Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[O:12]>CO>[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:1][N:2]([CH2:7][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:11]=1[OH:12])[CH3:3]
Reactant: CNC
Reactant: C=O
Solvent: CO
Solvent: Oc1ccccc1
Product: CN(C)Cc1ccccc1O
Temperature: 60 °C

Procedure:
0.45 kg of dimethylamine was passed, under normal pressure and at a reaction temperature of 20°-25° C., in the course of 5 hours into a mixture of 1.0 kg of phenol, 0.30 kg of paraformaldehyde and 3.1 kg of methanol and the reaction mixture was then warmed to 60° C. for 1 hour. After distilling off methanol and water in vacuo, 1.551 kg of a mixture which contained 0.242 kg of phenol, 0.605 kg of o-dimethylaminomethylphenol, 0.030 kg of p-dimethylaminomethylphenol, 0.302 kg of bis- and tris-dimethylaminomethylphenol and 0.392 kg of condensation and resinification products was obtained and 0.595 kg (49% of theory, relative to converted phenol), of o-dimethylaminomethylphenol could be obtained from this mixture.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:13]3[CH:32]=[CH:31][N:30](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]=3[N:15]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=3)[N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[OH-].[K+]>CO>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:13]3[CH:32]=[CH:31][NH:30][C:14]=3[N:15]=[C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=3)[N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)c3cc[nH]c3n2)cc1
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of N-(4-(4-(3-aminosulfonyl-phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (20 mg, 0.033 mmol) in MeOH (2 mL), aq. 1N KOH (0.60 mL, 0.60 mmol) was added. The mixture was heated at 60° C. for 3 h. It was concentrated in vacuo. The residue was acidified with HOAc (1 mL) before being purified by HPLC to give the titled compound (7 mg). MS 452.0 (M+H); UV 208.5, 284.1, 317.4 nm.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][N:27]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:46]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:11]1([CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=[C:2]([C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28](=[O:46])[N:27]([CH3:26])[CH:36]=4)[C:10]=3[O:9]2)[CH2:13][CH2:12]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1cc(Br)c2c(c1)CC(C1CC1)O2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)cc3c2OC(C2CC2)C3)c2ccccc2c1=O
Temperature: 90 °C
Yield: 18.4 %

Procedure:
To a solution of the title compound from Step 2 (80 mg, 252 umol) in dioxane (10.00 mL) and H2O (1.00 mL) was added Pd(dppf)Cl2 (9 mg, 12.61 umol), K3PO4 (134 mg, 631 umol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (79 mg, 278 umol) in one portion. The reaction mixture was degassed with N2 and heated to 90° C. for 3 hours. It was then concentrated and purified by prep-HPLC to give the title compound (18.36 mg, 19% yield). 1H NMR (CDCl3, 400 MHz) δ 8.53-8.51 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.63-7.56 (m, 2H), 7.33-7.31 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 4.43-4.37 (m, 1H), 3.68 (s, 3H), 3.50-3.46 (m, 1H), 3.32-3.16 (m, 1H), 3.09 (s, 3H), 1.21-1.06 (m, 1H), 0.60-0.59 (m, 2H), 0.39-0.32 (m, 2H). LCMS: 396.0 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([Mg]Br)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC(=O)c1ccc(F)cc1

Procedure:
100 mL of tetrahydrofuran was placed into a four-neck round-bottom flask, then 7.92 g (0.05 mol) of 4-fluorobenzoyl chloride and 0.53 g (1.5 mmol) of tris(acetylacetone)iron (III) were added and stirred under a nitrogen atmosphere. To this solution pentylmagnesium bromide was added at a room temperature and stirred at a room temperature for 10 min. After completion of the reaction, this solution was acidified with dilute hydrochloric acid and the organic phase was extracted with diethyl ether. Further, the organic phase was neutralized with satd. sodium hydrogencarbonate solution and washed with satd. sodium chloride solution. The organic phase was dehydrated with anhydrous magnesium sulfate, then diethyl ether was evaporated by a rotary evaporator and dried by a vacuum pump to obtain crude FPHxO.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][N:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[N:20][N:21]=4)[N:18]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:34]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]5[N:17]([CH:19]=[N:20][N:21]=5)[N:18]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: O=C(Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1)C1CCCC1
Yield: 8.7 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 2.00 g (5.37 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo-[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained by the same reaction as in Example 8-2), and using 1.07 g (8.06 mmol) of cyclopentylcarbonyl chloride in place of acetic anhydride to obtain 219 mg of the title compound as a white powder. (Yield: 9%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI.CCCCCCC.C(OCC)(=O)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([C:13]2([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:23])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(OC)cc2)CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(N(C)S(=O)(=O)c2ccc(OC)cc2)CCCCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 1-(4-methoxyphenylsulfonamido)cyclohexanecarboxylate (27 g, 82.5 mmol) was dissolved in acetone (450 ml), and K2CO3 (22.8 g, 165 mmol) was added thereto. Methyl iodide (10.3 ml, 165 mmol) was then added, and the suspension was heated overnight at 40° C. in a closed flask. Because the reaction was not yet complete (TLC monitoring, heptane/ethyl acetate 2:1), methyl iodide (7.7 ml, 124 mmol) was again added and stirring was carried out over the weekend at room temperature. Methyl iodide (2.6 ml, 41.8 mmol) was again added, and stirring was carried out overnight at 40° C. After cooling, the solid materials were filtered off and the filtrate was concentrated to dryness. The crude product was used further without being purified further.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C1C[O:17][CH2:16]C1.[Li]CCCC.CN(C=O)C>CCOC(C)=O>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:16]=[O:17])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:9][CH2:8]1
Reactant: C1CCOC1
Reactant: Cc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen flushed 50 mL round bottom flask were added 5-bromo-3,3,7-trimethyl-2,3-dihydro-1-benzofuran (0.11 g, 0.46 mmol) and THF (3 mL). A solution of n-BuLi (0.20 mL, 2.5 M solution in hexanes) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then DMF (0.053 mL, 0.68 mmol) was added. The reaction mixture was allowed to warm to room temperature. EtOAc (20 mL) and wet silica gel (5 g silica gel/0.5 mL of water) were added. The resulting mixture was stirred at room temperature for 10 minutes and then filtered. The resulting solid was rinsed with EtOAc. The filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (40 mg) as colorless solid.
Reaction SMILES: O[CH:2]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]>C(=O)C1C=CC=CC=1>[C:5]1([C@H:3]2[C@H:2]([N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:4]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(O)n1ccnc1
Solvent: O=Cc1ccccc1
Product: O=C1c2ccccc2O[C@@H](c2ccccc2)[C@@H]1n1ccnc1
Temperature: 110 °C
Yield: 79.6 %

Procedure:
A mixture of 2-hydroxy-α-(1-imidazolyl)-acetophenone (3.5 g), and benzaldehyde (200 ml) was heated at 110° C. for 8 hours. The benzaldehyde was evaporated under reduced pressure and the residue, taken up with CH2Cl2 (100 ml), washed with H2O, was extracted with a solution of 8% HCl. The acid solution, neutralized with NaHCO3, extracted with CH2Cl2, dried and evaporated, gave 2 g of trans 2-phenyl-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one m.p. 199°-203° C.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C@@H:4]([C:19]([NH:21][C:22]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1.O[Li].O>>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[C@@H:4]([C:19]([NH:21][C:22]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH2:23][CH2:24]2)=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 65.1 %

Procedure:
The title compound (E15) (15.8 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-((2R)-4-fluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D134) (25 mg). (LiOH H2O: 4 eq; reaction time: 5 hrs)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18](=O)[C:19]#[CH:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:19]=[CH:20][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Product: Fc1ccc(-c2nc3ccc(Br)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 61 %

Procedure:
In a similar manner as described in Example 2 from 1-[6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-propyn-1-one (1.0 g, 2.9 mmol), cyclopentylguanidine hydrochloride (0.71 g, 4.4 mmol) and anhydrous carbonate (0.6 g, 4.4 mmol), was obtained N-{4-[6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (0.8 g, 61%) as a solid. 1H NMR (CDCl3) δ 10.0 (broad s, 1H), 8.13 (d, 1H), 7.65 (m, 3H), 7.44 (dd, 1H), 7.17 (t, 2H), 6.45 (s, 1H), 5.30 (d, 1H), 4.40 (m, 1H), 2.1 (m, 2H), 1.4–2.0 (m, 6H); 19F NMR (CDCl3) δ −112.8; MS m/z 452 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:27]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:3])[C:7]=2[OH:27])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)c(F)c2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccc(F)c(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(3,4-difluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[N:30]([CH3:36])[C:31]([Br:35])=[C:32]([Br:34])[CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[N:30]([CH3:36])[C:31]([Br:35])=[C:32]([Br:34])[CH:33]=3)=[O:28])[CH:13]=2)[N:6]=1
Reactant: Cn1c(C(=O)NCCN=[N+]=[N-])cc(Br)c1Br
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: Cn1c(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc(Br)c1Br

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.116 g, 0.417 mmol) was reacted with N-(2-azidoethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide (0.145 g, 0.417 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), δ 7.32 (s, 1H), δ 6.81 (s, 1H), δ 6.49 (s, 1H), δ 6.17 (s, 2H), δ 4.52 (s, 2H), δ 3.94 (s, 3H), δ 3.84 (s, 2H), δ 2.65 (t, J=7.2 Hz, 2H), δ 2.30 (m, 2H), δ 1.58 (m, 13H), δ 1.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.2, 149.6, 148.2, 138.8, 127.4, 122.2, 114.9, 111.9, 106.5, 98.2, 84.5, 49.5, 39.7, 35.9, 29.3, 28.9, 28.2, 28.0, 27.7, 25.6 ppm; HRMS (ESI) calcd for C23H32N8O3 (M+) 626.0964. found 626.0960, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4,5-dibromo-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (0.151 g, 64% yield). 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), δ 6.86 (s, 1H), δ 6.56 (s, 1H), δ 4.71 (s, 2H), δ 3.81 (s, 5H), 2.78 (s, 2H), δ 2.44 (t, J=7.2 Hz, 2H), δ 1.69 (s, 2H), δ 1.59 (s, 2H), δ 1.37 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 161.4, 150.2, 159.8, 159.4, 147.3, 127.6, 127.3, 114.9, 111.6, 108.4, 97.9, 51.3, 39.0, 35.2, 28.3, 28.0, 27.6, 24.2, 23.8 ppm; HRMS (ESI) calcd for C18H24Br2N8O (M+) 526.0439. found 526.0425.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)\[CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C1COCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2]/[N:3]=[C:4](/[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)\[CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cn2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a stirring solution of ethyl 3-{6-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]pyridin-3-yl}propanoate (0.03 g, 0.067 mmol) in the mixture of THF and Ethanol was added aqueous NaOH (0.03 g, 0.067 mmol) at 0° C., then stirred at RT for 2 h. After the completion of the SM reaction mass was concentrated under vacuum at 25° C. to remove solvents and diluted with water. Aqueous portion was neutralized with citric acid up to neutral pH, then extracted with ethyl acetate organic layer was washed with water and brine, dried over Na2SO4 and concentrated. Crude product was purified by preparative TLC to afford colourless oil as product (0.01 g, Yield: 35%); purity: 85%.
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2)=C(C(C)C)C=1C(C)C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:30]([C@@H:32]1[C:36]2[NH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:35]=2[C:34](=[O:49])[NH:33]1)[CH3:31].[C:50]([NH:54][C:55]1[N:64]([CH3:65])[C:63](=[O:66])[C:62]2[C:57](=[C:58](I)[CH:59]=[CH:60][CH:61]=2)[N:56]=1)([CH3:53])([CH3:52])[CH3:51].[OH-].[Na+]>O1CCOCC1.O.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:50]([NH:54][C:55]1[N:64]([CH3:65])[C:63](=[O:66])[C:62]2[C:57](=[C:58]([C:38]3[NH:37][C:36]4[C@@H:32]([CH2:30][CH3:31])[NH:33][C:34](=[O:49])[C:35]=4[CH:39]=3)[CH:59]=[CH:60][CH:61]=2)[N:56]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: CC[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: [Pd]
Agent: CC(C)c1ccc(-c2ccccc2)c(C(C)C)c1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 52.6 %

Procedure:
A mixture of 2-(dicyclohexylphosphino)-2′,4′,6%-tri-isopropyl1,1′-biphenyl (Strem Chemicals, 16.02 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, 15.38 mg, 0.017 mmol), potassium phosphate tribasic (Sigma Aldrich, 267 mg, 1.260 mmol), (R)-6-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (505g, 232 mg, 0.840 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (Intermediate 701, 150 mg, 0.420 mmol) in 1,4-dioxane (4 mL), water (1.20 mL) in a sealed glass tube was heated at 80° C. for 1.5 h. The reaction mixture was treated with 1N NaOH and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude reaction mixture was chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording a dark brown oil. It was suspended in Et2O with sonication and filtered and washed with Et2O and dried in the vacuum oven at 34° C. for 2 h affording (R)-2-(tert-butylamino)-8-(6-ethyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one (505, 83.8 mg, 0.221 mmol, 52.6% yield) as a tan amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br. s.), 7.89 (2H, d, J=7.2 Hz), 7.65 (1H, br. s.), 7.18 (1H, br. s.), 6.71 (1H, br. s.), 5.94 (1H, br. s.), 4.45 (1H, br. s.), 3.48 (3H, br. s.), 1.84 (1H, br. s.), 1.61 (1H, br. s.), 1.50 (9H, br. s.), 0.85 (3H, br. s.). m/z (ESI, +ve) 380.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:7][O:6][C:5]([CH2:14][S:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]2[C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:29][CH:28]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.O.C(N(CC)CC)C>CO>[CH3:1][C:2]1([CH3:40])[CH2:3][O:4][C:5]([CH2:14][S:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]2[C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:6][CH2:7]1
Reactant: CCOC(=O)COc1ccc([C@@H]2[C@@H](SCC3(c4ccccc4)OCC(C)(C)CO3)C(=O)N2c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)COC(CS[C@H]2C(=O)N(c3ccccc3)[C@@H]2c2ccc(OCC(=O)O)cc2)(c2ccccc2)OC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl [4-((2R,3R)-3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}-4-oxo-1-phenylazetidin-2-yl)phenoxy]acetate (0.86 g, 1.53 mmol) in MeOH (25 ml) was added water (2.5 ml) and triethylamine (1.55 g). The reaction was stirred for 48 h at 50° C. The solvent was evaporated and the residue was purified by preparative HPLC using a gradient of 20-70% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions gave the title compound as a colourless solid. 1H NMR [(CD3)2SO), 400 MHz]□0.50 (s, 3H), 1.15 (s, 3H), 2.93 (d, 1H), 2.96 (d, 1H), 3.21-3.37 (m, 4H), 4.13 (d, 1H), 4.28 (s, 2H), 4.97 (d, 1H), 6.83-7.41 (m, 14H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].Cl>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: OCCCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCO)ccc(C(C)=O)c1O

Procedure:
A solution of 10 g. of 2,4-dihydroxy-3-propylacetophenone, 8 g. of potassium carbonate, and 7.1 g. of 6-chloro-1-hexanol in 50 ml. of methyl ethyl ketone was heated to reflux overnight. Upon cooling, dilute hydrochloric acid was added and the resulting organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The residue was purified by chromatography giving 2.87 g. of the title product as an oily solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([OH:23])=[O:22].OS(O)(=O)=O.[CH3:29]O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([O:23][CH3:29])=[O:22]
Reactant: CO
Reactant: Cc1ccccc1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccccc3C)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(1,3-dioxo-5-(o-tolyloxy)isoindolin-2-yl)acetic acid (10.1 g, 32.5 mmol) and concentrated H2SO4 (2.0 mL) in MeOH (41 mL) was heated to reflux with stirring for 18 hours. After cooling to room temperature, the solvent was removed in vacuo. To the residue was added sat'd NaHCO3 solution (100 mL) and EtOAc (100 mL). The layers were separated and the organic layer was dried over Mg SO4 and then concentrated in vacuo to give the title compound as white solid in 10.0 g. 1H NMR (CDCl3, 200 MHz): δ=7.78 (d, 1H, J=9.0 Hz), 7.31-7.13 (m, 5H), 6.98 (d, 1H, J=7.4 Hz), 4.40 (s, 2H), 3.75 (s, 3H), 2.18 (s, 3H).