Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+:18].[Na+].[Na+].[Na+].[Na+].Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:32]=[C:33]([C:40]([O-:42])=[O:41])[CH:34]=[C:35]([CH:39]=2)[C:36]([O-:38])=[O:37])[N:27]=[C:26]([NH:43][C:44]2[CH:45]=[C:46]([C:53]([O-:55])=[O:54])[CH:47]=[C:48]([CH:52]=2)[C:49]([O-:51])=[O:50])[N:25]=1>O.[OH-].[Na+]>[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Na+:18].[N:25]1[C:24]([NH:1][C:2]2[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=2)[C:7]([O-:9])=[O:8])=[N:29][C:28]([NH:30][C:31]2[CH:32]=[C:33]([C:40]([O-:42])=[O:41])[CH:34]=[C:35]([CH:39]=2)[C:36]([O-:38])=[O:37])=[N:27][C:26]=1[NH:43][C:44]1[CH:52]=[C:48]([C:49]([O-:51])=[O:50])[CH:47]=[C:46]([CH:45]=1)[C:53]([O-:55])=[O:54]
Reactant: O=C([O-])c1cc(Nc2nc(Cl)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(Nc2nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1

Procedure:
To a stirred solution of 3.62 g of 5-aminoisophthalic acid and 1.85 g of sodium bicarbonate in 80 ml of water plus 7.8 ml of 5N sodium hydroxide is added 11.24 g of crude 5,5'-[6-chloro-s-triazine-2,4-diyl)diimino]diisophthalic acid tetrasodium salt (prepared as described in Example 2). The reaction mixture is refluxed for 15 hours, then is filtered. The filtrate is diluted with 100 ml of absolute ethanol to give a precipitate. The precipitate is collected by filtration and is washed with (8:10) aqueous ethanol, 75% aqueous ethanol, ethanol and ether to give 14.2 g of crude product. The product is warmed with 80 ml of water and 0.1 ml of 5N sodium hydroxide is added to achieve pH 9. The mixture is filtered through diatomaceous earth and the filtrate is diluted with 100 ml of absolute ethanol with formation of a thick paste on stirring. The paste is filtered, stirred in absolute ethanol and filtered again, then is washed with ether and dried by conventional means to give a 9.9 g of a colorless powder as the product of the example.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]1([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC1CCCC1
Yield: 46.8 %

Procedure:
2-Nitrophenol (83.5 g, 0.60 mole), cyclopentyl bromide (98.0 g, 0.66 mole), anhydrous potassium carbonate (82.9 g, 0.60 mole) and dry acetone (600 cc) were refluxed for 72 hours, and filtered to remove the potassium bromide. The residue was washed with acetone and the solvent was removed by rotary evaporation. The residue was partitioned between 200 cc of dichloromethane and water. The dichloromethane layer was washed with 200 cc of 10% potassium hydroxide, separated and the solvent was removed by rotary evaporation. The crude product was fractionally distilled at 144°-146° C. at 1.0 mm. Hg to yield 58.2 g of product (46.8%).
Reaction SMILES: O.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:23]C)C=C4)N(CC2)C1.[CH2:60]([O:62][C:63](=[O:77])[C:64]1[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:73])[CH3:72])=[C:66](CC=C)[CH:65]=1)[CH3:61].S([O-])([O-])=O.[Na+].[Na+].[C:84]([OH:88])(C)([CH3:86])[CH3:85]>>[CH2:60]([O:62][C:63](=[O:77])[C:64]1[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:73])[CH3:72])=[C:66]([CH2:85][CH:84]([OH:88])[CH2:86][OH:23])[CH:65]=1)[CH3:61]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CCc1cc(C(=O)OCC)ccc1NC(C)=O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(NC(C)=O)c(CC(O)CO)c1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 66 %

Procedure:
To a solution of 1:1 water and tert-butanol (10 mL), AD-mix-α (Aldrich, 1.4 g) was added and the mixture stirred for 0.1 h. The mixture had two layers; the lower layer was yellow in color. To this mixture, ethyl-4-acetylamino-3-allylbenzoate (0.1 g, 0.0004 mol) was added in one portion and stirred at room temperature for 48 h. The reaction mixture was cooled to 0° C. and sodium sulphite (1.5 g, 0.0119 mol) was added. The reaction was stirred at 0° C. for 0.3 h and then at room temperature for 0.5 h. It was extracted with ethyl acetate (3×15 mL), the combined organic layers were dried over sodium sulphate, filtered, and concentrated. The residue was passed through a column of silica gel eluting first with 1:1 ethyl acetate:hexane to recover the starting material, and then with pure ethyl acetate to give 0.075 g (66%) of ethyl-4-acetylamino-3-(2',3'-dihydroxypropyl)benzoate (isomer A) as a white powder, mp 114°-116° C. The optical rotation of this solid was 0° at 589 nm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>[OH-].[Na+]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Br)cc1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-bromobenzenesulphonyl chloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous ethanol, had a melting point of 115°-116° C.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 12 g methyl acetoacetate, 4.3 g of NaH 60% dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane, 10 g of iso-valerophenone, and 300 mL of tetrahydrofuran.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:27]=[CH:26][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:7]=1)CCC.Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[N+:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][N:15]3[CH:23]=[CH:24][CH:25]=[C:14]3[CH2:13]2)=[O:11])=[CH:26][CH:27]=1)([O-:45])=[O:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2[N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Yield: 56.4 %

Procedure:
A mixture of 3.0 g of 10,11-dihydro-10-[4-(tributylstannyl)benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 200 mg of tetrakis(triphenylphosphine)palladium(O) and 2.0 g of 1-bromo-2-nitrobenzene in 200 ml of toluene is refluxed for 16 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 1.2 g of the desired product as a solid. Mass spectrum: M+H:410.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=O)[CH:8]=O.[CH2:15]([NH2:18])[CH2:16][NH2:17].[BH4-].[Na+].O>C(O)C.O1CCOCC1>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH:7]1[CH2:8][NH:18][CH2:15][CH2:16][NH:17]1
Reactant: NCCN
Reactant: Cc1c(C(=O)C=O)sc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Cc1c(C2CNCCN2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5 g portion of the above aldehyde was dissolved in a mixture of 100 ml of ethanol and 10 ml of dioxane. To this mixture, in an ice bath was added a solution of 1.61 g of ethylenediamine in ethanol. The mixture was stirred for one hour at room temperature, recooled to 0°-5° C. and 2.04 g of sodium borohydride added. The mixture was stored at room temperature overnight, water was added and all the solvents were removed. The residue was extracted with dichloromethane, water washed, dried, filtered and evaporated. This residue was purified by flash column chromatography, eluting with chloroform:-methanol (9:1), giving 2.39 g of 2-(3-methylbenzo[b]-thien-2-yl)piperazine.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])C.C1(=O)C2CCCCCC=2C=CC1.[H-].[Na+]>O1CCCC1>[C:7]1([CH2:6][C:4]([OH:5])=[O:3])[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1cccc2c1CCCCC2
Agent: O=C1CC=CC2=C1CCCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc2c1CCCCC2

Procedure:
(Benzocyclohept-1-en-1-yl)-acetic acid was prepared from 1-ethoxycarbonylmethylbenzocyclohept-1-ene, which was itself prepared from benzocycloheptan-1-one treated with ##STR11## and NaH in tetrahydrofuran, followed by separation of the two exocyclic unsaturated cis- and trans-isomers also formed, the separation being carried out by flash chromatography on silica gel with toluene as eluant.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Xe](F)[F:29]>C(#N)C.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])=[C:21]([F:29])[N:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: F[Xe]F
Reactant: CC(C)C(=O)c1cnc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)C(=O)c1[nH]c(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1F
Yield: 13.2 %

Procedure:
To a solution (13 mL) of 1-(2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)-2-methylpropan-1-one (0.507 g) in acetonitrile was added xenon difluoride (0.440 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60, volume ratio) and recrystallized from diethyl ether-hexane to give the title compound (0.07 g, yield 13%) as colorless crystals. melting point 161-162° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[F:15][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1cnc(-c2ccc(Cl)cc2F)cn1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.2 %

Procedure:
To a nitrogen sparged flask containing 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine (34.0 g, 152 mmol), 2-methylsulfonylphenylboronic acid (38.0 g, 190 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (2.39 g, 3.0 mmol) were added sparged THF (300 mL) and K3PO4(aq) (608 mL, 0.5 M). The mixture was stirred for 15 hours at rt and then concentrated under reduced pressure to remove the THF. The remaining portion was treated with toluene (325 mL) and THF (25 mL). The biphasic slurry was stirred for 20 h at rt and then filtered and the isolated solid washed with water (150 mL) and toluene (150 mL). The filter cake was dried to provide the title compound (47.1 g, 90%). MS (ESI): mass calcd. for C17H14FN3O2S, 343.08; m/z found, 344.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J=2.4, 1.5, 1H), 8.12 (dd, J=7.9, 1.4, 1H), 8.04 (d, J=1.5, 1H), 7.93 (m, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.48 (dd, J=7.6, 1.4, 1H), 7.37 (dd, J=12.3, 1.7, 1H), 7.32 (dd, J=8.1, 1.7, 1H), 6.76 (s, 2H), 2.95 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][CH:21]([N:23]([CH2:32][CH3:33])[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:22]>ClCCl.CO>[ClH:1].[CH3:22][CH:21]([N:23]([CH2:32][CH3:33])[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1)[CH3:20]
Reactant: CCN(CCC1CCCNC1)C(C)C
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CCN(CCC1CCCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1)C(C)C
Product: Cl
Yield: 43 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(methylethylethylamino)ethyl]piperidine in a yield of 43% of theory. Colourless crystals, m.p. 228°-230° C., Rf 0.39 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C1C=C(C(C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(O[Si](C)(C)C)C2CCCN2)C=C(C(F)(F)F)C=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[NH:62]1[CH:66]=[CH:65][CH:64]=[N:63]1>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([N:62]2[CH:66]=[CH:65][CH:64]=[N:63]2)[CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cn[nH]c1
Reactant: O=C/C=C/C1CCCCC1
Agent: C[Si](C)(C)OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=CCC(C1CCCCC1)n1cccn1
Reaction time: 72 h

Procedure:
A solution of (E)-3-cyclohexylacrylaldehyde (4.94 g) (made according to Organic Letters (2011), 13(1), 70-73), 2-(bis(3,5-bis(trifluoromethyl)phenyl)-(trimethylsilyloxy)methyl)pyrrolidine (0.712 g) and 4-nitrobenzoic acid (0.124 mL) in toluene (60 mL) was stirred at room temperature for 10 minutes and 1H-pyrazole (1.622 g) was added. The reaction mixture was stirred for 3 days, and purified by flash chromotography (silica gel, 0-50% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([OH:17])=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:29]1([C:34]2[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]3[CH:47]=[CH:46][C:45]([O:48][C:49]([F:52])([F:51])[F:50])=[CH:44][CH:43]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2([C:15]([NH:41][CH2:40][C:38]3[CH:37]=[C:36]([C:42]4[CH:43]=[CH:44][C:45]([O:48][C:49]([F:52])([F:50])[F:51])=[CH:46][CH:47]=4)[N:35]=[C:34]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:39]=3)=[O:17])[CH2:13][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Reactant: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
Acid 15C (260 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC (1.1 equiv, 0.17 ml) and [2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27C (1.1 equiv., 371 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in EtOAc (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded 130 mg of a white solid. Yield=22% 1HNMR (DMSO, 200 MHz) δ 0.71 (2H, bm), 1.08 (2H, bm), 1.92 (4H, m), 3.47 (4H, m), 4.29 (2H, d, J=5.6 Hz), 6.41 (1H, s), 7.09 (1H, s), 7.45 (4H, m), 7.82 (2H, m), 8.17 (2H, d, J=9 Hz), 8.38 (1H, t), 8.71 (1H, bs) [M+1] 579.4 (C27H26F4N4O4S requires 578.58).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35](O)=[O:36])[N:30]=[CH:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:35](=[O:36])[CH2:34][CH2:33][C:31]4[N:30]=[CH:29][NH:28][CH:32]=4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.00028 mol), 3-(1H-4-imidazolyl)propanoic acid (0.050 g, 0.00035 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0068 g, 0.00035 mol), N,N-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.038 g, 0.00028 mol) in anhydrous N,N-dimethylfornamide (13 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(1H-4-imidazolyl)-1-propanone (0.040 g, 0.00008 mol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[Cl:9][C:10]1[C:15]([NH2:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(CC)CC)C>O>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:15]=1[NH2:16]
Reactant: NCc1ccccn1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c(Cl)ncnc1NCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 3.7 parts of 2-pyridinemethanamine, 4.1 parts of 4,6-dichloropyrimidin-5-amine, 3.03 parts of N,N-diethylethanamine and 150 parts of water was stirred for 8 hours at room temperature. After cooling, the whole was stirred overnight. The product was filtered off, washed with water and dried overnight in vacuo at 80° C., yielding 5.35 parts (90.8%) of 6-chloro-N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine; mp. 140.3° C. (interm. 1).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[C:10]([NH:13][CH3:14])[NH:11][N:12]=[C:6]2[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]1=[O:23])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[C:10]([NH:13][CH3:14])[N:11]([CH3:26])[N:12]=[C:6]2[N:5]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]1=[O:23])[CH3:2]
Reactant: CCn1c(=O)c2c(NC)[nH]nc2n(Cc2ccc(C)cc2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(=O)c2c(NC)n(C)nc2n(Cc2ccc(C)cc2)c1=O
Temperature: 60 °C
Reaction time: 30 h

Procedure:
A mixture of 5-ethyl-3-methylamino-7-(4-methylbenzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.5 g, 1.6 mM), methyl iodide (0,46 g, 3.2 mM) and potassium carbonate (0,45 g, 3.2 mM) in DMF (8 ml) was stirred at 60° C. for 30 hours.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([NH2:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](O)=[O:28])=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:27]([C:23]2[C:24]([CH3:26])=[N:25][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:21][CH:22]=2)=[O:28])[CH:4]=1)[CH3:2]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CCc1cn(N)c2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2cnccc12
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A mixture of 3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine (93 mg, 0.577 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (134 mg, 0.757 mmol), HATU (263 mg, 0.692 mmol) and DIPEA (223 mg, 1.73 mmol) in DMF (3 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in heptane to afford 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (86 mg). MS: 376 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H), 8.15-8.26 (m, 2H), 7.70 (d, 1H), 7.55 (q, 1H), 7.49 (s, 1H), 7.29 (t, 1H), 2.80-2.90 (m, 5 H), 1.38 (t, 3H). IC50=7 nM.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(OC)C=CC=CC=1.C([NH:35][C:36]1[S:37][CH:38]=[C:39](/[C:41](=[N:69]/[O:70][CH2:71][C:72]([O:74]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:73])/[C:42]([NH:44][C@@H:45]2[C:67](=[O:68])[N:47]3[C:48]([C:55]([O:57]CC4C=CC(OC)=CC=4)=[S:56])=[C:49]([CH2:52][CH2:53][OH:54])[CH2:50][S:51][C@H:46]23)=[O:43])[N:40]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:35][C:36]1[S:37][CH:38]=[C:39](/[C:41](=[N:69]/[O:70][CH2:71][C:72]([OH:74])=[O:73])/[C:42]([NH:44][C@@H:45]2[C:67](=[O:68])[N:47]3[C:48]([C:55]([OH:57])=[S:56])=[C:49]([CH2:52][CH2:53][OH:54])[CH2:50][S:51][C@H:46]23)=[O:43])[N:40]=1
Reactant: COc1ccc(COC(=S)C2=C(CCO)CS[C@@H]3[C@H](NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CCO)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
(d-2) To a mixture of trifluoroacetic acid (4 ml) and anisole (0.8 ml) was added under ice-cooling 360 mg (0.349 mM) of p-methoxybenzyl 7β-{α-(2-tritylaminothiazole-4-yl)-α-[(Z)-benzhydryloxycarbonylmethoxyimino]acetamido}-3-(2-hydroxy)ethylthio-3-cephem-4-carboxylate, and the mixture was stirred for one hour. The reaction mixture was added slowly dropwise to a mixture of diethyl ether and petroleum ether (1:2, 50 ml), thecrystals which formed were collected by filtration to give 188 mg of 7β-{α-(2-aminothiazole-4-yl)-α-[(Z)-carboxymethoxyimino]acetamido}-3-(2-hydroxy)ethylthio-3-cephem-4-carboxylic acid trifluoroacetate. The crystals and 77 mg (0.917 mM) of sodium bicarbonate were dissolved in 5 ml of water, and the solution was applied to a Sephadex HL-20 column chromatography (eluent: water) to give 164 mg of 7β-{α-(2-aminothiazole-4-yl)-α-[(Z)-carboxymethoxyimino]acetamido}-3-2-hydroxy)ethylthio-3-cephem-4-carboxylic acid sodium salt.