Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].O1C[CH2:21][CH2:20][CH2:19]1>O.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]2[CH2:21][O:13][C:12](=[O:15])[CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: COc1cccc(B(O)O)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2=CC(=O)OC2)c1
Temperature: 25 °C

Procedure:
3-Methoxy-phenyl-boronic acid (2.16 g, 14.2 mmol) and trifluoromethansulfonic acid 5-oxo-2,5-dihydro-furan-3-yl ester1 (3 g, 12.92 mmol) in tetrahydrofuran (110 mL) is dissolved and de-gassed for 15 min. To this solution is added sodium carbonate (3.42 g, 32.3 mmol) in water (10 mL) and tetrakis-triphenylphosphine-palladium(0) (0.75 g, 0.646 mmol). The reaction mixture is refluxed for 45 min, cooled to room temperature, diluted with ether (50 mL) and filtered through a Celite® pad. The filtrate is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (3:7 ethyl acetate/hexanes) to yield the title compound, 1.9 g (71%), as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH3:19])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:21].[K+].[OH2:26]>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][N:10]=[C:11]([C:19]([OH:21])=[O:26])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine prepared as set forth in Example A-4 (5.83 g, 24.0909 mmol) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 ml) and tert-butanol (10 ml) was heated at reflux for 6 hours (or until all the potassium permanganate was consumed). The mixture was then stirred at room temperature overnight and then diluted with water (150 ml). Manganese dioxide was removed from the mixture by filtration. The filtrate was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1N HCl to increase the pH to about 6. A white precipitate formed, was collected by filtration, washed with water, and dried in a vacuum oven to give 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid (isolated as the monohydrate salt) (2.9777 g, 43.7%). Anal. Calc'd for C15H10N3FO2.H2O (283+18): C, 59.80; H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS (MH30): 284 (base peak)
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[C:4]([C:16]([OH:18])=O)=[CH:3][CH:2]=1>C1(C)C(C)=CC=CC=1>[CH:10]1[C:9]2[C:7](=[O:8])[C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[C:16](=[O:18])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1C(=O)O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Yield: 78.7 %

Procedure:
A mixture of 2.50 g of 2-aminobenzophenone-2'-carboxylic acid in 50 ml of xylene is stirred at reflux for 23 hours. The mixture is filtered to give is 1.82 g of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:13][C@H:10]([C:8]2[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][CH3:12])[N:25]=[CH:24][N:23]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 78.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (62 mg, 0.23 mmol), 4-amino-6-chloro-5-cyanopyrimidine (36 mg, 0.23 mmol) and DIPEA (0.08 mL, 0.46 mmol) in IPA (2 mL) was heated for 6 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in EtOAc) to afford 358 as a white solid (70 mg, 79%). LCMS (Method K): RT 4.10 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz): δ 7.81 (1H, s), 7.68 (1H, dd, J=8.8, 4.9 Hz), 7.56-7.44 (6H, m), 7.16 (2H, br s), 7.07 (1H, ddd, J=9.8, 8.8, 2.5), 6.79 (1H, dd, J=8.9, 2.5), 5.29 (1H, dt, J=7.7, 6.2), 1.97 (1H, dqd, J=14.9, 7.5, 6.2), 1.87 (1H, dqd, J=14.9, 7.5, 6.2), 0.75 (3H, t, J=7.5)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.CCOC(C)=O>[CH3:24][O:25][CH2:26][C:27]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:28]
Reactant: COCC(=O)Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1 g, 4.56 mmol) in THF (20 ml) was added triethylamine (0.95 ml, 6.84 mmol) and methoxyacetyl chloride (0.417 ml, 4.56 mmol) dropwise, the resulting mixture was stirred for 2 hours at RT. The reaction mixture was diluted with EtOAc and washed with water then brine, dried (Na2SO4) filtered and concentrated in vacuo to give the product (1.2 g) as an orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=O)[O:12][C:10](=[O:11])[CH:9]=[CH:8]1.O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:7]1(=[O:12])[N:1]([CH2:2][CH2:3][C:4]([O:6][N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=[O:21])=[O:5])[C:10](=[O:11])[CH:9]=[CH:8]1
Reactant: NCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Reactant: O=C1C=CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of β-alanine (1.8 g, 20 mmol) and maleic anhydride (2 g, 20 mmol) in DMF (30 mL) was stirred at room temperature for 3 h. After the solid was completely dissolved, N-hydroxysuccinimide (NHS; 2.3 g, 20 mmol) and dicyclohexylcarbodiimide (DCC; 4.6 g, 24 mmol) was added into the solution and the mixture was stirred at room temperature overnight. The solution was filtered and the precipitate was washed with water (100 ml) and dichloromethane (100 ml). The filtrate was collected and the organic layer was washed with 3×50 ml 5% NaHCO3 and one time with brine. The organic layer was dried with Na2SO4 and dichloromethane removed under reduced pressure to obtain a white solid (55%). This solid does not need further purification and can be directly used for next coupling step. 1H NMR (CDCl3, 400 MHz): δ 2.82 (s, 4H, two succinimido-CH2), 3.02 (t, J=7.0 Hz, 2H, COCH2), 3.94 (t, J=7.0 Hz, 2H, NCH2), 6.74 (s, 2H, two CH).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9](O)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([NH:35][C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2c3ccccc3oc(=O)c21
Yield: 56 %

Procedure:
Prepared by the method described for Ex. 17 from 4-ethyl-1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.2 g, 0.0077 mole), 1,1'-carbonyldiimidazole (2.4 g, 0.0148 mole) and 5-aminotetrazole monohydrate (0.76 g, 0.0076 mole) in dimethylformamide (30 ml). Recrystallization from dimethylformamide gives pale yellow crystals (1.5 g, 55%), m.p. above 300.
Reaction SMILES: C1C=CC(CCN)=CC=1.C1([OH:16])C=CC=CC=1.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C[C@:42]1([OH:72])[C@@H:56]2[C:51](=[C:52](O)[C@:53]3([OH:69])[C:60](=[O:61])C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2>>[CH:51](/[CH:56]=[CH:42]/[OH:72])=[CH:52]\[C:53]([C:60]([OH:16])=[O:61])=[O:69]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Reactant: Oc1ccccc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NCCc1ccccc1
Product: O=C(O)C(=O)/C=C/C=C/O

Procedure:
Screening for transformants carrying pheA and pheB. Transformants were spread on LB plates containing 1 mM phenol, 50 μg of ampicillin per ml, and 12.5 μg of tetracycline per ml and incubated overnight at 37° C. Colonies that became yellow (as a result of 2-hydroxymuconic semialdehyde) following spraying of a 0.1% of catechol solution were patched on LB plates containing 1 mM phenol. Colonies in which the yellow compound formed during growth without catechol addition were retained as putative carriers of both pheA and pheB.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=C[C:11]=2N=N1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])[CH:45]=[C:46]([CH:50]=3)[C:47](O)=[O:48])[CH:40]=2)[N:35](COCC[Si](C)(C)C)[N:34]=1.C(N)C.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:12]([NH:8][C:47](=[O:48])[C:46]1[CH:50]=[C:42]([C:39]2[CH:40]=[C:41]3[C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])=[N:34][NH:35][C:36]3=[N:37][CH:38]=2)[CH:43]=[C:44]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])[CH:45]=1)[CH3:11]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C(=O)O)cc(C(=O)N(C)C)c3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
In a microwave vial O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-fluorophosphate (34.8 mg, 0.9 mmol) was added to a solution of 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-iso-phthalamic acid (50 mg, 0.09 mmol), ethyl amine (69 μL, 0.14 mmol), and di-iso-propyl ethyl amine (47.8 μL, 0.27 mmol) in tetrahydrofuran (1 mL). The vial was sealed and the solution irradiated to 100° C. for 10 min in a microwave reactor. The solvent was then removed on under reduced pressure. Trifluoroacetic acid (1 mL) was then added to the residue and the mixture stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure and the residue purified by preparative high pressure liquid chromatography to give N-ethyl-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N′,N′-dimethyl-isophthalamide (5.30 mg, 13% yield). 1H-NMR (500 MHz, Dimethyl sulfoxide-d6) δ 1.15 (t, J=14 Hz, 3H) 2.97 (s, 3H); 3.03 (s, 3H)); 3.29 (dq, J=5.5 Hz, J=7 Hz, 2H); 3.84 (s, 3H); 7.11 (t, J=7.5 Hz 1H); 7.23 (d, J=8 Hz 1H) 7.48 (t, J=7.5 Hz, 1H); 7.67 (d, J=8 Hz 1H); 7.86 (s, 1H); 7.94 (s, 1H); 8.25 (s, 1H); 8.45 (s, 1H); 8.69 (t, J=5.5 Hz, 1H); 8.94 (s, 1H); 13.88 (s, br, 1H) MS: m/z 444.0 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](O)=O.[C:13]([C:19](OC)=O)#[C:14][C:15]([O:17][CH3:18])=[O:16].C(=O)=O.[C:26]([O:29][C:30](=O)C)(=[O:28])C>>[CH3:30][O:29][C:26]([C:10]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3][C:2]=12)=[O:28]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: O=C=O
Product: COC(=O)c1c(C(=O)OC)c2n(c1C)-c1ccccc1C2

Procedure:
A mixture of indoline 2-carboxylic acid (10.60 g, 65 mmol) and dimethyl acetylenedicarboxylate (9.24 g, 80 mmol) in acetic anhydride (110 mL) was stirred in a flask equipped with a reflux condenser and a gas bubbler to monitor carbon dioxide evolution during the reaction. The mixture was heated to 120° C. where carbon dioxide evolution was most intense. The temperature was maintained until gas evolution had ceased (ca. 10 h). The dark solution was concentrated in vacuo and the solid residue was crystallized from methanol to yield 3-methyl-8H-3a-aza-cyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester, 14.40 g (78%): mp 162-164° C.; 1H NMR (DMSO-d6) δ 2.74 (3H, s, Me), 3.85 and 3.89 (each 3H, s, 2×OMe), 4.01 (2H, s, CH2) 7.20-7.27 (1H, m, ArH), 7.33-7.37 (1H, m, ArH), 7.46-7.53 (2H, m, 2×ArH). Anal. Calcd. for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.30; H, 5.31; N, 4.85.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[O:20])[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].[Cl:25][C:26]([Cl:31])([Cl:30])C(O)=O.FF.C([O-])(=O)C=C>CO.CN(C)P(N(C)C)(N(C)C)=O>[Cl:25][C:26]([Cl:31])([Cl:30])[C:8]([C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])([C:7]1[C:2]([F:1])=[C:3]([F:24])[C:4]([F:23])=[C:5]([F:22])[C:6]=1[F:21])[OH:20]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: O=C(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Agent: C=CC(=O)[O-]
Agent: FF
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: OC(c1c(F)c(F)c(F)c(F)c1F)(c1c(F)c(F)c(F)c(F)c1F)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 4.9 g of decafluorobenzophenone and 2.7 g of trichloroacetic acid was added to 15 mL of hexamethylphosphoramide. The stirred reaction mixture was maintained at about 0° C. for about 2 hours and then allowed to warm to room temperature and continue stirring at ambient temperature for the next 15 hours. The reaction mixture was characterized by GC and fluorine NMR to show a conversion of approximately 20% to the desired carbinol. This carbinol can be converted to the corresponding acrylate by methods previously described (cf. Example 24).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.O[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:32][C:33]3[CH:46]=[CH:45][C:36]4[C@H:37]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:38][O:39][C:35]=4[CH:34]=3)[CH:26]=2)=[C:20]([CH3:47])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][C@H:37]1[C:36]2[CH:45]=[CH:46][C:33]([O:32][CH2:31][C:27]3[CH:26]=[C:25]([C:21]4[C:22]([CH3:24])=[CH:23][C:18]([O:5][CH:6]5[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]5)=[CH:19][C:20]=4[CH3:47])[CH:30]=[CH:29][CH:28]=3)=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)OC(C)(C)C)C5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate 14a (100 mg, 0.40 mmol, prepared by a method disclosed in PCT patent application WO2011097958”), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (80 mg, 0.19 mmol) and cesium carbonate (130 mg, 0.40 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction solution was heated to 80° C. and stirred for 12 hours. The resulting solution was mixed with 10 mL of water, and extracted with ethyl acetate (30 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-tert-butyl 3-((3′-(((3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)-2,6-dimethylbiphenyl-4-yl)oxy)azetidine-1-carboxylate 14b (60 mg, yield 50.0%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:29])[C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:16]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:16]([C:15]1[CH:14]=[C:13]([CH3:12])[C:20]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([CH3:29])[CH:18]=1)[NH:6][C:4]2=[O:5]
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Reactant: NC(=O)c1cccc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3c(Cl)cccc3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-3-chloro-benzamide (0.85 g, 5.00 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.23 g, 5.00 mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.37 g, 7.50 mmol) and p-toluenesulfonic acid monohydrate (3.80 g, 20.0 mmol). The reaction mixture was stirred at 140° C. for 16 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added, and the mixture was neutralized, to pH approximately 8 with 2 N aqueous NaOH solution. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and then 5% 7.0 M ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a brown solid. Yield: 0.49 g (25%). MP 216-217° C. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J=7.81 Hz, 1H), 8.01-7.87 (m, 3H), 7.43 (t, J=7.81 Hz, 1H), 3.89 (t, J=5.85 Hz, 2H), 2.81 (t, J=5.85 Hz, 2H), 2.53 (br s, 4H), 2.30 (s, 6H), 1.75-1.60 (m, 4H). MS (ES+) m/z 398.11 (100%), 400.13 (40%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.CON(C)[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:44])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)c4ccccc4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and THF (5 mL) is added 1.30 M n-Bu-Li (0.50 mL, 0.80 mmol). After 30 minutes N-methoxy-N-methyl-benzamide (0.13 mL, 0.84 mmol) is added, the solution is warmed to ambient temperature, and stirred overnight. The solution is diluted with EtOAc (20 mL), washed with sat. NH4Cl (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.066 g, 0.16 mmol, 21%). 1H NMR (CDCl3), δ 0.89 (t, J=7.4 Hz, 6H), 1.74-1.93 (m, 4H), 2.18 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H), 3.29-3.38 (m, 1H), 6.71 (s, 1H), 7.49-7.54 (m, 2H), 7.56 (s, 1H), 7.57-7.62 (m, 1H), 7.89-7.94 (m, 2H). LC/MS (m/z): calcd. for C25H27N3OS (M+H)+: 418.2; found: 418.2.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[CH:10](O)([CH3:12])[CH3:11].Cl.COC(OC)(C)C=O>O>[CH3:11]/[C:10](/[CH:12]=[N:5]/[N:6]=[C:7]([NH2:9])[NH2:8])=[N:5]\[N:6]=[C:7]([NH2:9])[NH2:8]
Reactant: N=C(N)NN
Reactant: CC(C)O
Agent: COC(C)(C=O)OC
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: CC(/C=N/N=C(N)N)=N\N=C(N)N
Temperature: 32 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Aminoguanidine bicarbonate (Aldrich 98.5%) was slurried in DI water at 35°-40° C. for about 30 minutes, the suspension was filtered to remove diaminoguanidine and other impurities amounting to about 1% w/w. 505 g, 3.8 mol of the filtered aminoguanidine bicarbonate was suspended in 200 g DI water and 300 g (156 mL) isopropanol to give a heavy, but stirrable mixture. Concentrated HCl (376 g, 37.8%) was cautiously added dropwise over a 1.5 hr period to prevent excessive foaming (Note 1). The mixture stirred readily after 5% of the HCl had been added. The reaction was endothermic and the temperature was maintained at between 19° C. and 28° C. At the end of the addition a clear colorless solution was obtained (Note 2). It was warmed to 32° C. and stirred for 20 minutes (Note 3). The methyl glyoxal dimethylacetal (212 g, 1.79 mol) (Fluka, 98%) was next added over 1.5 hours at a temperature of 30°-35° ) (Note 4). The suspension was stirred overnight at ambient temperature. The next morning isopropanol (2.0 kg) was added over 15-20 minutes. The suspension was cooled to about 10° C. and stirring was continued for 1.5 hours. The solids were collected by filtration and rinsed with 2×200 mL isopropanol. After drying overnight in a vacuum oven at 30°-35° C., 463 g (47%) of the crude MGBG was obtained. TLC [acetone 90, water 5, NH4OH 5]; HPLC (ETI~0.79%); nmr (dmsod6).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH:33]([CH3:35])[CH3:34])[N:3]=1.[C:36]1([C@H:42]([NH:44][C:45]([NH2:47])=[O:46])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[CH:33]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([NH:47][C:45]([NH:44][C@@H:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:43])=[O:46])[CH:11]=[C:10]3[N:12]([C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:13]=[C:8]1[C:9]=23)([CH3:35])[CH3:34]
Reactant: CC(C)N1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(C)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
7-chloro-3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (116 mg, 0.242 mmol), (R)-1-(1-phenylethyl)urea (60 mg, 0.363 mmol), cesium carbonate (237 mg, 0.726 mmol) and BrettPhos pre-catalyst (22 mg, 0.024 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (1.2 mL) before the mixture was heated reaction at 100° C. for 1 hour. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (R)-1-(3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C39H38N6O [M+H]+ 607. found 607.