Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.C([NH2:39])=O.CO[Na].O>CN(C=O)C.CO>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([N:8]2[C:9]3[C:10](=[O:28])[N:11]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C:22]5=[O:27])=[CH:17][CH:16]=4)[CH2:12][CH2:13][C:14]=3[C:6]([C:4]([NH2:39])=[O:3])=[N:7]2)=[CH:34][CH:33]=1
Reactant: NC=O
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Agent: CO[Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Method B. A solution of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 977 mg, 2.0 mmol) in DMF (5 mL) was treated with formamide (901 mg, 0.8 mL, 20 mmol, 10.0 equiv) at room temperature, and the resulting reaction mixture was cooled down to 0–5C before being treated dropwise with a solution of MeONa (864 mg, 0.92 mL, 4.0 mmol, 2.0 equiv) in methanol at 0–5C. The resulting reaction mixture was stirred at 0–5° C. for 30 min before being gradually warmed up to room temperature for an additional 3 h. When HPLC and TLC showed the reaction was complete, the reaction mixture was slowly poured into water (20 mL). The resulting mixture was then stirred at room temperature for 1 h to precipitate the desired product. The solids were collected by filtration, washed with water (2×10 mL) and methyl tert-butyl ether (2×10 mL), dried in vacuo at 40–45° C. for 12 h to afford the crude desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (62, 653 mg, 919 mg theoretical, 71%) as off-whit crystals. This product was found to be identical with the material prepared from method A.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[N:24]([CH3:26])[CH3:25].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([N:24]([CH3:26])[CH3:25])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: CN(C)c1cccc(I)c1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2cccc(N(C)C)c2)c(=O)c1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Reaction time: 13 h
Yield: 35.6 %

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (25 mg, 0.097 mmol), 3-iodo-N,N-dimethylaniline (20 mg, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (5 mg, 0.020 mmol), and potassium phosphate (44 mg, 0.206 mmol) in 0.5 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (13 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and with NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using a 0-100% EtOAc gradient/100-0% Hexane gradient. The fractions containing the product were concentrated in vacuo and then further purified by recrystallization using an Et2O/Hexane solvent mixture to give the title compound (13 mg, 37%). 1H NMR (DMSO) δ: 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.46 (m, 1H), 7.28-7.35 (m, 2H), 6.28 (s, 2H), 6.17 (m, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 3.00 (s, 6H), 2.66 (t, j=5.3 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O: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].N1C=CN=C1.Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].Cl>C(Cl)Cl>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:1][CH2:2][CH2:3][O:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14])([CH3:25])[CH3:24]
Reactant: O=C1c2ccccc2C(=O)N1OCCO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](OCCON1C(=O)c2ccccc2C1=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-(2-hydroxyethoxyl)isoindoline-1,3-dione (622 mg, 3.00 mmol) in dehydrated methylene chloride (6 mL), imidazole (306 mg) and chlorotriisopropylsilane (TIPSCl, 963 μL) were added under an argon atmosphere at room temperature. After the reaction mixture was stirred at room temperature overnight, 2M hydrochloric acid was added to stop the reaction, followed by distilling off methylene chloride under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, followed by washing the organic layer with saturated brine and then drying over magnesium sulfate. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=9/1→2/1) to afford 1.04 g of the title compound (yield 95%).
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Cl)cc1/C=C/C(=O)O
Yield: 76.9 %

Procedure:
t-Butyl (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoate (2 g, 7.8 mmol), was stirred in 3 ml of trifluoroacetic acid at ambient temperature for 1 hour. The reaction mixture was diluted with toluene, evaporated to dryness, and the residue triturated with diethyl ether to yield the title compound as a pale yellow solid (1.89 g, 6.0 mmol).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[Li].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:22])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetic acid, lithium salt (for a preparation see Intermediate 9)(125 mg, 0.284 mmol) and N1,N1-dimethylethane-1,2-diamine (32.5 mg, 0.369 mmol) in DMF (3 mL) were added HATU (162 mg, 0.426 mmol) and DIPEA (0.149 mL, 0.851 mmol). The resulting mixture was stirred at room temperature for 2 h, the reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-(dimethylamino)ethyl)acetamide (59 mg, 41%) as a colourless oil. LCMS (Formate, 2 min), Rt=0.65 min, MH+=511.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].[CH3:13][CH:14]([SH:16])[CH3:15]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:16][CH:14]([CH3:15])[CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccnc(Cl)n1
Reactant: CC(C)S
Product: CCOC(=O)c1ccnc(SC(C)C)n1
Yield: 68 %

Procedure:
2-Chloropyrimidine-4-carboxylic acid ethyl ester (0.024 g, 0.13 mmol) obtained in Step A and 2-propanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.02 g, 68%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]1[CH2:18][C:12]2[C:13](=[N:14][C:9]([S:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:41])=[N:10][CH:11]=2)[N:15]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:16]1=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc2N1C1CCNCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc2N1C1CCNCC1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a solution of 7-benzylthio-3-(2-chlorophenyl)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (920 mg, 1.62 mmol) in dichloromethane (16 mL) cooled to 0° C. was added 3-chloroperbenzoic acid (403 mg, 1.64 mmol). After an hour at room temperature 5 mL of 10% sodium thiosulphate was added. After 10 minutes, the dichloromethane layer was separated and washed with 10% potassium carbonate and brine, dried over magnesium sulfate, concentrated in vacuo to give 650 mg of 3-(2-chlorophenyl)-7-benzylsulfinyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white foam.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[S].C>C1C2C(CCCC2)CCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1ccc(C2=CCCn3c2cnc3C)cc1
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Cc1ccc(-c2cccn3c(C)ncc23)cc1

Procedure:
Combine 20 g (89.2 mmol) of the product of Example VIII with 5 g (0.16 mol) of sulfur in 250 ml of decalin and heat to 180-190° C. under nitrogen for 7 hr. Extract the reaction with 2 liters of 2N sulfuric acid solution. Charcoal treat the extract and neutralize with potassium carbonate. Extract the aqueous portion with 800 ml of ethyl acetate, dry over magnesium sulfate, treat with charcoal, and remove the solvents under vacuum. Crystallize from ether to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[N:24][CH:25]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccc(Cl)cn2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
Under argon, 3,4,5-trimethoxyphenylboronic acid (5.05 g, 24.0 mmol), dichloro[1,2-bis(diphenylphosphino)ethane]palladium (574.0 mg, 1.00 mmol) and a 2.0 M aqueous sodium carbonate (20 mL, 40 mmol) were added to a solution of 2,5-dichioropyridine (2.95 g, 20.0 mmol) in ethanol-toluene (1:5, 54.0 mL). After stirring at 100° C. for 3 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless crystalline powder (melting point: 61.0-63.0° C.)(4.13 g, yield 73%)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH:9]=[C:8]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH:7]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][P:12]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])=[O:13])[C@@H:7]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(CP(=O)(OCC)OCC)=CCN1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@H](CP(=O)(OCC)OCC)CCN1C(=O)OCC

Procedure:
A solution of 2.75 g of ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl)-2,5-dihydropyrrole-2-carboxylate in 35 ml ethyl alcohol and 1.5 g 10% Pd/C is hydrogenated at 3 atmospheres pressure to yield cis and trans ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl)-pyrrolidine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (99%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([SH:16])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:16][C:12]2[N:11]=[C:10]([NH2:9])[CH:15]=[CH:14][N:13]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)s1
Reactant: Nc1ccnc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccnc(Sc2cnc(N)s2)n1
Temperature: 90 °C
Yield: 54.3 %

Procedure:
A mixture of 2-amino-5-bromothiazole hydrochloride (2.2 g), 4-amino-2-mercaptopyrimidine (2.2 g) and potassium carbonate (6.5 g) in N,N-dimethylformamide (100 ml) was heated at 90° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The solution was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give solid. The solid was triturated with ethanol to give 2-amino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.25 g, yield: 55.6%). mp: 185°-187° C. (dec.)
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23]>>[OH:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[NH:16][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15]
Reactant: NC1CCCCC1O
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Product: O=C(NC1CCCCC1O)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and 2-aminocyclohexanol (CAN 6850-38-0) as starting materials, MS (EI): m/e=303.2 [M+H]+.
Reaction SMILES: COC1C=C2C(=CC=1)NC=C2C=O.[CH2:14]([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([NH2:29])=[O:28])[CH:22]=[C:21]2[N:30]=[C:31]=[O:32])C=C>>[N:30]([C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH3:14])[CH:19]=2)[N:23]([C:27]([NH2:29])=[O:28])[CH:22]=1)=[C:31]=[O:32]
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Agent: COc1ccc2[nH]cc(C=O)c2c1
Product: COc1ccc2c(c1)c(N=C=O)cn2C(N)=O

Procedure:
was prepared from 5-methoxy-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([C:8]([N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].CN(C=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:25][CH2:26]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[O:9])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc(N)cc3)CC2)cc1OC
Yield: 31.7 %

Procedure:
To a mixture of 1-(4-nitrobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (1.5 g) and ethanol (30 ml) were added DMF (5 ml) and 10% palladium on carbon (300 mg). The mixture was hydrogenated at 50° to 60° C. After competion of reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol= 100:2) and recrystallized from ethanol to give 1-(4-aminobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (0.45 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[NH2:13][C:14]([NH2:16])=[NH:15].Cl>O1CCOCC1>[NH:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:14]([NH2:16])=[NH:13]
Reactant: O=C(O)CCCCCCCCBr
Reactant: N=C(N)N
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)NCCCCCCCCC(=O)O

Procedure:
9-Bromo-nonanoic acid (5 gm; 21.1 mmoles) was dissolved in dioxane (50 ml) and the free guanidine solution from A was added. The mixture was refluxed overnight, and the white precipitate was filtered and washed three times with cold water and then lyophilized from one equivalent of 0.5M HCl. The yield was 2.77 g (85%) and the structure of the title compound was verified by FAB-MS, NMR, and elemental analysis.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:42]=3)=[N:15][C:16]([C:28]3[CH:33]=[CH:32][C:31]([C:34]5[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=5)=[CH:30][CH:29]=3)=[C:17]([Cl:27])[C:18]=4COCC[Si](C)(C)C)[CH2:8][O:9][C@H:3]12.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+]>C1COCC1>[OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:42]=3)=[N:15][C:16]([C:28]3[CH:29]=[CH:30][C:31]([C:34]5[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=5)=[CH:32][CH:33]=3)=[C:17]([Cl:27])[CH:18]=4)[CH2:8][O:9][C@H:3]12
Reactant: C[Si](C)(C)CCOCc1c(Cl)c(-c2ccc(-c3ccc(C#N)cc3)cc2)nc2nc(O[C@@H]3CO[C@H]4[C@@H]3OC[C@H]4O)[nH]c12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: N#Cc1ccc(-c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 6.5 h

Procedure:
A mixture of 4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-5-yl]phenyl]benzonitrile (49.4 mg, 0.082 mmol), formic acid (1.0 mL, 26.1 mmol), and saturated aqueous KHSO4 (0.06 mL) was heated to 40° C. with stirring. After 6.5 hours, the reaction mixture was cooled to room temperature and placed in the refrigerator overnight, and then cooled to 0° C. in an ice bath. The pH was adjusted to pH 14 through the addition of 5 N NaOH (5.2 mL, 26 mmol). THF (2 mL) was added to the reaction mixture, which was removed from the ice bath and allowed to warm to room temperature. After stirring for 45 minutes at room temperature, the pH was adjusted to 7 through the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1×20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a pale yellow solid. Purification by HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush afforded the title compound as a white solid following lyophilization from ethanol and benzene. LC-MS: calculated for: C25H19ClN4O4 474.11 observed m/e: 475.12 (M+H)+ (Rt 1.15/2 min).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C[O-].[Na+].C(N(CCCCCCCC)C(=O)C1C=CC(C(O)=O)=CC=1)CCCCCCC>CO>[CH2:15]([NH:23][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:13][CH3:14])=[O:12])=[CH:11][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCCCCN
Agent: CCCCCCCCN(CCCCCCCC)C(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCNC(=O)c1ccc(C(=O)OC)cc1
Yield: 90.9 %

Procedure:
19.4 g (0.1 mole) of dimethyl terephthalate and 12.9 g (0.1 mole) of octylamine are refluxed for 8 hours in 100 ml of methanol together with 9 g (0.05 mole) of sodium methylate (30% strength). Working up as in Example 1 produces 26.5 g (91%) of 4-carbomethoxybenzoic acid octylamide having a 30% terephthalic acid bisoctylamide content.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][N:5]([NH:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[C@@H:21]2[C@@H:16]([NH:17][C:18]([NH:20]2)=[O:19])[CH2:15][S:14]1)[CH3:6].[OH-].[Na+]>CO>[C:8]([NH:7][N:5]([CH3:6])[CH2:4][C:3]([OH:23])=[O:2])(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[C@@H:21]2[C@@H:16]([NH:17][C:18]([NH:20]2)=[O:19])[CH2:15][S:14]1
Reactant: COC(=O)CN(C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 30 °C
Reaction time: 14 h

Procedure:
To a solution of biotinamido-N-methyl-glycine methyl ester in methanol is added 1.5-2.0 equivalents of 1 N aqueous sodium hydroxide. The mixture is stirred at 15-45° C. for 4-24 h and then concentrated via reduced pressure rotary evaporation. The residue is diluted with deionized water and the pH of the solution is adjusted to 1-2 by addition of 6 N aqueous hydrochloric acid. The mixture is again concentrated via reduced pressure rotary evaporation. The residue is chromatographed on reverse phase C-18 silica gel, and eluted with methanol/water. The fractions containing the product are combined and concentrated to afford the final product (5).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH3:3].[C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])#[N:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:12][CH:11]=1)=[O:19])#[N:14]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN(C)Cc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1ccc(CNC(=O)c2cccc(C#N)c2)cc1

Procedure:
Prepared analogously to Example 9d from 4-dimethylaminomethyl-benzylamine, 3-cyanobenzoylchloride and triethylamine in methylene chloride.