Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15](C)CO)=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].N[C@@H](C)CO>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: C[C@H](N)CO
Product: CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1

Procedure:
The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting methylamine for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.31 (s, 1H), 7.88 (m, 1H), 7.72 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.58 (m, 2H), 2.89 (s, 3H), 2.18 (s, 3H). ESHRMS m/z 481.0684 (M+H calculated for C20H16BrF2N3O3 NH4 requires 481.0681).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine prepared as described in Example 1.D. (0.15 g, 0.51 mmol), 2-chloro-3-fluoropyridine (0.134 g, 0.10 mmol), N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reaction mixture 9 h at 170° C. to obtain 0.062 g of a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-c2nccs2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3nccs3)c2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of 4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid methyl ester (0.310 g, 1 mmol) in THF (10 mL) was added a solution of LiOH—H2O (1.2 mmol) in H2O (15 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred until the disappearance of the ester was confirmed by TLC. Solvent was removed under reduced pressure and the aqueous solution was acidified to pH=2 by dropwise addition of 10% aqueous HCl. The resulting solid was collected by filtration and dried to yield 4′-Methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (0.22 g, 75%). MS (M+H)=296.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH3:10]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)COC
Temperature: -78 °C
Yield: 75 %

Procedure:
1.5 ml of triethylamine was added to 500 mg of amino-acetic acid ethylester hydrochloride dissolved in 5 ml of chloroform, and the solution was cooled to −78° C. 0.34 ml of methoxyacetylchloride diluted with 3 ml of chloroform was slowly added thereto, and the resulting solution was heated slowly to room temperature and reacted for 6 hours. The reacted solution was washed with distilled water, adjusted to pH 8 to 9 by adding saturated sodium bicarbonate solution, extracted with organic solvent, dried over magnesium sulfate, and filtered and distilled under a reduced pressure to obtain the title compound (595 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N:11]=O>C(O)C.ClCCl.[Pd]>[NH2:11][C:3]1[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH2:1]
Reactant: Cc1nn(CCO)c(N)c1N=O
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cc1nn(CCO)c(N)c1N
Reaction time: 2 h
Yield: 96.6 %

Procedure:
5-Amino-1-(2-hydroxyethyl)-3-methyl-4-nitrosopyrazole (0.9 g, 5.3 mmole) was dissolved in a mixture of ethanol (40 ml) and dichloromethane (40 ml) and hydrogenated over 10% Pd/C (0.1 g) at 20 p.s.i. and 20° C. for 2 hours. The catalyst was filtered onto Arbocel and the solvent removed under reduced pressure yielding the title compound as a foam (800 mg, 97%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[S:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[K+].C(=O)=O>C(O)C.O>[CH2:19]([O:18][C:16]([C:15]1[S:10][C:9]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=2)=[N:11][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)(C)c1ccc(C(N)=S)cc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(C)(C)C)cc2)nc1C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
The solution of 3.87 g (20 mmol) of 4-tert-butyl-thiobenzamide and 3.45 g (21 mmol) of ethyl 2-chloro-acetoacetate in 15 ml of ethanol was heated at reflux for 3 hours. Afterwards, the reaction mixture was cooled to ambient temperature and a solution of 3 g of potassium bicarbonate in 15 ml of water was added and the mixture was stirred until the gas evolution (CO2) had ceased. The compound was then extracted with 3 portions of 50 ml of tert-butyl methyl ether, the combined organic phases were washed with water, then with brine, dried over anhydrous sodium sulfate and finally evaporated. 5.3 g of 2-(4-tert-butyl-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (87.4% of theory) were obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][CH2:2][C@:3]1([C@@H:31]2[O:35][C@@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@@H:32]2[CH3:47])[O:7][C@@H:6]([C@@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@H:18]([C@@H:20]([O:26][CH3:27])[C@@H:21]([C:23]([O-:25])=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[Na+].N12CCC(CC1)CN2.[CH2:57](Br)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(#N)C>[CH3:1][CH2:2][C@:3]1([C@@H:31]2[O:35][C@@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@@H:32]2[CH3:47])[O:7][C@@H:6]([C@@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@H:18]([C@@H:20]([O:26][CH3:27])[C@@H:21]([C:23]([O:25][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1
Reactant: CC[C@@]1([C@@H]2O[C@@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@@H]2C)CC[C@H]([C@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(=O)[O-])O3)O2)O1
Reactant: BrCc1ccccc1
Agent: C1CN2CCC1CN2
Agent: [Na+]
Solvent: CC#N
Product: CC[C@@]1([C@@H]2O[C@@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@@H]2C)CC[C@H]([C@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(=O)OCc4ccccc4)O3)O2)O1
Temperature: 25 °C
Reaction time: 336 h

Procedure:
Monensin sodium salt (1.0 g, 1.4 mmol) in acetonitrile (20 ml) was treated with diazabicyclo [2.2.2] octane (0.3 g, 2.7 mmol) followed by benzyl bromide (2 g, 11.7 mmol) and cryptand [2.2.2]. The reaction mixture was stirred at room temperature with exclusion of light for 14 days. After 10 days an additional quantity of benzyl bromide (2 g, 11.7 mmol) was added. The solvent was evaporated and the crude product redissolved in dichloromethane, washed with deionized water and dried over magnesium sulfate. The crude product was chromatographed on silica gel eluting with hexane-ethyl acetate gradient. Excess benzyl bromide eluted from the column first followed by benzylmonensin which was isolated as a colorless oil after removal of the solvent (280 mg, 26%), (MS, positive ion ESI showed 783 peak; calc. for sodiated product 783). This compound has been reported previously (Tsukube J. Org. Chem. 56, 875, 1991).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:18][O:19][C:20]1[CH:46]=[CH:45][C:23]([CH2:24][N:25]2[CH2:29][CH:28]([CH2:30][CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[N:27]([CH3:43])[C:26]2=[O:44])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][CH2:30][CH:28]2[CH2:29][N:25]([CH2:24][C:23]3[CH:45]=[CH:46][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:26](=[O:44])[N:27]2[CH3:43])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC(C)C
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)OC(C)C
Temperature: 55 °C
Yield: 84.8 %

Procedure:
3-(4-Hydroxy-phenyl)-2-isopropoxy-propionic acid methyl ester (1.7 g, 7.3 mmol), Toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.4 g, 8.0 mmol), and Cs2CO3 (3.6 g, 11 mmol) were combined in 10 mL of DMF and heated at 55° C. for 18 h. After cooling, the mixture is diluted with 100 mL of water and extracted with 3×20 mL of ethyl acetate. The organics were dried, concentrated, and the residue is purified by flash chromatography using 7/3 ethyl actate/hexanes to give 3.0 g (86%) of the title compound as an oil. NMR
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:34][CH3:35])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([CH3:33])[CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+]>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:34][CH3:35])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([CH3:33])[CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoate (3.49 g, 7.28 mmol) was dissolved in tetrahydrofuran (THF) (90 ml) and water (30.0 ml) was added. Lithium hydroxide (0.458 g, 10.92 mmol) was added and the mixture stirred under argon at room temperature overnight. The THF was rotavaped off, and the aqueous residue was adjusted to ˜pH of 6 with 1N HCL. A white solid formed and was filtered and washed 2× with water (10 mL). This solid was dried at 50° C. in a vacuum oven for 6 h to give the title compound as a white solid. LC-MS m/z 466.0 (M+H)+, 0.73 min (ret time); mp 236-239° C.; analytical HPLC shows 97.3% purity, (ret time 10.841 min).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[NH:7]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]C[C:8]1=[O:17].S(Cl)(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH:29]([Cl:32])(Cl)[Cl:30]>>[Cl:30][C:29]1([Cl:32])[CH2:10][C@H:11]2[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7][C:8]1=[O:17]
Reactant: ClC(Cl)Cl
Reactant: O=C1CC[C@@H]2CCCC[C@@H]2N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(=O)(Cl)Cl
Product: O=C1N[C@H]2CCCC[C@H]2CC1(Cl)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
28.8 g of phosphorus pentachloride were added to a solution of 23 g of cis-octahydro-1H-quinolin-2-one in 350 ml of anhydrous chloroform. To this were added dropwise 43.1 g of sulfuryl chloride in 45 ml of anhydrous chloroform at 20° to 30° C. within 30 min and the reaction mixture was stirred at the boiling point for 5 hours. After allowing to stand overnight, the mixture was neutralized with aqueous potassium carbonate cooled to 0° C. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The residue was recrystallized from ethanol with the addition of active charcoal. 32 g of pale yellow crystals, having a melting point of 176° to 177° C., were obtained.
Reaction SMILES: [CH2:1]([N:5]([C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1)[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([C:23]1[CH:24]=[C:25]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1)[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of ethyl [4-({butyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}sulfonyl)-2-methylphenoxy]acetate (100 mg, 0.18 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL), was added 2M NaOH aq. (2 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×20 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (85 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C@@:5]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=1)[CH3:2].[CH3:32][CH2:33][CH2:34]CB(O)O.C([O-])([O-])=O.[K+].[K+].[C:45]1([CH3:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:1]([O:3][C:4](=[O:31])[C@@:5]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:48]2[CH:49]=[CH:50][C:45]([CH2:51][CH2:32][CH2:33][CH3:34])=[CH:46][CH:47]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCCCB(O)O
Reactant: CCOC(=O)[C@@](C)(CCc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCc1ccc(-c2ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)OCC)cc2)cc1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
(R)-2-tert-Butoxycarbonylamino-2-methyl-4-(4-trifluoromethane sulfonyloxy-phenyl)-butyric acid ethyl ester (100 mg), 4-butylboronic acid (75 mg) and K2CO3 (44 mg) are suspended in dry toluene (3 ml). Argon is bubbled through the mixture for 10 min., tetrakispalladiumtriphenyl-phosphine (5 mg) is added and the mixture is stirred at 95° C. under Argon for 16 h. After cooling to RT, ethyl acetate (5 ml) is added and the mixture is washed with 0.5N NaOH (2 ml), water (2 ml), 1M citric acid (2×2 ml) and water (2 ml). The organic phase is dried over MgSO4, the solvent removed and the crude material purified by chromatography using diethylether/hexane=1/5 (Rf=0.14, MS: (ES+): 454.6 (M+H)+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16](N)=[O:17]>O>[O:17]=[C:16]1[NH:15][C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([Cl:14])[CH:7]=2)[NH:1]1
Reactant: NC(N)=O
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Temperature: 180 °C
Yield: 65 %

Procedure:
A mixture of 6.0 g (27.7 mmol) of 2-amino-5-chloro-4-nitrobenzoic acid and 10.0 g (0.166 mol) of urea was heated at 180° C. for 2.5 hrs. The resulting brown mass was boiled with 200 ml of water. Subsequently, it was filtered off, washed with water and with acetone and dried in a vacuum. 4.35 g (65%) of 2,4-dioxo-6-chloro-7-nitro-1,2,3,4-tetrahydroquinazoline were obtained as a dark brown powder;
Reaction SMILES: [OH:1][CH:2]([CH2:16][OH:17])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[H-].[Na+].F[C:21]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C1C[O:35]CC1>>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:21]=1[O:17][CH2:16][CH:2]([OH:1])[CH2:3][CH2:4][NH:5][C:13]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:6]([OH:35])=[O:15])=[O:14])#[N:24]
Reactant: O=C1c2ccccc2C(=O)N1CCC(O)CO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccc([N+](=O)[O-])cc1OCC(O)CCNC(=O)c1ccccc1C(=O)O

Procedure:
2-(3,4-dihydroxybutyl)isoindoline-1,3-dione was reacted as described in Intermediate Y(2) with sodium hydride and 2-fluoro-4-nitrobenzonitrile in THF to get 2-(4-(2-cyano-5-nitrophenoxy)-3-hydroxybutylcarbamoyl)benzoic acid which is used as-is in the next step. LC-MS (M+H)+=400.1.
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:7])=[CH2:6])=[O:3].[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH:25]=3)[C:15]([CH3:19])=[N:16]2)=[CH:11][N:10]=1>N1C=CC=CC=1>[CH2:6]=[C:5]([O:4][C:2](=[O:3])[NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH:25]=3)[C:15]([CH3:19])=[N:16]2)=[CH:11][N:10]=1)[CH3:7]
Reactant: Cc1nc2cc(N)ncc2cc1-c1ccc(F)c(NC(=O)NCCC(C)(C)C)c1
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc2nc(C)c(-c3ccc(F)c(NC(=O)NCCC(C)(C)C)c3)cc2cn1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
Add isopropenyl chloroformate (0.193 mL, 1.769 mmol) to a 0° C. solution of 1-(5-(7-amino-2-methyl-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,3-dimethylbutyl)urea (0.636 g, 1.608 mmol) in pyridine (10 mL) and stir the mixture for 1 h as it warms to RT. Add water, extract with DCM (3×), dry the combined organics over MgSO4 and concentrate to dryness to afford the title compound (585 mg, 76%). MS(ESI) m/z: 480.2 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:70]([CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@H:40]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:41][S:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:72])=[O:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](CSCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](CSCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
19.3 mg (20 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulfanyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 20) was dissolved in 1.2 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride, by analogy with the synthesis in Example 1. After lyophilization from dioxane, 8.6 mg (45% of the theoretical) of the title compound was obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:7]/[CH:8]=[CH:9]/[C:10]23[CH2:17][CH2:16][C:13]([C:18]([O:20][CH3:21])=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)[O:6][CH2:5][CH2:4][O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]23[CH2:11][CH2:12][C:13]([C:18]([O:20][CH3:21])=[O:19])([CH2:16][CH2:17]2)[CH2:14][CH2:15]3)[O:3][CH2:4][CH2:5][O:6]1
Reactant: [H][H]
Reactant: COC(=O)C12CCC(/C=C/CC3(C)OCCO3)(CC1)CC2
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C12CCC(CCCC3(C)OCCO3)(CC1)CC2
Reaction time: 3 h

Procedure:
Methyl 4-[(1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl]bicyclo[2.2.2]octane-1-carboxylate (4-B) (1.1 g) was stirred in ethanol (75 mL). A spatula tip scoop of 10% Pd on carbon (150 mg) was added. A hydrogen balloon was added and the mixture was stirred under hydrogen atmosphere for 3 h. The palladium-on-carbon was filtered and the ethanol was removed in vacuo to yield methyl 4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]bicyclo[2.2.2]octane-1-carboxylate (4-C).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:18])[NH:9][C:10](=O)[C:11]3[C:16]=2[C:15]=1[CH:14]=[CH:13][CH:12]=3)([O-])=O.[CH3:19][OH:20].[C:21](O)(=O)[CH3:22]>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:18])[N:9]([C@H:10]3[CH:6]4[CH2:21][CH2:22][N:9]([CH2:8][CH2:7]4)[CH2:10]3)[C:19](=[O:20])[C:11]3[C:16]=2[C:15]=1[CH:14]=[CH:13][CH:12]=3
Reactant: O=C1NC(=O)c2ccc([N+](=O)[O-])c3cccc1c23
Reactant: CO
Reactant: CC(=O)O
Agent: [Pd]
Product: Nc1ccc2c3c(cccc13)C(=O)N([C@@H]1CN3CCC1CC3)C2=O

Procedure:
A solution of (S)-2-(1-azabicyclo[2.2.2.]oct-3-yl)-2,3-dihydro-6-nitro-1H-benz[de]isoquinoline-1,3-dione (3.2 g; 8.8 mmol), prepared as in Example 2, in acetic acid (80 mL) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1.2 g) for 3 hours. The catalyst was removed by filtration, the filtrate concentrated to a small volume, and the residue dissolved in water. This aqueous solution was added dropwise to dilute NH4OH and the solid that precipitated was collected on a Buechner funnel. Drying under vacuum gave (S)-6-amino-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (2.57 g; 7.93 mmol), m.p. 305°-308° C., [α]D25 -44.2° (c=0.373, MeOH).