Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:10]([F:21])=[C:11]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].C(O)(=O)/C=C/C(O)=O>[Pt]=O.CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:21])=[C:11]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(S(=O)(=O)N(C)C)c2F)CC1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCN1CCC(c2cccc(S(=O)(=O)N(C)C)c2F)CC1

Procedure:
Preparation according to Example 3: 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N,N-dimethylbenzenesulfonamide (0.27 g, 0.86 mmol), methanol (10 ml), platinum oxide (0.05 g). Yield: 0.16 g (59%). The amine was converted to fumaric acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 151-152° C. MS m/z (relative intensity, 70 eV) 314 (M+, 18), 313 (11), 300 (17), 299 (bp) 191 (11).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.Cl.[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)([O:30][CH3:31])=[O:29].O>C(#N)C>[CH3:31][O:30][C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:34][CH:33]=1)=[O:29]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (250 mg, 0.968 mmol) in acetonitrile (5 mL) was added triethylamine (245 mg, 2.42 mmol) and 4-carbomethoxybenzylamine hydrochloride (215 mg, 1.07 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (372 mg, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.CO[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=COC)C(=O)OCC
Reactant: COc1ccc(N)cc1
Product: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a flask maintained under reduce pressure, p-methoxyaniline (35.1 g, 280 mmol) and diethyl 2-(methoxymethylene)malonate (73.97 g, 340 mmol) were stirred at 100° C. for two h. The crude mixture was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[N:16](CC3C=CC=CC=3)[CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.[Pd]>[CH2:1]([N:8]1[C:9](=[O:24])[CH:10]2[NH:16][CH:13]([CH2:12][CH2:11]2)[C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCC(C(=O)N1Cc1ccccc1)N2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1C2CCC(N2)C(=O)N1Cc1ccccc1
Yield: 80 %

Procedure:
To a stirred solution of 3,8-dibenzyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (0.00025 mol, 80 mg) in MeOH (2 mL) containing few drops of HCl was hydrogenated with 10% Pd—C (8 mg) for 4 h at room temperature. After completion of the reaction (checked by TLC), the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 60-120 mesh; EA-Hexane, 6:4) to afford the 3-benzyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (LXVI) in 80% yield.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=[O:35]>>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of betulin 1 (1 g, 2.26 mmol) in acetone (50 ml), cooled at 0° C., freshly prepared Jone's reagent was added dropwise. The resulting mixture was stirred for about 1.5 h at 0° C., quenched with methanol (25 ml), stirred for an additional 5 minutes, then water (40 ml) was added. The acetone was removed under vacuum and the aqueous residue was extracted with ethyl acetate (2×40 ml) and washed with water (30 ml) and brine (30 ml). Dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was submitted to FCC with petroleum ether 40-60° C./ethyl acetate (4:1) and afforded compound 11 (685 mg, 67%): IR (film) υmax 3070, 1703, 1686, 1642 cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.77 (brs, 1H, H-29a), 4.64 (brs, 1H, H-29b), 3.04 (dt, J=10.7 Hz, J=4.3 Hz, 1H, H-19), 1.72 (s, 3H, H-30), 1.09 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 218.2 (C3), 182.2 (C28), 150.3 (C20), 109.7 (C29). EI-MS m/z (% rel. intensity): 454 (19) M+, 408 (24), 393 (20), 248 (85), 189 (100), 175 (62), 133 (55), 119 (76), 105 (69), 79 (52).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A mixture of 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (1.38 g, 5.07 mmol), 2-chloroisonicotinoyl chloride (1.34 g, 7.6 mmol), DIPEA (1.81 ml, 10.1 mmol) and THF (30 ml) is stirred at room temperature for 12 hours. The mixture is quenched with water (100 ml). The crude product is extracted with EtOAc (2×50 ml), the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (3% MeOH in EtOAc) to afford 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide (1.07 g, 51%). 1H NMR (DMSO-d6) δ 10.61 (s, 1H), 8.62 (d, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 7.95 (m, 2H), 7.59 (d, 2H), 7.49 (d, 1H), 7.09 (d, 1H), 4.33 (m, 2H), 3.61 (m, 4H), 2.92 (m, 2H), 2.61 (m, 4H). MS: 412 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>CC(=O)C>[OH:20][C:17]([CH3:18])([CH3:16])[CH2:1][S:2]([N:5]1[CH2:6][CH2:7][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH2:25][CH2:26]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Solvent: CC(C)=O
Product: CC(C)(O)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 208 step B from 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 208, step A) and propan-2-one. White solid. MS (ESI): 451.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].C[O:12][C:13](=O)[CH2:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19].[O-]CC.[Na+]>C(O)C>[CH2:16]([C:15]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:6][C:13](=[O:12])[CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N=C(N)c1cccc(F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1cc(=O)[nH]c(-c2cccc(F)c2)n1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 3-fluorobenzamidine (1.14 g) and 3-oxoheptanoic acid methyl ester (1.0 g, Fluka, USA) in 15 mL of ethanol was added 3.15 mL of a 3 M solution of sodium ethoxide in ethanol. The mixture was heated to reflux for 48 h, allowed to cool to room temperature, and the volatiles were removed in vacuo. The residue was dissolved in chloroform and washed with water three times. The aqueous extractions were combined, acidified to pH=6, and washed three times with ethyl acetate. All organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The product was purified by column chromatography using 60% ethyl acetate in hexanes as the mobile phase to yield 6-butyl-2-(3-fluorophenyl)-3H-pyrimidin-4-one (0.9 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K58) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (31 mg).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C([O:29][N:30]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NO>CN(C=O)C.C(OCC)(=O)C>[OH:29][NH:30][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][N:10]2[CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2ccn(CCOc3ccccc3)c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccc2ccn(CCOc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.8 %

Procedure:
To a solution of 1-(2-phenoxyethyl)-1H-indole-6-carboxylic acid (0.66 g, 1.31 mmol) and TEA (0.92 mL, 6.6 mmol) in DMF (10 mL) was added HATU (0.52 g, 1.37 mmol). The solution was stirred 1 hr at room temperature, then NH2OH (50% wt/wt in H2O; 2 mL) was added and the solution was stirred 1 hr. The reaction solution was then diluted with ethyl acetate (150 mL) and washed with 1N HCl (100 mL) and then aq. NaHCO3 (100 mL). Then organic layer was dried (MgSO4), filtered and then concentrated to provide 0.57 g (93%) of N-hydroxy-1-(2-phenoxyethyl)-1H-indole-6-carboxamide a light yellow solid. 1H NMR (300 MHz, DMSO) δ 11.11 (s, 1H), 8.94 (s, 1H), 8.06 (s, 1H), 7.56 (m, 2H), 7.66 (dd, 1H, J=8.5 Hz, J=1.5 Hz), 7.24 (m, 2H), 6.88 (m, 3H), 6.48 (d, 1H, J=3.0 Hz), 4.61 (t, 2H, J=5.2 Hz), 4.30 (t, 2H, J=5.2 Hz). EM (calc.): 296.12; MS (M+H): 297.06.
Reaction SMILES: F[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:25])[CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][NH:22][CH2:23][CH3:24])[CH2:17][CH2:16]1)[CH3:11].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[CH2:23]([N:22]([CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:25])[CH2:16][CH2:17]1)[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: O=Cc1ncccc1F
Reactant: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2C=O)CC1

Procedure:
A mixture of 3-fluoropyridine-2-carbaldehyde (122.7 mg, 0.981 mmol), ethyl{trans-4-[(ethylamino)methyl]cyclohexyl}acetate (202.7 mg, 0.892 mmol), potassium carbonate (369.7 mg, 2.67 mmol) and dry toluene (13 mL) was heated at reflux under N2 overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-50% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[ethyl(2-formylpyridin-3-yl)amino]methyl}cyclohexyl)acetate as a yellow oil. Rf=0.79 (50% EtOAc/hexanes). LCMS calc.=333.2; found=333.3 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 10.13 (s, 1 H); 8.29 (d, J=4.1 Hz, 1 H); 7.41 (d, J=8.5 Hz, 1 H); 7.29 (dd, J=4.1, 8.4 Hz, 1 H); 4.08 (q, J=7.1 Hz, 2 H); 3.26 (q, J=7.0 Hz, 2 H); 3.05 (d, J=7.1 Hz, 2 H); 2.12 (d, J=6.9 Hz, 2 H); 1.71 (m, 4 H); 1.66 (m, 1 H); 1.41 (m, 1 H); 1.22-1.20 (t, J=7.1 Hz, 3 H); 1.06 (t, J=7.1 Hz, 3 H); 0.91-0.82 (m, 4 H).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.N[C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([OH:21])(=[O:20])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Product: O=C(O)C=Cc1ccccc1

Procedure:
First, a sample of a cell extract was diluted with a 25 mM Tris-HCl buffer solution (pH 8.8) to give a cell concentration of about 1% by wet weight and a 1.0 ml portion thereof was added to 4.0 ml of a 31.25 mM Tris-HCl buffer solution (pH 8.8) supplemented with 31.25 mM L-phenylalanine. The resultant solution was allowed to react at 30° C. for 20 minutes and then the reaction was terminated by addition of 1 ml of 1N-HCl. The amount of cinnamic acid produced in the reaction mixture was determined by liquid chromatography under the conditions as hereinafter described to estimate the PAL activity.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:35]#[N:36])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28]C5CCCCO5)[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:37]=[C:38]([Br:41])[CH:39]=[N:40][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl.CO>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:35]#[N:36])=[C:18]([O:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][OH:28])[CH2:24][CH2:25]4)[C:13]=3[C:12]3[CH:37]=[C:38]([Br:41])[CH:39]=[N:40][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCN(CCOC3CCCCO3)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ncc2c(c1OC1CCN(CCO)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 107.8 %

Procedure:
To a solution of 9-benzenesulfonyl-3-bromo-5-{1-[2-(tetrahydropyran-2-yloxy)-ethyl]-piperidin-4-yloxy}-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (330 mg, 0.52 mmol) in dichloromethane (5 mL) and methanol (10 mL) was added tosic acid monhydrate (100 mg, 0.52 mmol) and the reaction mixture heated to 40° C. for 4 hours then concentrated in-vacuo. The resultant residue was was taken up in dichloromethane, diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was dried (Na2SO4), filtered, evaporated in-vacuo to afford the crude title compound as a pale yellow solid (312 mg) which was used without purification. 1H NMR (300 MHz, CDCl3): 9.56 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.64-7.63 (m, 1H), 7.52-7.51 (m, 2H), 5.16-5.14 (m, 1H), 3.65 (t, J=5.3 Hz, 2H), 2.96 (m, J=11.5 Hz, 2H), 2.61 (t, J=5.3 Hz, 2H), 2.39 (t, J=11.3 Hz, 2H), 2.25 (m, J=12.5 Hz, 2H), 2.03-2.01 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]([CH3:12])[C:8]([NH:10][CH3:11])=[S:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I>C1COCC1>[CH3:17][S:9][C:8](=[N:10][CH3:11])[N:7]([CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CI
Reactant: CNC(=S)N(C)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN=C(SC)N(C)Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
In 50 ml of dry THF was dissolved 4.69 g (0.0205 mole) of N-(4-chlorobenzyl)-N-methyl-N'-methylthiourea, followed by addition of 0.82 g of 60% sodium hydride (oil). The mixture was refluxed for 1 hour. Then, under cooling with ice-water and stirring, 1.277 ml of methyl iodide was added dropwise and after completion of dropwise addition, the mixture was further stirred at room temperature for 45 minutes. The THF was distilled off and the residue was diluted with water (about 50 ml), saturated with sodium chloride, and extracted with AcOEt (100 ml×3). The extract was dried over MgSO4 and the solvent was distilled off to give 5.11 g of crude S-methyl-N-(4-chlorobenzyl)-N-methyl-N'-methylisothiourea as a colorless-pale yellow oil.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)=[O:36]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH:35]=[O:36])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(=O)OC(C)(C)C)c2c1
Yield: 53 %

Procedure:
To a solution of methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate in 1,4-dioxane (0.15 M) was added Na2CO3 (6 eq, 2 M solution), (2-formylphenyl)boronic acid (1.5 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.2 eq) and the mixture heated at reflux for 45 min. The reaction mixture was allowed to cool and filtered. The filtrate was diluted with EtOAc and the organic phase washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by flash chromatography (1:9 EtOAc/PE) to afford the title compound as a yellow solid (53%); MS (ES+) m/z 476 (M+H)+
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1.C(N(CC)CC)C.[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C

Procedure:
6-[5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (4; 0.39 g, 0.86 mmol) was completely dissolved in DMF (15 mL) with gentle warming. After cooling the solution to room temperature without reprecipitation, it was mixed with triethylamine (Et3N; 0.52 g, 5.15 mmol) followed by the addition of 5 (0.25 g, 1.14 mmol) in DMF (3 mL) dropwise while stirring. After overnight reaction at room temperature, the mixture was filtered, evaporated in vacuo, and loaded to a silica column for further purification. The products were separated by eluting with mobile phases of 5-20% MeOH in DCM to afford 6 (0.45 g; 93.8%) as a yellowish solid. 1H NMR (400 MHz) (CD3OD) δ: 4.53 (t, 1H, CHN), 4.34 (t, 1H, CHN), 3.25 (dd, 1H, CHS), 3.20 (t, 2H, CH2NH), 3.08 (t, 2H, CH2NH), 2.96 (d, 1H, CHHS), 2.73 (d, 1H, CHHS), 2.22 (t, 4H, CH2CO), 1.38-1.80 (m, 29H). 13C NMR (100.67 MHz) (DMSO) δ: 176.02, 175.97, 166.05, 158.50, 79.50, 63.39, 61.63, 57.01, 41.24, 41.04, 40.24, 36.99, 36.82, 30.90, 30.35, 30.13, 29.78, 29.49, 28.80, 27.56, 26.92, 26.74. HRMS (ESI) calculated for C27H49N5O5S, [M+Na]+ 578.3352 (calcd.), 578.3349 (found).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[C:11]12([C:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][N:8]=3)[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(C23CC4CC(CC(C4)C2)C3)n[nH]1
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Preparation C13, Step 3: 5-Adamantan-1-yl-2H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 3.64 mmol, 1 eq.) was dissolved in THF (20 mL) at RT then 1.000 N NaOH (7.29 mL, 7.29 mmol, 2 eq.) was added. Stirred overnight. Stripped off the THF in vacuo then adjusted the pH=3 with 1 N HCl. Extracted 3 times with ethyl acetate (25 mL). The organic layers were combined, dried and stripped to give 830 mg of 5-adamantan-1-yl-2H-pyrazole-3-carboxylic acid as an off-white solid. MS found: (M+H)+=247.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(N1CCOCC1)C>[CH3:15][C:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1
Agent: CCN1CCOCC1
Product: CC(C)(C)Nc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Reaction time: 25 h
Yield: 64 %

Procedure:
A mixture containing 9.58 g (34.7 mmoles) of 4-chloro-2,6-bis(1,1-dimethylethylamino)pyrimidine, 11.95 g (138.8 mmoles) of piperazine and 150 ml of N-ethylmorpholine is boiled under reflux and nitrogen atmosphere for 25 hours, then the solvent and the excess of piperazine are distilled off under atmospheric pressure. Subsequently, 100 ml of water are added to the residue and the distillation is continued until the head temperature reaches 100° C. After cooling down, the residue is distributed between 200 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 50 ml of water each, then dried and evaporated. The residue is purified by chromatography on a silica gel column by using a 9:1 mixture of chloroform/methanol as eluent. After evaporating the eluate the residue is recrystallized from hexane to obtain the title compound in a yield of 64%, m.p.: 142°-145° C.