Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-diphenylaminophenyl boronic acid (2.57 g, 8.9 mmol), 4-bromo-iodobenzene (5.03 g, 17.8 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (3.0 g, 22 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 80° C. for about 20 hours. The whole was mixed with water/dichloromethane, the organic phase was collected and washed with brine, dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 30:1). The desired fraction was collected, and concentrated to give a white solid (Compound 12), which was filtered and washed with methanol (2.70 g, in 76% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Solvent: O
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Reaction time: 20 h

Procedure:
A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54 mmol) and N-methyl-piperazine (17 mL) was stirred at room temperature for 6 hours. The reaction mixture was then diluted with water (800 mL) and maintained under magnetic stirring for 20 hours. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 40° C. The title compound was obtained as yellow solid (16.4 g, 94% yield), and was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25](OCC)=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.60 g (1.37 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate, obtained in step 7.5, and 3.40 ml (6.86 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.36 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:22])[C:19]([CH3:21])=[CH2:20].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH3:21][C:19](=[CH2:20])[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)=[O:22]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
71.5 g (0.3 mol) of 4-(6-hydroxy-hexyloxy)-benzoic acid and 101.5 g (1.18 mol) of methacrylic acid were dissolved in 950 ml of chloroform. After the addition of 7.2 g (0.07 mol) of hydroquinone and 7.2 g (0.04 mol) of p-toluenesulphonic acid the batch was boiled under reflux on a water separator for 48 hours. The clear brown solution was subsequently evaporated, the residue was taken up in 1.5 l of diethyl ether, filtered and shaken five time with 300 ml of H2O each time. The organic phase was dried over Na2SO4, evaporated and the residue was recrystallized twice from methanol. After drying at 40° C. in a water-jet vacuum 47.33 g of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoic acid remained behind as a white powder; m.p. 83° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Yield: 95.8 %

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g), potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:20]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 4-(trifluoromethoxy)-benzaldehyde (776 uL, 4.38 mmol) in methylene chloride (30 mL) was added cis-2,6-dimethyl piperazine (1.0 g, 8.77 mmol). After 1 hour sodium triacetoxy borohydride (2.45 g, 8.77 mmol) was added to the mixture. The solution was stirred at room temperature for an additional 4 hours. The reaction was concentrated in vacuo, diluted with ethyl acetate and extracted with 1N HCl (2×50 mL). The aqueous layer was then neutralized with NaOH and extracted with ethyl acetate (3×50 mL). The organic layer was dried (Na2SO4) and concentrated to provide cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine (1.01 g, 80%). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, 2H), 7.23 (d, 2H), 3.54 (s, 2H), 2.98-2.88 (m, 2H), 2.82-2.74 (m, 2H), 1.69 (t, 2H), 1.05 (d, 6H); LCMS 289.5 (M+I)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([O:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=2)[CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:18][C:19]2[N:20]=[C:21]([O:27][CH3:28])[N:22]=[C:23]([O:25][CH3:26])[N:24]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Yield: 83.4 %

Procedure:
A solution of 0.6 gram (0.001 mole) of phenylmethyl 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate in 50 mL of ethanol and 15 mL of acetic acid was hydrogenated in the presence of 5% palladium on charcoal using a Parr hydrogenation apparatus. Upon completion of the hydrogenation, the reaction mixture was filtered through diatomaceous earth. The diatomaceous earth filter cake was washed with tetrahydrofuran. The combined filtrate and wash was concentrated under reduced pressure to a residue. The residue was dissolved in 150 mL of methylene chloride and was washed with two 150 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was stirred in 10 mL of diethyl ether containing a few drops of heptane. The resultant solid was collected by filtration and was washed with cold diethyl ether to yield 0.26 gram of 2-chloro-6-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:21])[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(c1)N(CCN1CCC(NCc3cc4c(cn3)OCCO4)CC1)C(=O)CO2

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methyl-2H-1,4-benzoxazin-3(4H)-one (Intermediate 91), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carb aldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as an oil, 4.7 mg (2%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(Br)c1F
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): 1H-NMR (CDCl3) δ7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M+).
Reaction SMILES: CO.CC(OC[C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12](N)[C:13](=[O:14])N2[C:9]=1C(O)=O)=O.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=[O:23]>O1CCOCC1>[S:16]1[CH:17]=[CH:8][CH:9]=[C:11]1[CH2:12][C:13]([OH:14])=[O:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)Cc1cccs1

Procedure:
A solution of 15 mM of 7 ACA and 400 mM of thienylactic acid in 50% dioxane/50% acetate 50 mM is prepared at a ph 6. The column is thermostatized at 25° C., the flow and volume of the derivative are the same as in example 1. The moveable phase that we use for HPLC is 30% methanol/70% phosphate, 0.067M at a pH of 4.7, the rest of the conditions are maintained like those in example 1. After attaining the balance, the degree of conversion of 7-ACA into cephalothin is above 95%.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13](F)=[CH:12][N:11]=1>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:12][N:11]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cnc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.81 %

Procedure:
To a mixture of 2.0 ml 2,2,2-trifluoroethanol in 35 mL dry DMF was added 1.1 g sodium hydride was added and the mixture was stirred at room temperature for 15 minutes. The resulting solution was added drop wise at −10° C. to a solution of 7 g 2-chloro-4-(3,4-dichloro-phenyl)-5-fluoro-pyrimidine in 50 mL dry DMF during 39 min. The reaction mixture was then stirred at room temperature for 2 h. The resulting brown mixture was partitioned between water and ethyl acetate, the phases were separated the organic phase was dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane:dichloromethane=1:1 to dichloromethane to yield 5.575 g (61.81%) of the title compound as light yellow solid, MS 356.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (65) (58 mg, 0.26 mmol) was coupled to ethyl ester (60) (50 mg, 0.26 mmol) using Method C. The crude residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:31]([N:38]1[CH2:41][CH:40]([C:42](O)=[O:43])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:42]([CH:40]2[CH2:41][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39]2)=[O:43])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)c(Cl)c2)C(=O)N2CCN(c3ccccc3NS(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}azetidinecarboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl) propan-1-one (Example 2, Step 2) (320 mg, 0.67 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (140 mg, 0.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (400 mg, 1.3 mmol), HOAT (96 mg, 0.71 mmol), and DMF (5 mL) (448 mg crude). MS (ESI, pos. ion) m/z: 654 (M+H), (ESI, neg. ion) m/z: 652 (M−H). Calc'd for C29H37Cl2N5O6S: 653.18.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[NH:56][CH2:55][CH2:54][N:53](C(OC(C)(C)C)=O)[CH2:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:56]6[CH2:55][CH2:54][NH:53][CH2:52][C@@H:51]6[CH3:50])[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCNC[C@@H]4C)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (39.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted magnetic stir bar. The result solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and MeOH (2.0 mL) and 1 drop of concentrated HCl was added to the solution. The solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 14.5 mg (33.03%) of the title compound. LC-MS m/z 744 (M+H)+, 1.43 min (ret time).
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.Cl.S(Cl)(Cl)=O.[NH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:1]12[CH2:8][C:5]([C:9]([NH2:19])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: N
Reactant: CCOC(=O)C12CCCN(CC1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)C12CCCN(CC1)C2
Yield: 76 %

Procedure:
Ethyl 1-azabicyclo[3.2.1]oct-5-ylcarboxylate (E7, Example 7 hereinafter, 9.6 g, 0.053 mole) was treated with 8M hydrochloric acid (130 ml) and heated under reflux for 18h. The solution was concentrated in vacuo to give a white solid, which was treated with thionyl chloride (80 ml) and heated under reflux for 6h. The reaction mixture was concentrated in vacuo to leave a red semi-solid, which was suspended in dichloromethane (120 ml), cooled in an ice bath and treated with an excess of ammonia/dichloromethane solution. The mixture was stirred at room temperature for 1h, then treated with saturated potassium carbonate solution. The organic layer was separated and the aqueous was extracted with chloroform (3×70 ml). All the organics were combined, then dried (Na2SO4) and concentrated in vacuo to give the title compound (D20) as a brown solid (6.2 g, 76%), which was used without further purification.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].O=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH:18]=2)[CH2:13][CH2:12]1.[ClH:34]>CO>[ClH:34].[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[S:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][C:11]2=[N:5][NH:6][C:7](=[NH:9])[NH2:8])=[CH:15][CH:16]=1)(=[O:23])=[O:22]
Reactant: N=C(N)NN
Reactant: O=C1CCc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc21
Agent: Cl
Agent: O=C(O)O
Solvent: CO
Product: N=C(N)NN=C1CCc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc21
Yield: 36 %

Procedure:
Aminoguanidine hydrogencarbonate (45 mg, 0.33 mmol) was dissolved in 2 ml of 1 N HCl. A solution of N-(3-oxo-2,3-dihydro-1H-inden-5-yl)naphthalene-2-sulfonamide (100 mg, 0.30 mmol) in methanol (2 ml) was added and the mixture was heated to reflux for 1 hour. Then the mixture was concentrated in vacuo and the precipitated salt was crystallized from acetonitrile to give 48 mg (36%) of 2-{6-[(2-naphthylsulfonyl)amino]-2,3-dihydro-1H-inden-1-ylidene}hydrazinecarboximidamide hydrochloride.
Reaction SMILES: CCOCC.[CH3:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[CH:26](=[C:11]1[CH2:12][CH2:13][C:8]([N:7]([CH3:21])[CH3:6])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: C1CCOC1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: CCCC=C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butylate (2.75 g, 23.7 mmol) was provided in abs. ether (50 mL) in argon and mixed with butyl-triphenyl phosphonium bromide (9.45 g, 23.7 mmol). The batch was heated for 30 min to 40° C. 4-dimethylamino-4-phenyl cyclohexanone (5.00 g, 23.0 mmol) dissolved in abs. THF (50 mL) was then added carefully in drops (exothermic reaction). The batch was heated for 6.5 h to 50° C. and stirred overnight at room temperature. The batch was then concentrated in a vacuum until dry, taken up in dioxan (20 mL) and mixed with HO/dioxan (5 mL). A precipitate separated out during this. This was filtered off, washed with ether (10 mL), then basified with 2N NaOH and extracted with dichloromethane (2×40 mL). The organic phase was dried over Na2SO4, filtered and concentrated in a vacuum until dry.
Reaction SMILES: BrCCBr.Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[O:28][C:27]([C:29](OC)=[O:30])=[N:26][N:25]=1>C1COCC1>[C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:29]([C:27]2[O:28][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:25][N:26]=2)=[O:30])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Reactant: BrCCCCCCc1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A dry vial was charged with freshly activated Mg turnings (115 mg, 5 mmol), 100 μL of anhydrous THF and a drop of 1,2-dibromoethane under Ar. This mixture was treated dropwise with a solution of 6-bromohexylbenzene (240 mg, 1 mmol) in THF (1 mL) at 23° C. The mixture was warmed and sonicated repeatedly until Grignard formation occurred. The gray solution of the Grignard reagent was added to a solution of methyl 5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate (S7, 40 mg, 0.17 mmol) in THF (2 mL) at −40° C. Stirring was continued for 2 h before the reaction was quenched by the addition of MeOH at −40° C. The mixture was extracted with EtOAc and washed with water, saturated NaHCO3 and saturated aqueous NaCl followed by separation and evaporation. Flash chromatography (SiO2, 1×4 cm, 40% EtOAc-hexanes) afforded the title compound (30 mg, 51%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.85 (d, 1H, J=4.7 Hz), 8.30 (d, 1H, J=7.9 Hz), 7.93 (td, 1H, J=1.5, 7.8 Hz), 7.54 (ddd, 1H, J=0.9 4.7, 7.6 Hz), 7.26-7.30 (m, 2H), 7.16-7.19 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.6 Hz), 1.82 (quintet, 2H, J=7.3 Hz), 1.66 (quintet, 2H, J=7.5 Hz), 1.43 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 187.1, 165.0, 161.2, 150.8, 142.6 (2C), 137.3, 128.3, 128.2, 126.7, 125.6, 124.0, 40.0, 35.8, 31.2, 28.9, 28.8, 23.5; IR (film) νmax 2927, 2856, 1709, 1589, 1442, 1398, 1038, 986, 798, 754, 710 cm−1; HRMS-ESI-TOF m/z 336.1717 ([M+H]+, C20H21N3O2 requires 336.1706).