Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[N+:18]([O-])([OH:20])=[O:19].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCC2(CC1)CC(=O)c1ccccc1O2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCC2(CC1)CC(=O)c1cc([N+](=O)[O-])ccc1O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Sulfuric acid (55 ml) was cooled to 0° C. and was stirred as 3,4-dihydro-1'-methyl-spiro[2H-1-benzopyran-2,4'-piperidin]-4-one (11.56 g, 0.05 mol) was added over 20 minutes. Some gum separated. A solution of 90% nitric acid (2.5 ml, 0.0525 mol) in sulfuric acid (5 ml) was added over 20 minutes. The mixture was stirred for 2 hours at 0° C. and then for 1 hour at room temperature. A solution resulted but nitration was not complete. 90% Nitric acid (0.3 ml, 0.007 mol) was added and stirring was continued for 11/2 hours at room temperature. The reaction solution was poured into a mixture of ice, ethyl acetate, and sodium bicarbonate (210 g). The basic mixture was filtered, the ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (150 ml). The combined ethyl acetate extracts were washed with saturated NaCl, dried, filtered and concentrated in vacuo to yield 10.6 g (77%) of product
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[Br:4])[CH3:3]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Iodoethane (3.7 ml) was added to a mixture of 2-bromo-4-nitrophenol (4 g) and potassium carbonate (5.1 g) in N,N dimethylformamide (20 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water (300 ml) and ethyl acetate. After extraction with EtOAc. the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5 increasing to 90:10) to give the title compound as an oil (3.4 g). 1H NMR (250 MHz, CDCl3) δ 1.54 (3H, t, J=9.1 Hz), 4.21 (2H, q, J=7 Hz), 6.93 (1H, d, J=9.1 Hz), 8.19 (1H, dd, J=9.1, 2.7 Hz), and 8.47 (1H, d, J=2.7 Hz).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1(C(O)=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O>[C:10]1([C:1]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C(O)c1ccccc1
Solvent: O
Product: O=C(c1ccccc1)C1CCCCC1

Procedure:
A mixture of 11.5 g/h of benzoic acid, 36 g/h of cyclohexanecarboxylic acid and 13 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 450° C., over 100 ml of a catalyst which contained 2% by weight of potassium oxide, the remainder being anatase. The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of benzoic acid was 98%. The selectivity with respect to cyclohexyl phenyl ketone was 60%.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:15]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[CH:14][CH:13]=[C:12]([F:21])[C:9]=1[CH:10]=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.[Cl-].[Na+].O>[Cl:7][C:8]1[C:9]([CH:10]=[CH:1][CH3:2])=[C:12]([F:21])[CH:13]=[CH:14][C:15]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1c(F)ccc(C2OCCO2)c1Cl
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC=Cc1c(F)ccc(C2OCCO2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of ethyltriphenylphosphonium bromide (3.43 g) in tetrahydrofuran (15 mL) was added potassium tert-butoxide (1.31 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Successively, 2-chloro-3-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (1.35 g) was added to the mixture, and the mixture was stirred for 2.5 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 2-{2-chloro-4-fluoro-3-[prop-1-en-1-yl]phenyl}-1,3-dioxolane (1.41 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH2:27][CH2:28]OS(C)(=O)=O)[C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])[C:12]([N+:21]([O-:23])=[O:22])=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])(=O)=O.[Li+].[Br-:35].[Na+].[Br-:37]>CN(C=O)C>[Br:35][CH2:6][CH2:7][N:8]([CH2:27][CH2:28][Br:37])[C:9]1[C:10]([N+:24]([O-:26])=[O:25])=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[C:13]([CH:14]=1)[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16]
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cc(N(CCBr)CCBr)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 9a (1.80 g, 3.50 mmol) and LiBr (0.43 g, 4.95 mmol) in DMF (5 mL) was stirred at 60° C. for 2 h. The reaction was then poured into saturated NaBr solution and extracted with EtOAc (2×). The combined extracts were washed with saturated NaBr solution, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc, to give 5-[bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-2,4-dinitrobenzamide (10a) (0.78 g, 46%):
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:2]1.Cl.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C@@H:31]([N:33]2[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]2)[CH3:32])[CH2:26][CH2:25]1>>[OH:39][CH:36]1[CH2:35][CH2:34][N:33]([C@@H:31]([CH3:32])[CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:29][CH2:28]2)[CH2:38][CH2:37]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4ccoc4)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid, 95 (see example 36) and amine 50.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH3:20])=[N:6][CH:5]=1)([O-:3])=[O:2]>C(O)C>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH:20]=[CH:7][N:8]([CH3:9])[CH3:4])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ncc([N+](=O)[O-])n1CCOC(=O)c1ccccc1
Solvent: CCO
Product: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCOC(=O)c1ccccc1

Procedure:
27.5 g. (0.1 mole) of 5-nitro-2-methyl-1-(2-benzoyloxyethyl)-imidazole was reacted as indicated in Example 1. After cooling, the reaction solution was mixed with ethanol, and the precipitate was vacuum-filtered; m.p. 153°-154° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(CO)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCOc1ccc(COc2ccc(C(=O)OCC)cc2)cc1
Yield: 84.6 %

Procedure:
In 20 ml of benzene were dissolved 2.2 g of 4-heptyloxybenzyl alcohol and 1.7 g of ethyl 4-hydroxybenzoate, 1.8 g of diethyl azodicarboxylate and 2.6 g of triphenylphosphine were added to the solution, and a reaction was carried out with stirring. The reaction liquid was concentrated and the concentrate was separated and purified by the silica gel chromatography to obtain 3.1 g of ethyl 4-(4'-heptyloxybenzyloxy)benzoate. This ester was dissolved in 20 ml of ethanol and 4.2 ml of a 2N aqueous KOH solution was added to the solution to effect the hydrolysis. The reaction mixture was treated by customary procedures to obtain 2.7 g of 4-(4'heptyloxybenzyloxy)benzoic acid.
Reaction SMILES: S1(C2C(=CC=CC=2)C(=O)[NH:4]1)(=O)=O.[CH3:13]/[C:14](/O)=[CH:15]/[C:16]([CH3:18])=O.[CH3:20]/[C:21](/O)=[CH:22]/[C:23](C)=O.C/C(/O)=C/C(C)=O.[Fe]>C(OCCCO)(=O)C(C)=C.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Co+2]>[NH:4]1[C:18]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(=O)/C=C(/C)O
Agent: [Co+2]
Agent: [Fe]
Agent: C=C(C)C(=O)OCCCO
Product: c1ccc2c(c1)CCCN2

Procedure:
An adhesive formulation prepared and tested as in Example 1 containing hydroxypropyl methacrylate (8.15 g), saccharin (0.5 g), 0.1% cobalt naphthenate in hydroxypropyl methacrylate (1 g), 0.1% iron (III) acetylacetonate in hydroxypropyl methacrylate (0.25 g) and 1,2,3,4 tetrahydroquinoline (0.5 g) gave bond strengths of 3.3N/mm2 after 24 hours following air activation for 5 minutes.
Reaction SMILES: [Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1Br
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O

Procedure:
28 g (68 mmol) of ethyl 2-(2-bromo-3,4,5,6-tetrafluoro-benzoyl)-3-cyclopropylamino-acrylate are heated under reflux in 88 ml of dimethylformamide with 6.9 g (164 mmol) of sodium fluoride for 6 hours. After cooling, the mixture is poured into water and the precipitate (red) which has separated out is filtered off with suction, washed with a large quantity of water and dried at 80° C. in a circulating air cabinet.
Reaction SMILES: N[C:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH:3][C:4]#[N:5].[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>O1CCOCC1>[NH2:5][C:4]1[NH:16][C:14](=[S:15])[C:13]([C:11]#[N:12])=[C:2]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[CH:3]=1
Reactant: N#CCC(N)=S
Reactant: N#CC=C(N)c1ccco1
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccco2)cc(N)[nH]c1=S
Yield: 17 %

Procedure:
Following the method of Elnagdi and Erian (Arch. Pharm. 1991, 324, 853-858), to a stirred solution of 5.00 g (37.3 mmol) (E or Z)-3-amino-3-furan-2-yl-acrylonitrile in 50 ml dioxane at room temperature was added 7.46 (74.5 mmol) 2-cyanothioacetamide and the reaction mixture heated at reflux for 72 hours. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) afforded 1.40 g (17%) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3-carbonitrile as an orange crystalline solid, ES-MS m/e (%): 218 (M+H+, 100), and 0.46 g (6%) 2,6-diamino-4-furan-2-yl-nicotinonitrile as an orange crystalline solid, ES-MS m/e (%): 201 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1
Reactant: OCc1cc2cc(Br)ccc2o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCc1cc2cc(-c3cnccn3)ccc2o1
Temperature: 95 °C

Procedure:
To a solution of (5-bromo-benzofuran-2-yl)-methanol (1 g, 4.4 mmol) and 2-tributylstannylpyrazine (1.6 g, 3.7 mmol) in 15 mL toluene at room temperature under argon, was added tetrakis(triphenylphosphine)palladium (0) (130 mg), and the mixture was heated at 95° C. overnight. The precipitate was allowed to cooled, extracted with ethyl acetate, washed with brine and dried over MgSO4. Filtration afforded 2.1 g of crude product that was further purified by chromatography to afford (5-pyrazin-2-yl-benzofuran-2-yl)-methanol.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cccc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a suspension of 5.86 g of magnesium in 25 ml of THF is slowly added a solution of 42.16 g of 1-bromo-3-fluorobenzene in 100 ml of THF so as to reach and then maintain reflux of the THF, and the mixture is left at reflux for 1 hour with stirring. After cooling to rt, a solution of 38 g of 1-benzyl-4-piperidinone in 175 ml of THF is then added dropwise and the mixture is refluxed for 1 hour. After cooling to rt, the reaction mixture is poured into ice and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 38 g of the expected product are obtained after crystallization from cyclohexane.
Reaction SMILES: C1(N2CCC3(CCNC3)C2)CC1.C(O)(C(F)(F)F)=O.[F:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]3)[CH2:23][CH2:22]1>C(Cl)Cl>[F:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C@H:34]([NH2:38])[CH2:33][CH2:32][CH2:31]3)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CN3CCC(F)CC3)ccc21
Agent: C1CC2(CCN(C3CC3)C2)CN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCc2cc(CN3CCC(F)CC3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (2.0 g, 5.633 mmol, 1.0 eq.), 4-fluoropiperidine.HCl (0.78 g, 5.633 mmol, 1.0 eq.) and K2CO3 (2.33 g, 16.9 mmol, 3.0 eq.) in THF (25 ml) was heated at reflux for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml), washed with water (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 40% ethyl acetate/hexanes) to yield the title compound as a light yellow solid. Yield: 60% (1.22 g, 3.37 mmol) 2. TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (325 mg, 0.898 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 4 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was employed in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:37][O:38][NH2:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:39][O:38][CH3:37])=[O:19])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CONC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a dichloromethane (6 ml) suspension of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added N-methylmorpholine (77.7 μl, 0.708 mmol), O-methylhydroxylamine hydrochloride (23.6 mg, 0.283 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.3 mg, 0.283 mmol). The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added tetrahydrofuran (1 ml). After stirring at room temperature for 18 hours, the reaction mixture was diluted with dichloromethane. The diluted mixture was washed with water and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated to give a white solid. The resulting solid was washed with ethyl acetate to give the title compound (55.1 mg, 0.122 mmol, 52%) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH3:9])[CH2:4][N:3]1[CH2:10][C:11]1[N:15]([CH2:16][C:17]([OH:19])=O)[CH:14]=[N:13][CH:12]=1.C(N(CC)CC)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:27]([NH:34][C:17](=[O:19])[CH2:16][N:15]1[C:11]([CH2:10][N:3]2[CH2:4][CH:5]([CH2:7][CH2:8][CH3:9])[CH2:6][C:2]2=[O:1])=[CH:12][N:13]=[CH:14]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: CCCC1CC(=O)N(Cc2cncn2CC(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(Cc2cncn2CC(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
In a 10 ml, three necked flask fitted with a magnetic stirrer, under inert atmosphere, {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic acid x50 (0.1 g, 0.33 mmol) is dissolved in DMF (1 ml). Triethylamine (0.1 ml, 0.66 mmol), benzylamine (37 μl, 0.33 mmol) and TBTU (0.16 g, 0.33 mmol) are added and the mixture is stirred for 0.5 h at room temperature. An additional amount of benzylamine (0.0165 mmol) is added and stirring is continued overnight. The solvent is evaporated and the residue is purified by chromatography on silicagel (AcOEt/MeOH/NH4OH: 90/9/1 (v/v/v)). The product is treated with a methanolic solution of HCl and the obtained solid is recrystallized from acetonitrile to afford N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide 124.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH:6]([OH:7])[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)n1CCN1CCC(C(O)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 2.6 parts of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione and 120 parts of methanol are added portionwise 2 parts of sodium borohydride. Upon completion, stirring is continued overnight at room temperature. Water is added and the whole is evaporated. The residue is stirred in water. The solid product is filtered off and crystallized from 2-propanone, yielding 1.2 parts of 3-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 212.8° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16](N1C=CN=C1)([N:18]1C=CN=[CH:19]1)=O.C(N(CC)CC)C.Cl.CNC>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([N:18]([CH3:19])[CH3:16])=[O:15]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
Three grams of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.6 g of carbonyldiimidazole was dissolved in 50 ml of DMF. The solution was stirred for 20 minutes and 2.3 g of triethylamine and 1.8 g of dimethylamine hydrochloride were added to the reaction mixture. The mixture was stirred at room temperature for 3 hours and was poured into ice water. The precipitated solid was collected by filtration and recrystallized from ethanol/water to afford 1.2 g of 5-bromo-1-phenyl-N,N-dimethyl-1H-pyrazole-4-carboxamide. Yield 37%. mp=79°-81° C.
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[N:8]2)=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)=[N:8]2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(-n2nc(-c3ccc(NS(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3)cc2N)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(-c3ccc(NS(=O)(=O)c4ccc(N)cc4)cc3)cc2N)cc1

Procedure:
To a solution of 1-(4-tolyl)-3-(4′-(4-nitrophenyl)sulfonylamino phenyl)-5-aminopyrazole (0.8 g, 1.8 mmol) in EtOAc (30 mL) at room temperature was added 10% Pd-C (0.2 g). The mixture was treated with hydrogen gas at 30 psi for 4 h on a Parr shaker. The mixture was filtered through Celite and the solvent evaporated to yield 1-(4-tolyl)-3-(4′-(4-aminophenyl)sulfonylamino phenyl)-5-aminopyrazole as a solid, which was used without further purification.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[NH:16][C:17]4[C:18]([N:31]=2)=[C:19]2[C:24](=[C:25]5[C:30]=4[CH:29]=[CH:28][CH:27]=[N:26]5)[N:23]=[CH:22][CH:21]=[CH:20]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:35].CO>CN(C)C=O>[CH3:35][N:31]1[C:18]2[C:17](=[C:30]3[C:25](=[C:24]4[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]4)[N:26]=[CH:27][CH:28]=[CH:29]3)[N:16]=[C:15]1[C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CI
Reactant: c1ccc2c(-c3nc4c5cccnc5c5ncccc5c4[nH]3)c3ccccc3cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(-c2c3ccccc3cc3ccccc23)nc2c3cccnc3c3ncccc3c21
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of the 2-(9-anthryl)imidazo[4,5-f]-[1,10]phenanthroline (10 grams) and sodium hydride (11.5 grams) in 300 milliliters of dimethylformamide was stirred at ambient temperature (about 23° C.) for 30 minutes. Into the resulting mixture was added 18.7 grams of iodomethane. The reaction was stirred overnight at room temperature when 100 milliliters of methanol was added. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give the crude product which was further purified by sublimation. The product and its structure was confirmed by proton NMR analysis.