Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Br:11])[C:3]=1[OH:12].CC(C)([O-])C.[K+].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][C:25]=1[CH:26]([CH3:28])[CH3:27]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Br:11])[C:3]=1[O:12][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[C:25]([CH:26]([CH3:28])[CH3:27])[CH:24]=1
Reactant: OCCc1cc(Br)c(O)c(Br)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)c1cc(Oc2c(Br)cc(CCO)cc2Br)nnc1Cl
Temperature: 100 °C
Yield: 49.7 %

Procedure:
A mixture of 2,6-dibromo-4-(2-hydroxy-ethyl)-phenol (11) (183.3 g, 0.619 mol) in N,N-dimethyl acetamide (300 mL) was treated with potassium tert-butoxide (70.5 g, 0.59 mol) under nitrogen at room temperature. The suspension was heated to 100° C. and stirred until a solution formed. At this time, 3,6-dichloro-4-isopropyl pyridazine (7) (100 g, 0.50 mol) was added to the solution and the reaction mixture was stirred at 135° C. for 24 h. The reaction was cooled to room temperature, diluted with water (350 mL) and extracted with tert-butyl methyl ether (1×600 mL) followed by isopropyl acetate (1×600 mL). The organic layers were combined and washed with a 1N aqueous sodium hydroxide solution (1×256 mL) and water (2×200 mL). The organic layer was distilled to about 300 mL. The residue was treated with heptane (300 mL). The mixture was stirred under reflux for 30 min and then was cooled to room temperature. The resulting solid was filtered, washed with a 2:1 mixture of tert-butyl methyl ether: heptane (240 mL) and dried overnight to afford 2-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (12) (112 g, 49%) as an off-white solid; LRMS for C15H15Br2ClN2O2 (M+) at m/z=450. Molecular Weight=450.5600; Exact Mass=447.9189
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:17][C:18]([O:20]C(C)(C)C)=O)=[C:6]([NH:9][C:10](OC(C)(C)C)=[O:11])[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH:1]1([C:4]2[C:5]3[NH:17][C:18](=[O:20])[C:10](=[O:11])[NH:9][C:6]=3[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1scc(C2CC2)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2scc(C3CC3)c2[nH]c1=O
Yield: 47 %

Procedure:
A mixture of di-t-butyl 4-cyclopropylthiophene-2,3-dicarbamate (1.66 g, 4.7 mmol), diethyl oxalate (20 ml, 146 mmol) and glacial acetic acid (20 ml) was refluxed for 12 h. The mixture was concentrated in vacuo and the residue recrystallized from glacial acetic acid to afford 460 mg (72%) of the title compound. M.p.>250° C. 1H-NMR (DMSO-d6, δ): 0.6 (m, 2H), 0.85 (m, 2H), 2.0 (m, 1H), 6.55 (s, 1H), 12.0 (s, 1H), 12.2 (s, 1H).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[NH2:12][C:13]([NH2:15])=[O:14].Cl>CCO>[NH:12]1[C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7](=[O:9])[NH:15][C:13]1=[O:14]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of ethyl 2-oxocyclopentanecarboxylate (15.6 g, 0.10 mol), urea (9.0 g 0.15 mol) and hydrochloric acid (37%, aqueous, 5 mL) in EtOH (100 mL) was heated to 80° C. for 24 h. The mixture was cooled to rt and the precipitate was collected by filtration and dried to afford 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (11.1 g, 73%) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@H:11]2[CH2:13][C@H:12]2[CH2:14][CH2:15][OH:16])[CH2:7][CH2:6]1)=[NH:4].[C:17](Cl)(=O)[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O>[CH:18]([C:20]1[O:1][N:2]=[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C@H:11]3[CH2:13][C@H:12]3[CH2:14][CH2:15][OH:16])[CH2:7][CH2:6]2)[N:4]=1)([CH3:19])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: N=C(NO)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1nc(N2CCC([C@H]3C[C@H]3CCO)CC2)no1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-hydroxy-4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboximidamide (4.8 g, 21.10 mmol) was dissolved in Pyridine (60 ml) and isobutyryl chloride (18.44 ml, 176 mmol) was added. The mixture was stirred at 80° C. for 3 h and the solvent was evaporated to dryness. The residue was dissolved in MeOH (100 ml) and potassium carbonate (24.32 g, 176 mmol) was added. The mixture was stirred at 50° C. for 2 h. Another potassium carbonate (24.32 g, 176 mmol) was added and the mixture was stirred at 50° C. for another 2 h. The mixture was cooled down and diluted with EtOAc (100 mL), washed with water, sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by silica gel column eluting with 20-70% EtOAc in hexane to afford the desired product. LC/MS (m/z): 280 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:3])[CH3:2].Cl.[NH2:46]O.C([O-])(=O)C.[Na+]>CO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22]2[O:27][N:46]=[C:24]([CH3:25])[CH:23]=2)[CH2:9][C@@H:8]1[CH2:43][CH3:44])=[O:6])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)CC(C)=O)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C)no2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Yield: 5.4 %

Procedure:
To a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (225 mg, 0.35 mmol) in MeOH (1.7 mL) at 0° C., add hydroxylamine hydrochloride (37 mg, 0.53 mmol) and sodium acetate (1.4 mg, 0.017 mmol). Stir the reaction mixture under reflux overnight. Cool the mixture and remove the solvents under reduced pressure. Dilute the residue with ethyl acetate and brine. Separate the layers, and dry the organic phase over magnesium sulfate, filter, and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (12 mg, 5%). MS (ES+): 639 (M+H).
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])[CH2:30][CH2:29]1>CCOC(C)=O>[C:39]([C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=3)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:29][CH2:30]2)[CH:43]=[CH:42][CH:41]=1)#[N:40]
Reactant: N#Cc1cccc(CCC2CCNCC2)c1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C#N)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (723 mg) was added to an acetonitrile (10 ml) solution of 3-[2-(4-piperidyl)ethyl]benzonitrile hydrochloride (475 mg) and TEA (0.58 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, followed by washing with an aqueous saturated sodium hydrogencarbonate solution and drying over anhydrous magnesium sulfate. The solvent was evaporated, the resulting residue was subjected to basic silica gel column chromatography (eluent: hexane:EtOAc=1:1 (v/v)) and the side-product, nitrophenol was removed. Then, this was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:2 (v/v)) to obtain methyl 5-[({4-[2-(3-cyanophenyl)ethyl]-1-piperidyl}carbonyl)oxy]nicotinate (284 mg).
Reaction SMILES: O[NH-].[O:3]1[CH2:7][CH2:6]C[CH2:4]1.C(#[N:10])C.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:24]1([P:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[O:3]1[CH2:7][CH2:6][N:10]=[CH:4]1
Reactant: CC#N
Reactant: C1CCOC1
Agent: [NH-]O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C1=NCCO1

Procedure:
Hydroxyamide IX is then subjected to cyclodehydration in an inert organic solvent (e.g., tetrahydrofuran, acetonitrile or chloroform) under an inert atmosphere (e.g., argon) with triphenylphosphine (employing a molar ratio of V:triphenylphosphine of from about 0.8:1 to about 1:1) and carbon tetrachloride in the presence of an amine base (e.g., triethylamine or diisopropylethylamine) to form oxazoline ##STR23##
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[CH:17][N:18]([CH3:20])[CH3:19])[C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CC(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: CCCCc1ccc(C(=CN(C)C)C(C)=O)cc1

Procedure:
This ketone (4.6 g) was reacted with dimethylformamide dimethyl acetal (4.0 ml) as described in Example 1 to give 3-(4-butylphenyl)-4-dimethylamino-3-buten-2-one which was used without purification to prepare ethyl 5-(4-butylphenyl)-4-oxo-4H-pyran-2-carboxylate (mp 65° C.), by the method described in Example 17.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(N)=O

Procedure:
4-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (2.90 g, 9.78 mmol) was treated with mCPBA (5.5 g, 25 mmol), concentrated ammonium hydroxide (100 mL of 29%), and p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) according to the method described in Part E of Example 3. After the reaction solution was dried with potassium carbonate, it was decanted, and charcoal (2 g) was added. The mixture was heated at reflux for two hours, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure. The crude solid was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) and combined with material from another run. The solid was recrystallized from 5:1 toluene:methanol (18 mL), dried overnight in a vacuum oven, recrystallized from ethanol:water, and dried overnight in a vacuum oven to provide 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a tan solid, mp 249-251° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]([NH2:17])=[S:16])[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]2[S:16][CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:17]=2)[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(-c4ccccc4)cs3)[C@H]2SC1
Reaction time: 8 h
Yield: 101.9 %

Procedure:
A mixture of 539 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 240 mg of 2-bromo-1-phenylethanone, 85 mg of potassium carbonate and 7 ml of acetonitrile was stirred overnight, then filtered through hydrous magnesium silicate. The filtrate was evaporated, giving 660 mg of the desired compound [α]D26 =+68°±3° (c, 0.4 chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23]1>>[OH:22][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: CC(C)C1CO1
Product: CC(C)C(O)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with 1,2-epoxy-3-methylbutane gave 2-(3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propyl)isoindoline-1,3-diorie as yellow oil. Yield (1.105 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.11-8.14 (m, 1H), 7.52-7.57 (m, 2H), 7.33-7.36 (m, 1H), 7.17-7.21 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J=8.4, 2.0 Hz, 1H), 3.75 (d, J=5.6 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.84-2.03 (m, 5H), 1.03 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[S:9][C:10]([C:13]2([OH:20])[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:25][CH:24]([NH:26][C:27]([CH2:29][NH:30][C:31](=[O:42])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:28])[CH2:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[S:9][C:10]([C:13]2([OH:20])[CH2:18][CH2:17][CH:16]([N:22]3[CH2:25][CH:24]([NH:26][C:27](=[O:28])[CH2:29][NH:30][C:31](=[O:42])[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=4)[CH2:23]3)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C2(O)CCC(=O)CC2)s1
Product: CC(C)(C)OC(=O)Nc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of [5-(1-Hydroxy-4-oxo-cyclohexyl)-thiazol-2-yl]-carbamic acid tert-butyl ester, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7](=[O:22])[NH:6]1.[H-].[Na+].[Cl-].CN([CH:30]=[O:31])C>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7](=[O:22])[N:6]1[CH2:11][C:12]1[CH:21]=[CH:20][C:19]([O:31][CH3:30])=[CH:14][CH:13]=1
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc3ccccc3c2)C1=O
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC1C(=O)N(Cc2ccc3ccccc3c2)C(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
A 0° C. solution of compound (1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester (6.29 g, 20.1 mmol) in DMF (60 mL) is treated with sodium hydride (60% dispersion, 0.97 g, 24.3 mmol) and warmed to room temperature and stirred under N2 for 20 minutes. The resultant mixture is cooled to 0° C. and then treated with 4-methoxybenzyl, chloride (6.35 g, 40.6 mmol) and then warmed to room temperature and stirred for 16 hours. The reaction is quenched with aqueous 1 N HCl (100 mL) and then worked up extractively with Et2O and water. The organic layer is dried and the solvent removed to give crude product that is purified by flash chromatography using a gradient of 4:1 hexanes:acetone to afford 8.31 g (95%) [3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. Rf=0.44 (1:1 hexanes:acetone). 1H NMR.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=CC=C[CH:5]=1.N[C@H](C(O)=O)CCCCN>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
* 6.00 (6); Phe. 3.64 (4); Lys. 2.17 (3)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1.CN1CCOCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:2][CH2:3][C:4](=[O:5])[NH2:6])=[CH:22][CH:23]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(S)cc1
Reactant: NC(=O)CCBr
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(SCCC(N)=O)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 3-Bromopropionic acid amide (0.075 g, 0.5 mmol) in THF (5 ml) was added to a solution of [4-(4-mercaptophenyl)butyl]carbamic acid tert-butyl ester 560 (0.13 g, 0.46 mmol) dissolved in THF (15 mL) and 4-methylmorpholine (NMM) (0.3 mL). The reaction mixture was stirred at 50° C. for 4 h and then cooled to room temperature. Two more equivalents of 3-bromoprionic acid amide (0.15 g, 1 mmol) were added. The mixture was further stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to afford the desired product {4-[4-(2-carbamoylethylsulfanyl)phenyl]butyl}carbamic acid tert-butyl ester 570 (0.13 g, 80%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.48 (m, 2H) 1.60 (m, 2H), 2.46 (m, 2H), 2.58 (t, 2H), 3.09 (t, 2H), 3.13 (m, 2H), 7.14 (d, 2H), 7.29 (d, 2H). m/z (ESI) 353 [C18H28N2O3S+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[Cl:1][C:2]1[N:7]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[O:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(I)n1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
In a 0.5-2 mL microwave vial was placed 3-(6-chloro-2-iodopyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (16, 50 mg, 0.142 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (35.4 mg, 0.142 mmol) in DME (1.5 ml) to give an orange solution. Na2CO3 (2M solution in water) (0.284 ml, 0.569 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution. Pd(PPh3)4 (16.43 mg, 0.014 mmol) was added and the mixture was heated under microwave irradiation for 60 min at 100° C. The mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4) and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (10-25%). Collected fractions were concentrated to give 39 mg (0.11 mmol, 79%) of the title compound as an off-white/yellow solid. The thus obtained compound was identical to the same compound prepared according to Scheme 5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:36][C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2, mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:27](=[O:28])[CH:26]([O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:32][CH:31]=2)[CH3:30])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a mixture of 4-nitrophenol (21.8 g) and triethylamine (33 ml) in ethyl acetate (360 ml) at 0° C. was added 2-(4-nitrophenoxy)-propionyl chloride (36 g) dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was filtered to remove the salts, washed with 5% sodium bicarbonate, followed by water, and the ethyl acetate layer was dried over anhydrous sodium sulphate. The solvent was distilled off under vacuum and the compound was precipitated by adding cold methanol. Filtration and drying gave pure 2-(4-nitrophenoxy)-propionic acid-4-nitrophenyl ester (35 g) as white powder. The product had a melting point of 136-139° C., with a purity of 99%. The product was characterized by 1H NMR (CDCl3) δ 1.85 (d, 3H, CH3), 5.15 (q, 1H, CH), 7.05 (d, 2H, Ar), 7.28 (d, 2H, Ar), 8.30 (m, 4H, Ar).