:6]1[N:7]=[C:2]([N:23]([CH3:24])[CH3:22])[C:3]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:4]=2[N:5]=1)[CH3:10]
Reactant: CNC
Reactant: CN(C)c1nc(Cl)c2nnn(Cc3ccccc3F)c2n1
Solvent: CCO
Product: CN(C)c1nc(N(C)C)c2nnn(Cc3ccccc3F)c2n1
Reaction time: 0.5 h

Procedure:
In a manner analogous to that described in Example 12, 1.95 g (6.36 mmol) of 7-chloro-5-(N,N-dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine are dissolved in 200 ml of warm ethanol, 7 ml of aqueous dimethylamine solution (40%) are added and the mixture is left to stand for 30 minutes. After dilution with 200 ml of water, the product is filtered off with suction and recrystallised from ethanol. In this manner 5,7-bis(N,N-dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 123°-125° is obtained.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(O)c1F
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(F)c(O)c1F
Yield: 86.7 %

Procedure:
A mixture of 2,4-difluoro-3-hydroxybenzaldehyde (0.255 g, 1.613 mmol) and malonic acid (0.168 g, 1.613 mmol) in pyridine (6 ml) and piperidine (0.06 ml) was heated to reflux for 1 h. All the volatile were removed and the residue was partitioned between NaHCO3 sat. and Et2O. The aqueous phase was acidified with 37% HCl until pH <3 and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to give (E)-3-(2,4-difluoro-3-hydroxyphenyl)acrylic acid (280 mg) as pale a brown solid. The compound was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=Nc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-fluoro-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.45 (q, 2H, J=4.7 Hz), 7.23 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.25 (m, 3H), 1.8 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[F:13][CH2:14][C:15]([CH2:17][F:18])=O.N1CCCC1>CO>[F:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([F:1])[CH:7]=1)[O:12][C:15]([CH2:17][F:18])([CH2:14][F:13])[CH2:10][C:9]2=[O:11]
Reactant: O=C(CF)CF
Reactant: CC(=O)c1cc(F)cc(F)c1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC(CF)(CF)Oc2c(F)cc(F)cc21
Yield: 80.9 %

Procedure:
A solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (4.98 g, 28.9 mmol), MeOH (50 mL), 1,3-difluoroacetone (5.44 g, 57.9 mmol), and pyrrolidine (4.79 mL, 57.9 mmol) was heated at 60° C. for 20 hours. The dark solution was cooled, concentrated, chased with toluene, and then passed through a silica gel plug, washing with toluene (200 mL) and MTBE (200 mL). The filtrate was washed with 2N NaOH (50 mL×2), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.80 g, 23.37 mmol, 81%), which was used without further purification in the next step. MS (DCI) m/z 299 (M+51)+.