Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:20][C:21]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]1[CH:37]=[N:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:30]=1[C:31]([NH2:33])=O>O1CCOCC1>[F:20][C:21]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]1[CH:37]=[N:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:30]=1[C:31]#[N:33]
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#Cc1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
Pyridine (28 μL, 0.35 mmol) and trifluoroacetic anhydride (27 μL, 0.19 mmol) were added to a solution of 3-(2-fluoro-4-iodo-phenylamino)-5-(2-fluoro-phenyl)-isonicotinamide (78 mg, 0.17 mmol) in dioxane (2 mL) at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was quenched with 2M NaOH and stirred for 10 minutes. The reaction solution was diluted with EtOAc and satd. NH4Cl, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated to provide a precipitate. The precipitate was washed with MeOH and dried under vacuum to afford the desired product (60 mg, 80%). LC-MS (M+H=434, obsd.=434).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:13]=[C:14](/[CH:16]=[CH:17]/[CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C1(C)C=CC=CC=1.C1(S(NN)(=O)=O)C=CC=CC=1>CCOCC>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC/C=C/c1cc(/C=C/COC)cc(C(=O)OC)c1
Agent: NNS(=O)(=O)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCCCc1cc(CCCOC)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3,5-bis[(1E)-3-methoxyprop-1-en-1-yl]benzoate (1 eq.) from the previous step in refluxing toluene was added benzenesulfonohydrazide (5 eq) in five portions over 2 h. The reaction was stirring as reflux for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with 1 N aqueous HCl, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][CH2:9][C:10](Cl)=[O:11]>CCOCC>[Cl:8][CH2:9][C:10]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:11]
Reactant: NCC(=O)O
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CNC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Glycine (1.5 g, 20 mmol) was dissolved in 2N NaOH (25 ml, 50 mmol) and ether (20 ml) was added. Chloroacetyl chloride (2.26 g) dissolved in Et2O (20 ml) was added dropwise at 0° C. The mixture was stirred at 0° for 30 minutes and at room temperature 1 hour. The layers were separated and the water layer was washed with Et2O (2×20 ml). The water layer was then acidified to pH 2 with concentrated HCl and the product was extracted into EtOAc (3×50 ml). The combined EtOAc extracts were washed with brine, dried (MgSO4), and freed of solvent in vacuo to give title acid compound as a solid (2.56 g, 84%) which was used without further purification.
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2.[OH-].[K+]>CO.O>[O:4]=[C:5]1[CH2:3][CH:6]2[CH2:7][C:8]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9][CH:10]([CH2:11][CH:12]1[CH2:13]3)[CH2:14]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of diazomethane (Diazald, 3.97 mmol) was added dropwise to a cold (0° C.) solution of ketone 1C (0.886 mmol) and KOH (40 mmol) in MeOH (10 mL) and water (2 mL) over a period of 3 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The resulting white-grey suspension was concentrated and the residue was partitioned between water (10 mL) and DCM (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated to yield ketone 1D in 90% yield. The ketone was used in the next step without further purification. Data: LC/MS (ESR) m/z 280 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([C:7]1[C:13]([OH:14])=C(CC=C(C)C)[C:10](=[O:11])[C:9]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:8]=1[OH:30])=[O:6])[CH3:3]>[OH-].[Na+]>[CH3:1][CH:2]([CH2:4][C:5]([CH:7]1[C:8](=[O:30])[C:9]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:10](=[O:11])[C:13]1=[O:14])=[O:6])[CH3:3]
Reactant: CC(C)=CCC1=C(O)C(C(=O)CC(C)C)=C(O)C(CC=C(C)C)(CC=C(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=CCC1(CC=C(C)C)C(=O)C(=O)C(C(=O)CC(C)C)C1=O

Procedure:
4 g lupulone are dissolved, with stirring, in 100 ml 0.5 N sodium hydroxide solution, filtered into a 250 ml three necked flask provided with a gas inlet tube, reflux condenser, and internal thermometer, and mixed with 1 g catalyst (see Table). After flushing out with oxygen, the apparatus is heated to the predetermined temperature. The lupulate solution is then oxidized with vigorous stirring, while oxygen is passed through. After completion of the reaction, which can be recognized by a marked fall in the absorption of oxygen, or after the consumption of 250 ml of oxygen, the solution is allowed to cool, the catalyst is filtered off, and the solution is acidified and twice extracted with 50 ml n-hexane on each occasion. The combined hexane solutions are dried over sodium sulphate and evaporated. The hulupone is obtained in the form of a bright yellow to brownish yellow oil (see Table).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:31]4=[O:40])[CH2:26][CH2:25]3)=[O:23])=[C:17]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:33][CH2:32][C:31]4=[O:40])[CH2:28][CH2:29]3)=[O:23])=[C:17]([O:41][CH2:42][C:43]([F:44])([F:45])[F:46])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a stirred solution of (N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1.2 g, 1.8 mmol) from Step 1 above in EtOAc (75 mL) at 0° C. was bubbled HCl gas for 15 min. The resulting suspension was stirred at 0° C. for 45 min. Excess HCl was removed by bubbling argon though the mixture for 15 min. Ether (150 mL) was added and the cold suspension was filtered. The solids were washed with additional ether and then dried under reduced pressure for 18 h to give the hydrochloride salt of the title compound as an amorphous white powder.
Reaction SMILES: CN[C@H]1CCCC[C@@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[NH:30]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:31]1>CCOC(C)=O.[Cu](I)I.C1(C)C=CC=CC=1>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[N:31]2)=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: COC(=O)c1cc[nH]n1
Agent: I[Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 110 °C

Procedure:
A 30 mL pressure tube was charged with (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine 61 (0.41 mL, 2.6 mmol), copper iodide (361 mg, 1.9 mmol), potassium phosphate (6.1 g, 29 mmol), 1-iodo-4-(trifluoromethyl)benzene 62 (3.2 g, 12 mmol), methyl 1H-pyrazole-3-carboxylate 60 (1.5 g, 12 mmol), and 15 mL of toluene. This mixture was heated at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated onto silica and purified by flash column chromatography on silica gel (0% to 3% MeOH in DCM) to give methyl 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate 63.
Reaction SMILES: COP([O-])(OC)=O.[C:8]1([I+:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]12([CH2:31][S:32]([OH:35])(=[O:34])=[O:33])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][C:22]2=[O:23].N>C(Cl)Cl>[C:21]12([CH2:31][S:32]([O-:35])(=[O:33])=[O:34])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][C:22]2=[O:23].[C:15]1([I+:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: COP(=O)([O-])OC
Agent: N
Agent: c1ccc([I+]c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Yield: 90.7 %

Procedure:
Diphenyliodonium dimethylphosphate (315 mg; 1 mmol) and camphorsulfonic acid (254 mg; 1.1 mmol) were dissolved in methylene chloride (10 ml), and the resultant mixture was stirred, followed by addition of 1% aqueous ammonia (10 ml). After the alkalinity of the solution was confirmed, the solution was stirred vigorously. The thus-obtained mixture was allowed to stand, and the aqueous layer was separated. The aqueous layer was washed with water successively until the aqueous layer exhibited neutral pH. The methylene chloride solution was dried, and the solvent was removed through distillation. The residue was washed in ether by stirring, to thereby precipitate 465 mg of the target compound as white crystals (yield: 91%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:24][C:21]([NH:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)Nc1cccnc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Nc1cccnc1N1CCNCC1

Procedure:
1-Benzyl-4-[3-(1,1-dimethylethylamino)pyridyl]piperazine (PREPARATION 96, 4.25 g, 13.10 mmol) is dissolved in 100 ml ethanol. Palladium (10% on carbon, 1.0 g) is added and the solution hydrogenated at 40 psi hydrogen gas. The mixture is filtered and concentrated to give the title compound, NMR (300 MHz, CD3OD) 7.53, 7.19, 6.93, 2.95, 1.39 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.[O:17]1[CH2:19][CH:18]1[CH2:20][N:21]1[C:29]2[CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25][C:24]=2[C:23]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[N:22]1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:19][CH:18]([OH:17])[CH2:20][N:21]4[C:29]5[CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25][C:24]=5[C:23]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=5)=[N:22]4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: Clc1ccc2oc(C3CCNCC3)nc2c1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(c3nc4cc(Cl)ccc4o3)CC2)C1
Temperature: 60 °C
Yield: 96 %

Procedure:
A solution of 130 mg (0.55 mmol) of 5-chloro-2-piperidin-4-yl-benzooxazole was dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 156 mg (95%) of a white solid. MS (electrospray): exact mass calculated for C30H31ClF3N5O3, 601.21; m/z found, 602.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers):7.76 (d, J=8.41 Hz, 1H), 7.71 and 7.67 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65-7.61 (m, 2H), 7.38 (d, J=8.61 Hz, 1H), 7.26 (dd, J=8.61, 1.96, 1H), 4.86 and 4.74 (A and B of AB quartet, J=15.65 Hz, 1H), 4.64 (br s, 1H), 4.24-4.10 (m, 2.3H), 4.07-3.97 (m, 1.7H), 3.89-3.67 (m, 2H), 3.06-3.00 (m, 1H), 3.00-2.90 (m, 2H), 2.90-2.74 (m, 2H), 2.51-2.38 (m, 3H), 2.25-2.10 (m, 2.3H), 2.20 (s, 1.5H), 2.15 (s, 1.5H), 2.06-1.83 (m, 2.7H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:1]([CH:8]1[CH2:12][C:13](=[O:14])[O:15][C:9]1=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(Cc1ccccc1)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CC(Cc2ccccc2)C(=O)O1
Yield: 94 %

Procedure:
The commercially available alpha-benzylsuccinic acid 9 (1 g, 4.8 mmol) was refluxed for 1 h in 30 mL trifluoroacetic anhydride. Afterwards, the solvent was removed in vacuo. The crude residue was washed with cold hexane to yield alpha-benzylsuccinic anhydride 10 as a white solid (858.2 mg, 93.95%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.I[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][OH:20].[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>[Cu]I.C1(C)C=CC=CC=1>[OH:20][CH2:19][C:18]1[CH:17]=[C:16]([N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])[CH:23]=[CH:22][CH:21]=1
Reactant: OCc1cccc(I)c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCCN1c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %) and K3PO4 (430 mg, 2.03 mmol), evacuated and backfilled with argon. N,N′-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol %), 3-iodobenzyl alcohol (128 μL, 1.01 mmol), 2-pyrrolidinone (94 μL, 1.24 mmol) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 3 h. The resulting white suspension was allowed to reach room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 5:1 ether-methanol (10 mL). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane-methanol 25:1; 15 mL fractions). Fractions 14-19 provided 180 mg (93% yield) of the product as a white solid. Mp: 120-121° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:20][NH2:21])[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1cc(Cl)nc(SCc2ccccc2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCc1cc(NN)nc(SCc2ccccc2)n1

Procedure:
A mixture of 40 g (0.014 mole) of 2-benzylthio-4-chloro-6-n-propylpyrimidine (from Part B) and 15 g (0.3 mole) of hydrazine hydrate in 300 ml of ethanol was heated at reflux for 2 hours, cooled and evaporated. Water was added to the residue. The white solid was collected by filtration and dried to provide 2-benzylthio-4-hydrazino-6-n-propylpyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[C:20]12([N:30]=[C:31]=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]([NH:30][C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:32])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)NC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a mixture of (S)-methyl 2-amino-3,3-dimethylbutanoate (200 mg, 1.377 mmol) and DIEA (0.481 mL, 2.75 mmol) in DCM (2 mL) solution was added 1-adamantyl isocyanate (334 mg, 1.515 mmol). The reaction mixture was stirred at rt overnight. The compound was purified by silica gel column chromatography (20% EtOAc/80% hexane) to give a white solid (265 mg, 59%) as product.
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(=[O:19])C.[K+].C(O)(=O)C>O>[CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCc1ccc(CCl)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc(CO)cc1
Yield: 53.4 %

Procedure:
A mixture of 16.2 g (68 mMols) of 4-octylbenzyl chloride, 41,8 g (0.43 mols) of potassium acetate and 200 ml of glacial acetic acid was heated for 20 h to 130° C. After cooling, the mixture was poured into approximately 1 liter of water and the aqueous phase was extracted with tert.-butyl methyl ether. The organic phase was washed twice with water, repeatedly with potassium hydrogen carbonate solution (2N) and then with saturated sodium chloride solution. After the solvent had been distilled off, the residue was taken up in 160 ml of 1,2-dimethoxyethane and, after the addition of 64 g of sodium hydroxide in 130 ml of water, the solution was heated for 45 h to boiling point. After the solvent had been distilled off, the residue was extracted with tert.-butyl methyl ether, the ether phase was washed with water, the solvent was distilled off, the residue was taken up in petroleum ether and the solution was reconcentrated by evaporation after treatment with active carbon and fuller's earth. Fractionation under reduced pressure produced 8 g (54% of theoretical) of 4-octylbenzyl alcohol boiling at 128° C./0.11 mbar and having a refractive index n of 1.5033.
Reaction SMILES: C(OC([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:42])[NH:19][CH2:20][C:21]([NH:23][CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][C:26]([O:28]CC2C=CC=CC=2)=[O:27])=[O:22])=[CH:13][CH:12]=1)=O)(C)(C)C.[H][H]>CN(C=O)C.[Pd]>[NH2:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:42])[NH:19][CH2:20][C:21]([NH:23][CH:24]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(NC(=O)NCC(=O)NC(CC(=O)OCc2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: NN=Cc1ccc(NC(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.38 g (0.66 mmol) of benzyl 3-((3-(4-(tert-butyloxycarbonylaminoiminomethyl)phenyl)ureido)acetylamino)-3-phenylpropionate is dissolved in 30 ml of DMF and treated with 0.07 g of Pd/C (10%). Hydrogen is then passed through for 24 h, solid is filtered off, the filtrate is concentrated in vacuo and the residue is treated with 1.53ml of trifluoroacetic acid (99%) and 0.15 ml of water. After stirring at room temperature for 48 h, the mixture is concentrated in vacuo and the residue is chromatographed on Sephadex (LH-20).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C(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>[OH:14][C:15]([CH3:47])([CH3:48])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:12][CH2:11][NH:10][C:9]4=[O:13])=[N:6][CH:7]=3)=[CH:30][CH:31]=2)[CH3:25])[CH2:19][CH2:18]1
Reactant: O=C1NCCN1c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cnc(N3CCNC3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (1 mg) was added to a mixture of 1-(5-bromopyrimidin-2-yl)imidazolidin-2-one (13 mg), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (38.6 mg) and Na2CO3 (17 mg) in toluene (3 mL), ethanol (2 mL), and H2O (1 mL) at room temperature. The reaction mixture was heated to 100° C. under nitrogen and stirred at this temperature for 2 h. After cooling to room temperature, the mixture was concentrated to give an oil, which was purified by preparative HPLC to afford the title compound. Yield: 3.1 mg (11% of theory); LC (method 4): tR=0.93 min; Mass spectrum (ESI+): m/z=516 [M+H]+; 1H NMR (CD3OD) δ 0.92 (s, 3H), 1.32 (s, 3H), 1.58 (d, 3H), 2.06 (s, 2H), 2.19 (m, 2H), 2.50 (m, 2H), 3.58 (m, 2H), 4.20 (m, 2H), 5.62 (m, 1H), 7.11 (d, 2H), 7.33 (m, 5H), 7.42 (d, 2H), 8.78 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C.O>ClCCl>[N+:24]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[N:22][CH:21]=[CH:20][CH:19]=2)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A solution of tert-butyl 3-aminopropylcarbamate (15.7 g, 90.2 mmol) in dichloromethane (50 mL) was added dropwise over 30 minutes to a solution of 4-chloro-3-nitro[1,5]naphthyridine (18.0 g, 85.9 mmol) and triethylamine (15.6 mL, 112 mmol) in dichloromethane (235 mL) at room temperature. The reaction mixture was stirred for 2.5 hours and then concentrated under reduced pressure to afford an orange solid. Water (300 mL) was added and the mixture was stirred for one hour. The solid was isolated by filtration, washed with water (3×50 mL), and dried under vacuum at 70° C. to afford 29.5 g of tert-butyl 3-[(3-nitro[1,5]naphthyridin-4-yl)amino]propylcarbamate as a yellow solid.