Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCOCC1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)(O)[O-].[Na+]>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]>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: OCc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ncccc1CO
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (2-chloropyridin-3-yl)methanol (500 mg, 3.48 mmol, 1.00 equiv) in a solvent mixture of dioxane and H2O (10/10 mL). (2-Methoxyphenyl)boronic acid (532 mg, 3.50 mmol, 1.20 equiv), sodium bicarbonate (882 mg, 10.50 mmol, 3.00 equiv), and Pd(dppf)Cl2 (286 mg, 0.39 mmol, 0.10 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 100° C., and then it was diluted with 100 mL of H2O. The resulting solution was extracted with 2×100 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to furnish 650 mg (87%) of [2-(2-methoxyphenyl)pyridin-3-yl]methanol as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][CH:40]1[CH2:43][CH2:42][CH2:41]1)[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1>[CH:40]1([O:39][CH2:38][C@H:27]([OH:26])[C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=2)=[O:29])[CH2:43][CH2:42][CH2:41]1
Reactant: Cc1cnc(NC(=O)[C@H](COC2CCC2)O[Si](C)(C)C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (7.39 mL, 7.39 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R2) (2.7 g, 7.39 mmol) in tetrahydrofuran (25 mL) and the resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate (50 mL) and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with ethyl acetate to afford the product (1.5 g, 81%). 1H NMR (400 MHz, CDCl3) δ 1.48-1.56 (1H, m), 1.70-1.76 (1H, m), 1.90-2.00 (2H, m), 2.19-2.26 (2H, m), 2.54 (3H, s), 3.61 (1H, d), 3.67-3.73 (2H, m), 3.97-4.05 (1H, m), 4.35-4.38 (1H, m), 8.14 (1H, d), 9.15 (1H, s), 9.43 (1H, d); m/z (ESI+) (M+H)+=252; HPLC tR=1.31 min.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[N:4]1.Br[CH2:12][CH2:13]Br.[Cl-].[NH4+]>CS(C)=O>[N:3]1([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: N#CCn1cccn1
Reactant: BrCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: N#CC1(n2cccn2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 27.8 %

Procedure:
Sodium hydride (4.65 g, 121 mmol, 60% oil dispersion) was washed with petroleum ether under a nitrogen atmosphere. The supernatant was removed after the suspension settled in order to remove the mineral oil. Then a solution of 2-(1H-pyrazol-1-yl)acetonitrile (3 g, 27 mmol) and 1,2-dibromoethane (6.98 mL, 81 mmol) in dimethylsulfoxide (90 mL) was added at 20° C. over a period of 40 min. The reaction mixture was stirred at room temperature for 5 d. A saturated aqueous solution of ammonium chloride was added and the mixture was stirred at 0° C. for 15 min, extracted with diethyl ether, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via column chromatography (100-200 mesh silica gel, 5-12% ethyl acetate in petroleum ether) to afford 1-(1H-pyrazol-1-yl)cyclopropanecarbonitrile (1 g, 28%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.[C:26]([O:30][C:31](=[O:43])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][C:35]=1[CH:41]=[O:42])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:26]([O:30][C:31](=[O:43])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][C:37]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][C:35]=1[CH:41]=[O:42])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC(=O)OC(C)(C)C)c(C=O)c1
Temperature: 55 °C

Procedure:
A flame-dried 100 mL round bottomed flask was charged with toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (3.74 g, 10.5 mmol), 3-(2-formyl-4-hydroxyphenyl)acrylic acid tert-butyl ester (2.0 g, 8.05 mmol), and anhydrous DMF (40 mL). Cesium carbonate (3.94 g, 12.1 mmol) was added, and the reaction was heated to 55° C. under a nitrogen atmosphere for 18 h. The volatiles were removed in vacuo, and the crude residue was dissolved in EtOAc (250 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a yellow oil (1.70 g, 49%). 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H), 2.38 (s, 3H), 3.01 (t, J=6.6 Hz, 2H), 4.34 (t, J=6.6 Hz, 2H), 6.24 (d, J=15.6 Hz, 1H), 7.12 (dd, J=8.8, 2.9 Hz, 1H), 7.38 (d, J=2.9 Hz, 1H), 7.40-7.45 (m, 3H), 7.58 (d, J=8.8 Hz, 1H), 7.98 (dd, J=6.4, 2.0 Hz, 2H), 8.33 (d, J=15.6 Hz, 1H), 10.3 (s, 1H). MS (ES) m/e 434 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=O)[CH2:3]1>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCCC)C=CC=CC=1>[CH2:7]([CH:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)[CH:8]=[CH:6][CH2:2][CH2:3][CH3:4]
Reactant: O=CCC1CCC(O)C1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCC=CCC1CCC(O)C1
Yield: 42.7 %

Procedure:
Using the procedure of Example 3, 5 g of 3-hydroxy cyclopentyl-acetaldehyde and 20 g of triphenyl butyl phosphonium bromide were reacted and the product was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 1.4 g of 3-(2-hexenyl)-cyclopentanol.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([N:28]([CH3:41])[C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([N:28]([CH3:41])[C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](N)CCc1ccccc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Condensation of BocPheOPFP (8.63 g.) and MePHeOMe (5.50 g.) by the active ester method gave BocPhe-MePheOMe in 95% yield. De-t-butoxycarbonylation of BocPhe-MePheOMe using hydrogen chloride in ethyl acetate gave HPhe-MePHeOMe in 48% yield. Condensation of BocProOH (0.71 g.) and HPhe-MePheOMe (1.13 g.) by the mixed anhydride method using diphenylphosphinic chloride gave BocPro-Phe-MePheOMe in 73% yield. Hydrazinolysis of BocPro-Phe-MePheOMe (3.10 g.) gave BocPro-Phe-MePheNHNH2 in 84% yield.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]#[N:15].O.O.O.C([O-])(=O)C.[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[Br:1]
Reactant: BrBr
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)cc(Br)c1N
Temperature: 80 °C

Procedure:
Bromine (a total of 4.9g) was added in two portions to a stirred suspension of 4-amino-3-cyano-benzotrifluoride (3g) and sodium acetate trihydrate (1g) in carbon tetrachloride (65ml). The mixture was heated to 80° C. until the absence of starting material was confirmed by gas liquid chromatography. Evaporation of the solvent under reduced pressure gave a pale green solid, which was dissolved in ethyl acetate, and washed with water and brine. After drying over anhydrous magnesium sulphate, the solvent was removed to give 4-amino-3-bromo-5-cyano-trifluoromethylbenzene (3.63g) as an oil which solidified on standing.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[OH:13])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:21]1[CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH:21]1[CH2:24][CH2:23][CH2:22]1)#[N:2]
Reactant: BrC1CCC1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC2CCC2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a solution of methyl 4-cyano-3-hydroxybenzoate (0.067 g, 0.38 mmol) in 2 ml of DMF was added cesium carbonate (0.2 g, 0.62 mmol), bromocyclobutane (0.051 g, 0.38 mmol), and the reaction mixture was heated at 60° C. and stirred at this temperature for 3 hrs. The reaction mixture was cooled to RT, poured into ice water, and extracted several times with ethyl acetate (3×20 ml). The organic solution was dried over Na2SO4, filtered, rotary evaporated to dryness then dried in vacuo to provide methyl 4-cyano-3-(cyclobutyloxy)benzoate (0.055 g, 63%). 1H NMR (400 MHz, CD3OD): 7.74 (d, 1H), 7.67 (d, 1H), 7.54 (s, 1H), 3.93 (s, 3H), 2.57-2.52 (m, 2H), 2.26-2.21 (m, 2H), 1.94-1.90 (m, 1H), 1.94-1.78 (m, 2H). MS (EI) for C13H13NO3: 232 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:21][CH2:20]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[OH:29])=[O:7])=[CH:4][CH:3]=1.[C:32](N1C=CN=C1)([N:34]1C=CN=[CH:35]1)=[O:33].CN.O>C1COCC1.C(OC)(C)(C)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:23][CH2:24]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[O:29][C:32](=[O:33])[NH:34][CH3:35])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1c2cc(N3CCN(C4COC4)CC3)ccc2OC[C@@H]1O)c1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)O[C@H]1COc2ccc(N3CCN(C4COC4)CC3)cc2[C@@H]1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide (72.0 g, 168 mmol) in THF (648 mL) add 1,1′-carbonyldiimidazole (35.5 g, 219 mmol) and stir the solution at room temperature overnight. Cool the mixture to 5° C. and add a solution of 2 M methylamine in THF (210 mL, 421 mmol, 2.5 eq) dropwise over a period of 15 min. Stir for 30 min. and pour over a mixture of water (720 mL) and methyl tert-butyl ether (216 mL). Stir the mixture for 30 min. and decant the phases. Extract the aqueous phase with dichloromethane (3×216 mL). Wash the combined organic phases with brine (3×100 mL), dry over anhydrous sodium sulfate, and concentrate in vacuo. Suspend the residue in ethyl acetate (720 mL), heat at reflux for 2 hr. and cool to 10° C. Collect the solid by filtration and dry under vacuum overnight to obtain the title compound (64.0 g, 78%) as a white solid. LC-ES/MS m/z 485 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=O)[NH2:23])[N:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OCC2C=CC=CC=2)=C(C(=O)N(C)C)N(C2C=CC(F)=CC=2)C=1C([O-])=O)C1C=CC=CC=1.C([NH+](CC)CC)C.[Cl-].[NH4+].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]#[N:23])[N:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(N)=O)n1-c1ccc(F)cc1
Agent: CC[NH+](CC)CC
Agent: CN(C)C(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)[O-])n1-c1ccc(F)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C#N)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
To a stirred solution of ethyl 3,4-bis(benzyloxy)-5-carbamoyl-1-(4-fluorophenyl)-1H-pyrrole-2-carboxylate (15) (1.1 g, 2.25 mmol) [prepared using the same procedure as Example B step (v) using triethylammonium 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-fluorophenyl)-1H-pyrrole-2-carboxylate and ammonium chloride] and triethylamine (1.26 mL, 9.0 mmol) in DCM (60 mL) at 0° C. was added trifluoroacetic anhydride (0.48 mL 3.38 mmol). The reaction mixture was allowed to warm to RT and partitioned between 1M HCl (aq.) (25 mL) and DCM (50 mL) the organic layer was washed with 1M HCl (aq.), and sat. NaHCO3 (aq.) (25 mL), dried (MgSO4), filtered and the volatiles removed in vacuo to afford the crude product. The crude residue was purified by silica gel chromatography (40 g, 0-20% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-5-cyano-1-(4-fluorophenyl)-1H-pyrrole-2-carboxylate (UL1-060) (1.01 g, 94%) as yellow solid: m/z 471 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.57-7.27 (m, 14H), 5.27 (s, 2H), 5.11 (s, 2H), 4.05 (q, J=7.1 Hz, 2H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
10% Palladium on carbon (10% Pd/C) (1.5 g) was added to a solution of 1-methoxy-2-methyl-4-nitrobenzene (9.5 g, 57 mmol) in methanol (100 mL). The mixture was stirred under a hydrogen atmosphere (1 atm.) at room temperature for 16 h. The mixture was filtered through a pad of CELITE™ and the filtrate was evaporated in vacuo to yield 4-methoxy-3-methylphenylamine (8.0 g, 57 mmol, 100%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Fluoro-3-nitroaniline (500 mg, 3.20 mmol) and DMAP (586 mg, 4.80 mmol) were dissolved in 25 mL of DCM. Trimethylacetyl chloride (0.587 mL, 4.80 mmol) was added dropwise and the solution was stirred at rt for 3 h. The solution was washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 35% EtOAc in hexanes as eluent on silica gel to produce the desired title compound. Yield: 713 mg (93%). 1H NMR (400 MHz, CHLOROFORM-D:) δ 1.34 (s, 9H), 7.25 (dd, J=10.25, 9.08 Hz, 1H), 7.50 (br.s, 1H), 7.88 (ddd, J=9.08, 3.71, 2.83 Hz, 1H), 8.26 (dd, J=6.44, 2.73 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:25])[CH3:26])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:40]2[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 85.3 %

Procedure:
Following general procedure F, tert-butyl 2-{4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]phenyl}propan-2-ylcarbamate (76 mg, 0.145 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (63 mg, 0.212 mmol) to afford the crude product (75 mg) as a yellow solid: ESI MS m/z 606 [C33H33Cl2N3O4+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>C(O)(=O)C.CO>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCCn1ccnc1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Yield: 170.1 %

Procedure:
A solution of 3-imidazol-1-yl-propylamine (6 μL, 0.036 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (30 mg, 0.08 mmol) in 0.5 mL of acetic acid was heated to 110° C. for 0.5 hour. After cooling to room temperature, the mixture was dissolved in 2 mL of methanol and loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 26 mg of 8-Cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.49 (s, 1H), 7.57 (br, 1H), 7.09 (br, 1H), 6.96 (br, 1H), 6.10 (br, 1H), 5.02 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.11 (t, J=6.6 Hz, 2H), 3.51 (br, 2H), 2.20-1.50 (m, 8H), 1.40 (t, J=7.2 Hz, 3H), 1.26 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H28N6O3: 425.22 (M+H). Found: 425.2.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:19].Cl>C1COCC1.O.CO>[CH2:1]([O:8][NH:9][CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]([OH:18])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC1=CN(OCc2ccccc2)C1=O
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(CNOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 1-benzyloxy-3-pentylazetin-2-one (1.82 g, 7.37 mmol) in a mixture of THF—H2O-MeOH (100 mL, 3:1:1 v/v) was added LiOH monohydrate (3.60 g, 73.68 mmol). After stirring at room temperature overnight, water (50 mL) was added to the mixture. The solution was acidified to pH 6 with 3N HCl and extracted with EtOAc (100 mL×2). The combined organic layers were dried over MgSO4, and evaporated under vacuum to yield the title compound (1.60 g, 82%). 1H NMR (400 MHz, CHCl3) δ 9.80 (br s, 1H), 7.37 (m, 5H), 4.75 (m, 2H), 3.14 (m, 2H), 2.74 (m, 1H), 170 (m, 1H), 1.53 (m, 1H), 1.38–1.25 (m, 6H), 0.91 (t, J=6.8 Hz, 3H). MH+ 266.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:16][CH2:17][CH3:18])[N:5]([C:7]2[S:11][CH:10]=[N:9][C:8]=2[NH:12][C:13](=O)[CH3:14])[CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>>[CH3:14][C:13]1[C:6]2[N:5]([C:4]([CH2:16][CH2:17][CH3:18])=[N:3][C:2]=2[CH3:1])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[N:12]=1
Reactant: CCCc1nc(C)cn1-c1scnc1NC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)c2c(C)nc3ncsc3n12
Temperature: 110 °C
Yield: 66.7 %

Procedure:
N-(5-(4-methyl-2-propyl-1H-imidazol-1-yl)thiazol-4-yl)acetamide from example 2.5 (8 mg, 0.030 mmol) and phosphorus pentoxide (21.48 mg, 0.15 mmol) were added sequentially quickly to POCl3 (5 mL). The mixture was heated to 110° C. for 4 h, POCl3 was evaporated and the residue was quenched with ice-water. The mixture was neutralized with saturated Na2CO3 solution and extracted with EA (3×20 mL). The combined organic layer was washed with brine and concentrated to give brown liquid. It was purified by pre-HPLC to give the title compound (5.0 mg, 0.02 mmol, 67.1%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=2)[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=2)[C:18]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1cccc(NC2CCN(Cc3ccccc3)CC2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cccc(N(c2ccccc2)C2CCN(Cc3ccccc3)CC2)c1
Temperature: 110 °C
Yield: 117.8 %

Procedure:
A mixture of 3-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide (compound 10) (360 mg, 0.98 mmol), Ph3Bi (1.10 g, 2.50 mmol), and Cu(OAc)2 (0.45 g, 2.48 mmol) in toluene (10 mL) was heated at 110° C. for 12 h. Another portion of Cu(OAc)2 (0.45 g) was added and the mixture was heated at 110° C. for an additional 12 h and allowed to cool to room temperature. Water (10 mL) was added and the mixture filtered through Celite®. The layers in the filtrate were separated, and the organic phase was washed with water, brine, dried over Na2SO4 and concentrated. Chromatography of the residue (9:1 EtOAc/heptane) gave the tide compound 11 (255 mg, 59%) as a pale yellow thick oil.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CCCCCC>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[O:34])[CH:11]=2)[C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[O:34])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1)N(Cc1cccc(CN(C(=O)Nc2ccc(F)cc2)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 0.5 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 0.46 g 4-fluorophenyl isocyanate under ice cooling, and stirring was continued at room temperature for two hours. The solid which separated out was collected by filtration, washed with n-hexane and recrystallized from methanol, giving 0.75 g of 1,3-bis[[1-cycloheptyl-3-(p-fluorophenyl)ureido]methyl]benzene.