Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1.O.N([O-])=O.[Na+].[I-:32].[K+].[OH-].[Na+]>C(#N)C.O.C(OCC)(=O)C>[I:32][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:15]
Reactant: CCOC(=O)C(C)c1ccc(N)c(C)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)c1ccc(I)c(C)c1
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-methylphenyl)propanoate (944 mg, 4.55 mmol) in acetonitrile, p-TsOH.H2O (2.62 g, 13.66 mmol) was dropped slowly. The reaction mixture was activated for 10 min. Then NaNO2 (629 mg, 9.11 mmol) in water was added dropwise. The mixture was stirred for 10 min. Then potassium iodide (1.89 g, 11.39 mmol) in water was added slowly dropwise. The reaction mixture was stirred at room temperature for 4 h. After the reaction is complete, 1M NaOH solution was added to neutralize the reaction then ethyl acetate and water was used for work up. The organic layer was washed with water two times, then dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(4-iodo-3-methylphenyl)propanoate (1.22 g) was obtained as 84% yield.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH:33][CH3:34])[CH3:32]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:33]([CH2:31][CH3:32])[CH3:34])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: CCNC
Agent: Cl
Product: CCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 13.3 mg (0.23 mmol) of ethylmethylamine are reacted together by general method E. 20.1 mg (36.8% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10]C)=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>[Cu](I)I>[CH2:8]([C:6]1[C:5](=[O:10])[NH:4][C:3]([CH3:12])=[C:2]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:7]=1)[CH3:9]
Reactant: CCc1cc(Br)c(C)nc1OC
Reactant: c1nc[nH]n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2cncn2)c(C)[nH]c1=O
Temperature: 180 °C
Yield: 18.9 %

Procedure:
Into a microwave vial is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (400 mg, 1.74 mmol), potassium carbonate (360 mg, 2.61 mmol), copper iodide (50 mg, 0.263 mmol) and 1,2,4-triazole (240 mg, 3.47 mmol). The vial is flushed with N2 before anhydrous dimethylformamide (5 mL) is added and then sealed. The reaction is heated in the CEM Discover microwave at 180° C. for 40 minutes. LC/MS shows the reaction is incomplete. Further 1,2,4-triazole (120 mg) and copper iodide (30 mg) are added, the reaction flushed with N2 and is re-microwaved to 180° C. Initially the pressure limit of 20 bar is reached and the process is aborted. The residual pressure is released and the reaction is re-microwaved to 180° C. for 40 min with a maximum pressure of 9-11 bar attained. LC/MS shows the reaction to be complete. The reaction is diluted and extracted with 11 portions of dichloromethane. The combined extracts are then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (19:1). Clean fractions containing the product are combined, the solvent evaporated, and the residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1) then dichloromethane:heptane (1:1, increasing to 1:0). Clean fractions containing the product are combined and evaporated to give an orange residue. The product is triturated with ether/heptane to give 3-ethyl-6-methyl-5-(1,2,4-triazol-1-yl)-1H-pyridin-2-one as an orange powder (67 mg, 19% yield). This material (57 mg) is suspended in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0 M, 0.444 mL). The mixture is stirred for 1.5 h and then evaporated to give 3-ethyl-6-methyl-5-1,2,4-triazol-1-yl-1H-pyridin-2-one hydrochloride (70 mg) as a cream-orange solid. LC/MS: RT: 1.79 min, MS: m/e=205 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([N:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:7]=1.C(OCC)(=O)C>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH:10]2[CH2:11][CH2:12]2)[CH3:9])[C:5]([NH2:13])=[CH:4][C:3]=1[F:16]
Reactant: CN(c1cc(Cl)c(F)cc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1cc(Cl)c(F)cc1N)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.8 %

Procedure:
To a solution of 400 mg (16.35 mmol) (5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-methyl-amine in 4 mL methanol was added 40 mg 10% palladium on activated charcoal (Fluka). The reaction mixture was stirred at room temperature under a hydrogen atmosphere of 1.7 bar for two hours. Ethyl acetate (10 mL) was added and the reaction mixture was filtered over Dicalite® speed plus (Acros) and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give 240 mg (68%) of the title compound as a brown liquid. MS (ESI): m/z=215.075 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.C(=O)(O)[O-].[Na+].[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 80 °C
Yield: 85.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (290 g, 1058 mmol) in ethanol (1.5 L) was added aqueous ammonium chloride (283 g, 5290 mmol dissolved in 1.5 L water). The resulting mixture was stirred at 80° C. to which iron powder (472 g, 8451 mmol) was added in a portion wise manner. The resulting reaction mixture was heated at 80° C. for 12 h. Upon completion as determined by TLC, the reaction mixture was hot filtered over Celite® and the celite bed was washed with methanol (5 L) followed by washing with 30% MeOH in DCM (5 L). The combined filtrate was concentrated in-vacuo, the residue obtained was diluted with aqueous sodium bicarbonate solution (2 L) and extracted with ethyl acetate (5 L×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (220 g, 85%). The compound was taken directly into the next step. 1H NMR (CDCl3, 400 MHz) δ 7.37 (s, 1H), 6.92 (s, 1H), 3.94 (s, 3H), 3.80 (bs, 2H), 2.31 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C(OCC)C.C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)c(Cl)cc2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)c(Cl)cc2c1N
Temperature: 25 °C

Procedure:
Dissolve 3-nitro-2-carbethoxy-5,6-dichloroindole (38.1 g) in ethanol (1L) and add tin (II) chloride dihydrate (163 g). Warm to between 65° and 75° C. for 4 to 5 hours. Cool to room temperature and pour intoa mixture of ethyl acetate (3L) and water (2L). Add solid potassium carbonate and stir occasionally until the carbon dioxide evolution ceases.Filter through diatomaceous earth and separate the organic phase of the filtrate. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [Li:1].C1([P:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]2[CH3:16])C=CC=CC=1>O1CCCC1>[Li:1].[CH3:16][C:9]1[PH:8][C:12]([CH3:13])=[C:11]([CH3:14])[C:10]=1[CH3:15]
Reactant: Cc1c(C)c(C)p(-c2ccccc2)c1C
Agent: [Li]
Solvent: C1CCOC1
Product: Cc1[pH]c(C)c(C)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Corresponding to the procedure described in Organometallics 7 (1988), 921, 0.52 g (0.074 mole) lithium was added to a solution of 7 g (0.032 mole) of compound 7 in 150 ml tetrahydrofuran (THF) and was stirred overnight. The red solution obtained was filtered through a frit to remove residual solids and the filtrate was cooled to 0° C. Thereafter, a solution of 1.45 g (0.01 mole) AlCl in 20 ml THF was added drop-wise and the solution was brought to room temperature. An aliquot portion was taken for analysis and the remaining solution was used directly for the preparation of compound 9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br.Br.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25](CC3C=CC(F)=CC=3)[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[NH:25][C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1
Reactant: Clc1ncccn1
Reactant: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2[nH]c(NC3CCN(CCNc4ncccn4)CC3)nc2c1

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 9.66 parts of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-5-ol trihydrobromide, 5 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and methanol, yielding 5.2 parts (83%) of 1-[(4-fluorophenyl)methyl[-2-[[1-[2-(2-pyrimidinylamino)-ethyl]-4-piperidinyl]amino]-1H-benzimidazol-5-ol; mp. 194.4° C. (compound 64).
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:10]=3[CH:9]=2)[CH2:4][C@@H:3]1[CH3:19].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:18][O:17][C:16]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][N:2]=[C:3]([CH3:19])[CH2:4]3)[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc2sc([C@H]3CCN(Cl)[C@@H](C)C3)cc12
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2sc(C3CCN=C(C)C3)cc12
Reaction time: 17 h
Yield: 111.8 %

Procedure:
A solution of the crude cis-(±)-N-chloro-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (2.348 g, 7.93 mmol) in THF (80 mL) was treated with DBU (1.18 mL, 7.93 mmol). After stirring 17 h, the DBU salt was filtered off through a sintered funnel, rinsed with Et2O, and the filtrate was concentrated under reduced pressure to give 4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-3,4,5,6-tetrahydropyridine as a golden oil (2.3 g, 99%) that was immediately used in the next step.
Reaction SMILES: OO.[S:3](=[O:7])(=[O:6])([OH:5])[OH:4].[OH-].[Al+3:9].[OH-].[OH-]>O>[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[Al+3:9].[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[Al+3:9]
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])[O-]

Procedure:
By advancing the reaction in the presence of a peroxide, such as hydrogen peroxide solution, in the reaction system, a decomposition reaction of the peroxide, (H2O2→H2O+1/2O2↑+98.4 kJ when the peroxide is hydrogen peroxide) is induced during the reaction, and contributes to the elevation of the temperature of the reaction system. Thus, not only can the reaction rate be improved, but also the reaction can be completed without using a heating source. For this reason, the reaction temperature is started from room temperature immediately after charging the starting materials and elevated to about 70 to 110° C. due to the heat of hydration caused by sulfuric acid and water, the reaction heat caused by sulfuric acid and aluminum hydroxide, and the heat of decomposition of hydrogen peroxide solution, and then the resultant reaction mixture is maintained or matured at that temperature, and the thus desired aluminum sulfate can be efficiently obtained.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[N:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].C(OCC)C>ClCCl>[CH:8](=[N:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)(=[O:31])=[O:30])[CH2:21][CH2:22]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1ccccn1)N1CCC(CN=Cc2ccccc2)CC1
Reaction time: 14 h
Yield: 68.4 %

Procedure:
Triethylamine (6.3 ml) was added to a cloudy solution of N-benzylidene-4-piperidylmethylamine (4.05 g) and pyridine-2-sulphonyl chloride (4.0 g) in dichloromethane (100 ml) and the resulting clear yellow solution was stirred for 14 hours. Removal of the solvent under reduced pressure gave a yellow solid which on addition of diethyl ether (100 ml) partly dissolved. The insoluble white solid (triethylamine hydrochloride) was removed by filtration. Evaporation of the filtrate afforded a flocculent yellow solid which recrystallised from ethanol to give 4-[N-(benzylidene)aminomethyl]-1-(2-pyridinesulphonyl)piperidine as a white crystalline solid (4.7 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:14][N:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:23])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Li+].Cl[O:28][C:29](C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO.O1CCCC1>[CH3:29][O:28][C:11]1([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][N:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:23]
Reactant: CC(C)(C)OCl
Reactant: O=C(Cc1ccccc1)N[C@H]1CN(OCc2ccccc2)C1=O
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC1(NC(=O)Cc2ccccc2)CN(OCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-3-[(phenylacetyl)amino]-1-[(phenylmethyl)oxy]-2-azetidinone (1mM; see example 4B) in freshly distilled tetrahydrofuran (10 ml) at -78° C. is added via syringe a solution of lithium methoxide (3mM) in dry methanol (5 ml). After 5 minutes, t-butyl hypochlorite (130 μl) is added and the mixture is stirred at -78° C. for 30 minutes. The reaction mixture is poured into 0.5 M monobasic potassium phosphate buffer and extracted with two 100 ml portions of methylene chloride. The combined organic extracts are dried over sodium sulfate and concentrated to an oily residue. The title compound is isolated by column chromatography as a racemate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2C(O)=O.C(=O)(O)[O-].[Na+].[I-:23].[Na+].II>ClC(Cl)C.O.ClCCl>[I:23][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:17])([F:16])[F:1])[CH:5]=2)[NH:9][N:8]=1
Reactant: [I-]
Reactant: O=C(O)c1n[nH]c2ccc(OC(F)(F)F)cc12
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc2[nH]nc(I)c2c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 66.8 %

Procedure:
To a mixture of 5-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.2 g, 813 μmol), and sodium bicarbonate (225 mg, 104 μL, 2.68 mmol) in dichloroethane (2 mL) and water (2.00 mL) were added in one portion sodium iodide (317 mg, 2.11 mmol) and iodine (268 mg, 1.06 mmol) and the mixture heated at 100° C. (oil bath temperature) with vigorous stirring for 45 minutes. After cooling to 25° C. the mixture was diluted with dichloromethane, then washed with 10% Na2S2O3 and saturated NaHCO3. The organics were dried (MgSO4) and concentrated to an off-white solid which was dissolved in dichloromethane, cyclohexane added to promote solid formation, and allowed to stand. The solid was separated by filtration and dried to give 3-iodo-5-(trifluoromethoxy)-1H-indazole (178 mg, 543 μmol, 67%) as white needles. MS (M−H)−=326.8; 1H NMR (CDCl3) δ: 7.51 (d, J=9.1 Hz, 1H), 7.40 (s, 1H), 7.32-7.38 (m, 1H).
Reaction SMILES: F[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].CCN(C(C)C)C(C)C.[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=2)[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH:31][C:2]3[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=3)[C:5]#[N:6])[CH:27]=2)[CH2:25][CH2:24]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.8 %

Procedure:
To a solution of 3,5-difluoro-2-nitrobenzonitrile (Method 99, 5.8 g, 31.5 mmol) and DIEA (5.5 ml, 31.5 mmol) in THF (50 ml) was added drop wise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (4.66 g, 37.8 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 20 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (DCM-EtOAc=10:1) to give the title compound as a yellow solid (5.5 g, 61%). 1H NMR (400 MHz) 12.43 (s, 1H), 9.70 (s, 1H), 8.22 (dd, J=11.2 and 2.0 Hz, 1H), 7.51 (d, J=5.2 Hz, 1H), 5.92 (s, 1H), 1.90 (m, 1H), 0.95 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 287; Found: [M+H]+ 288.
Reaction SMILES: C([O:5][C:6]([CH:8]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:9]([NH:11][CH:12]1[C:35](=[O:36])[N:14]2[C:15]([C:28]([O:30]C(C)(C)C)=[O:29])=[C:16]([CH:19]=[CH:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:17][S:18][C@H:13]12)=[O:10])=[O:7])(C)(C)C.NC1C(=O)N2C(C(OC(C)(C)C)=O)=C(C=CC(OC(C)(C)C)=O)CS[C@H]12.CC1C=CC(S(O)(=O)=O)=CC=1>>[C:6]([CH:8]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:9]([NH:11][CH:12]1[C:35](=[O:36])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])[CH2:17][S:18][C@H:13]12)=[O:10])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(C(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Agent: CC(C)(C)OC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(O)C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccccc3)[C@H]2SC1

Procedure:
In a manner similar to the procedure described in Example 21, the titled acid compound was prepared from tert-butyl 7-(2'-tert-butoxycarbonyl-2'-phenylacetamido)-3-(2'-tert-butoxycarbonylvinyl)-3-cephem-4-carboxylate, which ester was prepared by acylating tert-butyl 7-amino-3-(2'-tert-butoxycarbonylvinyl)-3-cephem-4-carboxylate-p-toluene sulfonate as described in Example 6.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([N:32]([CH2:36][CH3:37])[C:33]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[CH:21][CH:20]=3)=[O:23])[CH2:25][CH2:26]1)=[O:34])[CH3:31]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and N,N-diethylcarbamoyl chloride. Off-white solid. MS (m/z): 470.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[OH:18].[CH2:19](I)[CH3:20]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:18][CH2:19][CH3:20]
Reactant: CCI
Reactant: COC(C)(OC)c1cc(Br)c(O)c(C(C)(C)C)c1
Product: CCOc1c(Br)cc(C(C)(OC)OC)cc1C(C)(C)C

Procedure:
2-Bromo-6-tert-butyl-4-(1,1-dimethoxyethyl)phenol (20 g; for synthesis see CA02515715) was alkylated with ethyl iodide analogously to the conditions of O4.070. 19.67 g of the title compound were obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](CC3C=CC=CC=3)[C:16]([CH2:28][NH:29][O:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[N:15][C:14]=2[N:13]([CH3:37])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:38])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:28][NH:29][O:30][C:31](=[O:36])[C:32]([F:35])([F:33])[F:34])=[N:15][C:14]=2[N:13]([CH3:37])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CNOC(=O)C(F)(F)F)n2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(CNOC(=O)C(F)(F)F)nc2n(C)c1=O
Yield: 82 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methyl-8-(N-(trifluoroacetoxy)aminomethyl)xanthine (1.0 g, 1.9 mmol) and 10% palladium on carbon (50% water, 300 mg) in glacial acetic acid (50 ml) was treated with hydrogen gas (80 psi) on a Parr sharker at room temperature for 18 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-methyl-8-(N-(trifluoroacetoxy)aminomethyl)xanthine (700 mg, 85% yield) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:8](=[O:22])[N:9]2[CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:14][CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[N:6]=[C:7]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:8]1=[O:22]
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)c(C(C)(C)C)nc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1nc2ccc(Br)cc2n(CCN)c1=O

Procedure:
tert-butyl 2-(7-bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethylcarbamate (360 mg, 0.85 mmol), the compound of formula (a), prepared as described in Example 3B, was dissolved in dioxane (1 mL) and reacted with 4N hydrochloric acid in dioxane (1 mL) at room temperature for 3 days. The solution was concentrated to provide 1-(2-aminoethyl)-7-bromo-3-tert-butylquinoxalin-2(1H)-one hydrochloride as a tan solid. This solid was dissolved in chloroform (8 mL), and acetoxyacetyl chloride (0.107 mL) and triethylamine (0.5 mL) were added in small portions over a period of 3 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting 2-(2-(7-bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethylamino)-2-oxoethyl acetate (b) was crystallized from methanol, then taken up in ethyl acetate (10 mL) and washed 3 times with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure to provide 280 mg of 2-(2-(7-bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethylamino)-2-oxoethyl acetate as an oil that crystallized upon standing into a white solid.