Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10](=[O:23])[NH:11][C:12](=[O:22])[N:13]([CH:21]=1)[C@@H:14]1[O:20][C@H:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=O.[O-:26][P:27]([O:30][P:31]([O:34][P:35]([O-])([O-:37])=[O:36])([O-:33])=[O:32])(=[O:29])[O-:28]>>[P:35]([O:19][CH2:18][C@H:17]1[O:20][C@@H:14]([N:13]2[CH:21]=[C:9]([C:8]#[C:7][CH2:6][NH2:5])[C:10](=[O:23])[NH:11][C:12]2=[O:22])[CH2:15][CH2:16]1)([O:34][P:31]([O:30][P:27]([OH:28])([OH:29])=[O:26])([OH:33])=[O:32])(=[O:36])[OH:37]
Reactant: O=C(NCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Product: NCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 3.5 h

Procedure:
Alkynylamino nucleoside 22 (0.30 mmol) was converted to the corresponding triphosphate and its trifluoroacetyl group was removed following the general procedure given in Example 5E. After addition of the second aliquot of phsophorus oxychloride, phosphorylation was allowed to proceed for 210 minutes. Assuming an absorption coefficient for the product equal to that of the starting material (13,000), the yield of triphosphate 23, based on its UV absorption at 291.5 nm, was 18%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14]>>[CH3:11][N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CNC(C)(C)C
Product: CN(C(=O)c1cccc(F)c1)C(C)(C)C

Procedure:
3-Fluorobenzoyl chloride was reacted with N-methyl-N-tert-butylamine using General Method E1 or E2 to produce N-methyl-N-(tert-butyl)-3-fluorobenzamide. This compound was used in General Method A to prepare the title compound. Kugelrohr distillation afforded 12.07 g of analytically pure desired material. m.p. 32-35° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:19]([CH3:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:17][C:4]=2[N:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:7]=1.NC(N)=[S:28].C(O)C>O>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[CH2:8][C:6]1[NH:7][C:2](=[S:28])[C:3]2[C:19]([CH3:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:17][C:4]=2[N:5]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)nc(Cl)c2c1C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=S)c2c1C
Temperature: 25 °C
Reaction time: 35 h
Yield: 94 %

Procedure:
A mixture of 1.23 g of ethyl 4-chloro-2-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate, 594 mg of thiourea and 50 mL of ethanol was stirred at room temperature for 35 hours. Then 50 mL of water was added, followed by 30 minutes' stirring. Crystals were recovered by filtration and washed with water. Drying the same under aeration, 1.15 g of the title compound was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]=O>CO>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: C=O
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Solvent: CO
Product: CN1CCN(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)CC1
Yield: 81.2 %

Procedure:
A stirred solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.0 g, 3.6 mmol), N-methylpiperazine (3.6 g, 36.0 mmol) and formaldehyde (37% wt solution in water, 2.9 mL, 36.0 mmol) in methanol was refluxed for 20 h. The solution was concentrated in vacuo to dryness and recrystallized from ether in hexanes to afford the free base form of 1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one as a pale orange solid (1.15 g, 81%). To a solution of 1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.50 g, 12.7 mmol) in methanol (5 mL) was added hydrochloric acid saturated methanol (10 mL). The precipitate that formed was filtered and dried in vacuo to afford 1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrogen chloride (0.65 g, quantitative) as a colorless solid: mp>175° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ11.59 (br s, 1H), 9.43 (br s, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.6, 7.6 Hz, 1H), 7.15 (d, J=6.6 Hz, 1H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.66 (s, 1H), 6.47 (s, 1H), 5.89 (s, 2H), 4.86-4.73 (m, 3H), 4.61 (d, J=9.5 Hz, 1H), 3.54-3.28 (m, 4H), 3.27-2.94 (m, 4H), 2.71 (s, 3H); MS (ES+) m/z 394.0 (M+1). Anal. Calcd. for C20H23N3O4.2HCl.0.5H2O: C, 55.59; H, 5.51; N, 8.84. Found: C, 55.47; H, 5.43; N, 8.78.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][NH:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.O>ClCCl>[Si:5]([O:13][CH2:12][CH2:11][NH:10][CH3:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CNCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyldimethylchlorosilane (4.2 g, 27.9 mmol) in dichloromethane (10 mL) was added dropwise over 3 min to a stirred solution of 2-(methylamino)ethanol (2.0 g, 26.6 mmol) and imidazole in dichloromethane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane then the combined organic phases were passed through a phase separation cartridge and the solvent removed under reduced pressure to afford a colorless oil (5.10 g, 95%). This was taken through to the next step with no further purification.
Reaction SMILES: [C-:1]1([CH2:6][C:7](Cl)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].N1C=CC=CC=1.[OH2:22]>CN(C)C1C=CN=CC=1>[C-:1]1([CH2:6][C:7]([OH:8])=[O:22])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: O=C(Cl)C[c-]1cccc1
Reactant: O
Agent: [Fe+2]
Agent: CN(C)c1ccncc1
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Product: O=C(O)C[c-]1cccc1
Reaction time: 0.17 h

Procedure:
A 50 ml round-bottom flask, equipped with magnetic stirrer and nitrogen inlet, is charged with 0.50 g (0.19 mmol) of ferrocene acetic acid chloride (prepared in analogy to a process slightly modified from Macromolecules 26 (1993) 1936-1940), 10 ml of pyridine, 1.28 g (0.95 mmol) of brominated and, hydroxymethylated tetra(α-2,4-dimethyl-3-pentyloxy)palladium-phthalocyanine and 12 mg (0.1 mmol) of 4-dimethylaminopyridine under argon, and the dark green solution is stirred for 20 hours at room temperature. The reaction mixture is then poured, with thorough stirring, on 100 ml of water and the precipitate is collected by filtration and washed with 4×50 ml of water. After drying the residue for 4 hours at 60° C. and 125 torr, it is dissolved in 15 ml of toluene and then 1.3 g of silica gel are added and the mixture is stirred for 10 minutes. The suspension is filtered and the residue is washed with 3×10 ml of toluene. Using a rotary evaporator, the filtrate is concentrated by evaporation to 4.8 g of a solution which is then poured, with stirring, on 49 ml of acetonitrile and stirred for 10 minutes. The precipitate is collected by filtration, washed with 3×50 ml of acetonitrile and dried overnight at 60° C. and 125 torr, yielding 1.2 g (80.5% of theory) of a green powder (brominated and hydroxymethylated tetra(α-2,4-dimethyl-3-pentyloxy)palladium-phthalocyanine which is esterified with ferrocene acetic acid) having the following analytical values:
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]#[N:13])[CH:5]=1>[Pd].C(O)C>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])[CH:5]=1
Reactant: N#Cc1ccccc1-n1cnnc1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccccc1-n1cnnc1
Reaction time: 48 h

Procedure:
2-(1,2,4-Triazol-4-yl)cyanobenzene (0.3 g; 1.76 mmol) from step A of example 5 was combined with 30% by weight of palladium on carbon, 10% catalyst (100 mg) in ethanol (75 ml) and placed on a PARR Hydrogenation apparatus under a hydrogen atmosphere at 55 psi. for 48 hours. The mixture was filtered through celite and concentrated to give 2-(1,2,4-triazol4-yl)benzylamine; 1H NMR (CD3OD) δ 8.77 (s, 2H), 7.69–7.59 (m, 4H), 3.61 (s, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN1CCCCC1=O>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CN1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
4-Phenylpiperidine (0. 5 g), p-fluorobenzonitrile (0.37 g) and potassium carbonate (0.78 g) are dissolved in N-methylpiperidone (5 ml), and the mixture is stirred at 120° C. for five hours. To the reaction solution is added ethyl acetate (50 ml), and the mixture is washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the resulting residue is added methanol, and the insoluble crystals are collected by filtration, dried under reduced pressure to give 4-phenyl-1-(4-cyanophenyl)piperidine (0.39 g) as white needles.
Reaction SMILES: [C:1]1([N:7]2[C:19](=O)[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][CH2:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[CH:34]1([CH2:40][CH:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[O:43]1CCCC1>C(#N)C>[CH:34]1([CH2:40][CH:41]([C:19]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]3[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][C:10]3=[O:43])[OH:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=CCC1CCCCC1
Reactant: O=c1c2c([nH]n1-c1ccccc1)CNc1ccccc1-2
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC#N
Product: O=c1[nH]c2ccccc2c2c(C(O)CC3CCCCC3)n(-c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinoline-one (4.7 g, 17.9 mmol) was combined with N,N,N′,N′-tetramethylethylenediamine (12 mL), and tetrahydrofuran (200 mL) under an atmosphere of nitrogen. The mixture was chilled to 0° C. A solution of n-butyllithium in hexanes (19 mL of 2.5 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes at 0° C. and then cooled to −78° C. To the cooled solution was added cyclohexylacetaldehyde (12 g, 35 mmol). The reaction mixture was warmed to ambient temperature and stirred for 30 minutes before quenching with saturated aqueous ammonium chloride. The aqueous layer was extracted with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a yellow oily solid. The oily solid was purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-30% CMA in chloroform) to provide a yellow solid. The solid was boiled in acetonitrile and filtered. The filtrate was adsorbed onto silica gel and purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-20% CMA in chloroform) to provide a white foam. The foam was stirred in acetonitrile and filtered to provide 213 mg of 1-(2-cyclohexyl-1-hydroxyethyl)-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a white powder, mp 254-259° C. MS (APCI) m/z 388 (M+H)+; Anal. calcd for C24H25N3O2: C, 74.39; H, 6.50; N, 10.84. Found: C, 74.40; H, 6.37; N, 10.89.
Reaction SMILES: [O:1]=[C:2](N1C=CN=C1)[C:3](N1C=CN=C1)=[O:4].[CH3:15][N:16]1[C:20]([NH:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([NH2:41])[CH:18]=[N:17]1.[NH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49].C(OCC)(=O)C>CN(C)C=O>[CH3:15][N:16]1[C:20]([NH:21][C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([NH:41][C:3](=[O:4])[C:2]([NH:42][CH2:43][CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:1])[CH:18]=[N:17]1
Reactant: O=C(C(=O)n1ccnc1)n1ccnc1
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(NC(=O)C(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 1,1′-(1,2-dioxo-1,2-ethanediyl)bis-1H-imidazole (761 mg) in N,N-dimethylformamide (8 ml) was added 1-methyl-N5-trityl-1H-pyrazole-4,5-diamine (709 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a solution of tert-butyl 2-aminoethylcarbamate (1.28 g) in N,N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 27 hours. To the reaction mixture was added ethyl acetate (50 ml). After the precipitate was filtered off, the filtrate was washed successively with water, 5% aqueous citric acid solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crystalline residue was washed with a mixed solvent of diethyl ether and ethyl acetate and dried in vacuo to give tert-butyl {2-[(2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoacetyl)amino]ethyl}carbamate (823 mg) as a solid.
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH2:11]O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>ClCCl>[ClH:10].[C:1]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH2:11][Cl:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1nn(CO)cc1Cl
Solvent: ClCCl
Product: CC(C)(C)c1nn(CCl)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.82 g of 3-t-butyl-4-chloro-1H-pyrazole-1-ylmethanol was dissolved to 45 ml of dichloromethane. 3.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 0.98 g of 3-t-butyl-4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:37]([N:36]([CH3:40])[CH3:35])=[O:38])[CH2:15][CH:16]=3)[N:8]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1c(C2=CCNCC2)cc2c(Cl)ncnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 15 °C
Reaction time: 5 h

Procedure:
To a solution of Example 75B (4.25 g, 10.33 mmol) and diisopropylethylamine (5.41 ml, 31.0 mmol) in 120 mL dichloromethane was added dimethylcarbamic chloride (1.333 g, 12.40 mmol). The mixture was stirred at 15° C. for 5 hours. The reaction was concentrated in vacuo, and the crude material was purified via flash chromatography: Analogix Intelliflash™ 280, 80 g silica column, 1:1 hexane/ethyl acetate to give the title compound. LC-MS (ESI+) m/z 446.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30][C@H:29]1[CH3:34])[CH3:27]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CCN1CCNC[C@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, J=7.20, 7.20 Hz, 6H) 2.33 (d, J=2.27 Hz, 3H) 2.91-4.72 (m, 9H) 7.63 (br. s., 1H) 7.71-7.79 (m, 1H) 7.94-8.81 (m, 4H) 9.52-10.21 (m, 1H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:9][CH:10]=1.[N+:20]([CH3:23])([O-:22])=[O:21]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:9][CH:10]=1)[CH2:23][N+:20]([O-:22])=[O:21]
Reactant: COC(=O)/C=C/c1ccc(-c2ccnc(SC)n2)s1
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(-c2ccnc(SC)n2)s1

Procedure:
A solution of (E)-3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-acrylic acid methyl ester (200 mg, 0.684 mmol), nitromethane (3 ml) and Triton B (0.3 ml) was heated to 80° C. for 4 hours. After cooling, the mixture was diluted with EtOAc and washed with saturated ammonium chloride solution, water and brine. Drying over sodium sulfate and evaporation gave a red-brown oil. Yield: 100 mg (41%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[N:20]1[CH:21]=[CH:22][C:17]([NH:16][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1Cl
Yield: 74.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), 4-aminopyridine (165 mg,1.75 mmol) and triethylamine (0.36mL,2.58 mmol) were reacted to form the desired product (446 mg, 76%). EI-MS m/z 346(M-H)−.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:7][CH2:6]CC1.Cl.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.[CH3:20]O>>[CH3:13][CH2:14][CH2:9][CH2:10][CH2:11][CH3:12].[CH:7]([O:3][CH:9]([CH3:14])[CH3:19])([CH3:6])[CH3:20]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)OC(C)C
Product: CCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
19.3 g (511 mmol) of NaBH4 were added to a solution of 78.5 g (341mmol) of the isomer mixture 3/3a in 700 ml of a solvent mixture of tetrahydrofuran/analytical grade methanol (2:1) at room temperature. After the mixture had been stirred at room temperature for 2 hours, 120-130 ml of half-concentrated HCl were added, and the mixture was extracted with ether. The combined organic phases were dried with Na2SO4. The residue which remained after the solvent had been stripped off was taken up in 500 ml of methylene chloride, and the mixture was heated under reflux with 6.5 g (34mmol) of p-toluenesulfonic acid for 15 minutes. The residue which remained after the solvent had been stripped off was chromatographed on 1.5 kg of silica gel 60.56 g of the isomer mixture 4/4a were able to be isolated in the form of a colorless oil with a mobile phase mixture of hexane/diisopropyl ether 20:1. The overall yield was 86%.
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]([O:22]CC)=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]([OH:22])=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
LiOH (1.2 g, 29.6 mmol) was added to a solution of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (9 g, 29.6 mmol) in THF/H2O (3:1, 240 mL). The mixture was then stirred at rt overnight. The reaction mixture was washed with EtOAc twice, then the aqueous solution was adjusted pH 2-3 with 1N HCl. The resulting mixture was extracted with DCM three times, and the combined organic layer was dried over saturated Na2SO4 and concentrated in vacuum to provide (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (7.0 g, 77.7%), which was directly used in the next step without further purification. ESI-MS (EI+, m/z): 277.31. 1H NMR (300 MHz, CDCl3) δ 7.49-7.29 (m, 5H), 5.06 (d, J=11.4 Hz, 1H), 4.91 (d, J=11.4 Hz, 1H), 4.15-4.10 (m, 1H), 3.36-3.34 (m, 1H), 3.15-3.11 (m, 1H), 2.83 (d, J=11.8 Hz, 1H), 2.32-2.15 (m, 1H), 2.11-2.01 (m, 2H), 1.74-1.56 (m, 1H).
Reaction SMILES: C([Mg]Br)C.[C:5]12([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[OH:23])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[CH2:24]=[O:25].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]12([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH:24]=[O:25])[C:16]=3[OH:23])[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: COc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C=O)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
Into a 500 ml reactor thoroughly purged with nitrogen, 16.50 ml of an ether solution containing 49.60 mmol of ethylmagnesium bromide and 10 ml of THF were introduced. To the reactor, a solution containing 12.31 g (47.20 mmol) of 2-(1-adamantyl)-4-methoxyphenol diluted with 50 ml of a THF was dropwise added at 0° C. over a period of 15 minutes. Then, 150 ml of toluene was added, and the system was heated to 95° C. to distill off about 40 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 20° C., 3.43 g (114.30 mmol) of paraformaldehyde and 9.40 ml (67.50 mmol) of triethylamine were added, followed by stirring at 90° C. for 30 minutes. The reaction solution was allowed to cool to room temperature and then quenched with 32 ml of 18% hydrochloric acid. The organic layer was washed with 100 ml of water, 50 ml of a sodium hydrogencarbonate aqueous solution and 100 ml of a sodium chloride aqueous solution, and then concentrated. The resulting solid was purified by silica gel column chromatography to obtain 4.95 g (yield: 37%) of 3-(1-adamantyl)-5-methoxysalicylaldehyde.